Microbial cell factories producing prostaglandins

Abstract

The present disclosure relates to genetically modified host cells producing prostaglandins, to genetic constructs for expression of such mutants; to cultures of the genetically modified host cells and its use to produce the said products; to fermentation liquids comprising the said products resulting from such production; to compositions comprising the fermentation liquid; to pharmaceutical preparations made from such compositions and to the uses of such compositions and preparations.

Description

Microbial cell factories producing prostaglandins.Technical Field

[0001] The present disclosure relates to genetically modified host cells producing prostaglandins, to genetic constructs for expression of such mutants; to cultures of the genetically modified host cells and its use to produce the said products; to fermentation liquids comprising the said products resulting from such production; to compositions comprising the fermentation liquid; to pharmaceutical preparations made from such compositions and to the uses of such compositions and preparations.Background

[0002] In nature, prostaglandins are produced by most animals. The biosynthetic pathway for prostaglandins in natural organisms is generally well described in the art and the pathway is shown in figure 1.

[0003] The use of microorganism-based cell factories is a potential route for the biosynthetic production of prostaglandins. The advantages of recombinant microorganisms such as E. coli as a microbial cell factory for the production of bio-products are widely recognized due to the fact that: (i) E. coli has unparalleled fast growth kinetics; with a doubling time of about 20 minutes when cultivated in glucose-salts media and under optimal environmental conditions, (ii) it easily achieves a high cell density; where the theoretical density limit of an E. coli liquid culture is estimated to be about 200 g dry cell weight / L or roughly 1X1013viable bacteria / mL. Additionally, there are many molecular tools and protocols at hand for genetic optimization of E. coli; as well as it being an organism that is amenable to the expression of heterologous proteins; both of which may be essential for obtaining high-level production of desired bio-products.

[0004] Previous work in the field of recombinant production of prostaglandins have produced PGF2a in vitro from arachidonic acid (ARA) in cell extracts using Yarrowia as well as via Agrobacterium transfection into complex systems such as Marchantia polymorpha (CN116144620 and JP2013183639A). In US2010272780A1 mammalian cells were upregulated to produce more PGF2a. ME Mohamed and CM Lazarus (FEMS Yeast Research, Volume 9, Issue 3, May 2009, Pages 420-427) produced prostanoid in S. cerevisiae that were fed ARA as an in vitro assay system for antiinflammatory drugs.

[0005] Other work has been done in prokaryotic hosts, e.g. CN111294289B, WO2021132536A1 and CN110951814B, to produce other prostaglandins such as PGE2, typically from ARA. Howevereukaryotic hosts are typically advantageous when expressing complex mammalian proteins. W02007104000A8 used COX-2:synthase fusion proteins to convert ARA to multiple prostaglandins in complex mammalian cells. Wada et al expressed a human prostaglandin synthase in Spodoptera frugiperda via baculovirus cloning (Masayuki Wada, Chieko Yokoyama, Toshihisa Hatae, Manabu Shimonishi, Masahiko Nakamura, Yoshio Imai, Volker Ullrich, Tadashi Tanabe, Purification and Characterization of Recombinant Human Prostacyclin Synthase, The Journal of Biochemistry, Volume 135, Issue 4, April 2004, Pages 455-463). However, these hosts are typically utilized for therapeutic protein production which is not a low-cost production system.

[0006] There remains a need for production of PGF2a in robust industrial yeasts such as S. cerevisiae, from glucose or other low cost feedstocks, in a scalable system. This would lead to an improvement in manufacturing costs that could lead to lower-cost pharmaceuticals from renewable resources.Summary

[0007] Against this background art, prostaglandin enzymes may be expressed in robust host cells such as S. cerevisiae or Yarrowia lipolytica at high level.

[0008] Microbial production of prostaglandins offers several advantages over traditional chemical synthesis, including higher yields, greater selectivity, and environmentally friendly processes. Additionally, genetic engineering enables the generation of designer microorganisms tailored for specific prostaglandin derivatives, paving the way for the production of novel therapeutics and research tools.

[0009] Further, the present inventors have now surprisingly found that native host cell enzymes catalyze undesirable side-reactions, converting key prostaglandin intermediates into unwanted byproducts or other prostaglandins, thereby reducing both the yield and the purity of the desired target prostaglandin. Accordingly, the present disclosure provides for a solution to this previously unrecognized problem by identifying and genetically modifying these competing endogenous enzyme reactions, for example by attenuating or deleting endogenous genes encoding enzymes, such as glutathione S-transferases, or esterases, which significantly improves the specificity and purity of the target prostaglandin production.

[0010] Furthermore, the inventors have discovered several non-obvious strategies to significantly increase the overall yield of prostaglandins produced de novo from a simple carbon source, such as glucose. In one particularly surprising finding, contrary to what a person skilled in the art might expect, it was demonstrated that the attenuation or deletion of an endogenous gene encoding an antioxidant enzyme, such as a thioredoxin peroxidase (e.g., TSA1), unexpectedly leads to a significant increase in PGF2a production. In other aspects, overall yield is substantially increased by genetically modifyingthe host cell to increase the metabolic flux towards arachidonic acid or DGLA precursors, for example by expressing a mutated acetyl-CoA carboxylase (ACC1) or by overexpressing the endogenous delta-9 desaturase gene (ScOLE1).

[0011] A further surprising finding of the present disclosure is that prostaglandin production is significantly enhanced by the expression or overexpression of certain auxiliary polypeptides that are not part of the direct biosynthetic prostaglandin pathway. It has been found that the expression of specific cellular support proteins substantially improves the overall performance of the prostaglandin pathway. These auxiliary polypeptides include, for example, those involved in protein folding and trafficking within the endoplasmic reticulum (e.g., ER chaperones and protein disulfide isomerases) and those involved in cofactor supply and electron transport (e.g., cytochrome bS-like polypeptides). The strategic use of these auxiliary genes represents a powerful tool to optimizing complex metabolic pathways in a recombinant host.

[0012] In one aspect, a genetically modified host cell is provided comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor.

[0013] In one aspect, a genetically modified host cell is provided comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, and wherein the host cell is further genetically modified by at least one modification enhancing the yield of one or more prostaglandins or prostaglandin precursors relative to the corresponding host cell without the modification; and wherein the host cell is of a genus selected from the group consisting of: Saccharomyces, Aspergillus, Kluyveromyces, Candida, Komagataella (formerly Pichia), Debaromyces, Hansenula, Zygosaccharomyces, and Schizosaccharomyces.

[0014] In one aspect, a genetically modified host cell is provided comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, wherein the host cell is further genetically modified by at least one modification enhancing the yield and / or purity, for example enhancing the yield, of one or more prostaglandins or prostaglandin precursors.

[0015] In one aspect, a genetically modified host cell is provided comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, wherein the host cell is further genetically modified by at least one modification selected from the group consisting of: i) the attenuation, disruption or deletion of one or more endogenous genes encoding a polypeptide that catalyzes an unwanted side-reaction on one or more prostaglandin precursors and / or retards the catalytic activity of one or more of the polypeptides of the metabolic pathways capable of producing one or more prostaglandins, optionally wherein the one or more endogenous genes are selected from the group consisting of a glutathione S-transferase, an esterase, a thioredoxin peroxidase, and an oxidoreductase;ii) the overexpression of a gene that increases the supply of one or more prostaglandin precursors, optionally wherein said gene is selected from the group consisting of: a gene encoding a mutant acetyl-CoA carboxylase (ACC1) and an endogenous delta-9 desaturase gene; andiii) the expression or overexpression of an auxiliary gene encoding a polypeptide that enhances folding or function of one or more of the polypeptides of the metabolic pathways capable of producing one or more prostaglandins, optionally wherein said polypeptide is selected from the group consisting of an endoplasmic reticulum (ER) chaperone, a protein disulfide isomerase, and a cytochrome bS-like polypeptide.

[0016] In one aspect, a method is provided for enhancing the production of one or more prostaglandins in a host cell, the method comprising genetically modifying the host cell by performing at least one modification selected from the group consisting of:a) attenuating, disrupting, or deleting one or more endogenous genes encoding a polypeptide that catalyzes an unwanted side-reaction on a prostaglandin or a prostaglandin precursor; b) expressing or overexpressing one or more genes that increase the supply of one or more prostaglandin precursors; andc) expressing or overexpressing one or more auxiliary genes encoding a polypeptide that enhances the folding or function of a polypeptide in a prostaglandin biosynthesis pathway.

[0017] In one aspect, a polynucleotide construct is provided comprising a polynucleotide sequence encoding a heterologous polypeptide as defined herein operably linked to one or more control sequences.

[0018] In one aspect, cell culture is provided, comprising the host cell as defined herein and a growth medium.

[0019] In one aspect, provided for herein is a genetically modified host cell having improved production of prostaglandins, wherein the host cell expresses one or more heterologous PGX enzymes converting arachidonic acid into PGH2 in the host cell, whereby the production of the prostaglandin in the genetically modified host cell is altered compared to an unmodified parent host cell.

[0020] In one aspect, provided for herein is a genetically modified host cell having production of prostaglandins, wherein the host cell expresses one or more heterologous PGX enzymes catalysing the transformation of PGH2 into PGD2, PGI2, PGE2 or PGF2-alpha in the host cell, whereby the production of the prostaglandins in the genetically modified host cell is improved compared to an unmodified parent host cell.

[0021] In one aspect, provided for herein is a method for producing prostaglandins comprising a) culturing the cell culture at conditions allowing the host cells to produce the prostaglandins andb) optionally recovering and / or isolating the prostaglandins.

[0022] In one aspect, provided for herein is a fermentation composition comprising the cell culture and the prostaglandins.

[0023] In one aspect, provided for herein is a composition comprising the fermentation composition and one or more carriers, agents, adjuvants, additives and / or excipients.

[0024] In one aspect, provided for herein is a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of the composition to the mammal.Description of drawings and figures

[0025] The figures included herein are illustrative and simplified for clarity, and they merely show details which are essential to the understanding of the invention, while other details may have been left out.Figure 1: Biosynthetic pathway of PGG2and PGH2in yeastProstaglandins are produced from natural yeast precursors stearic acid or oleic acid CoA compounds via desaturase and elongase enzymes followed by sequential oxygenation of arachidonic acid by cyclooxgenases to form the key intermediate PGH2. Alternatively, Arachidonic acid can be fed to yeast.Figure 2: Additional Prostaglandins produced from Arachidonic acid.Figure 3A: Production of PGI2 from glucose in Saccharomyces cerevisiae expressing COX-2 was determined by detection of the hydrolysis product 6-keto-PGFla. In this method 6-keto-PGFla has an elution time of 1.46 minutes.Figure 3B: Biosynthesis of PGI2 from ARA feeding in S. cerevisiae using COX-2 from Rattus norvegicus, as measured by 6-keto-PFGla.Figure 4A: Detection of PGE2 production from glucose in Saccharomyces cerevisiae using PGEeS from Homo sapiens and COX-2. In this method PGE2has an elution time of 2.22 minutes.Figure 4B: Prostaglandin E2 production from ARA feeding in Saccharomyces cerevisiae using mammalian COX-2 enzymes. From left to right on the x-axis the bars represent strains containing (1) pOC33(HsCOX2)pOC35(HsPGES-l)pRIV39, (2) pOC45(RnCOX2)pOC35(HsPGES-l)pRIV39, and (3) pOD524pRIV23pRIV39.Figure 5: Exemplary fermentation of PGF2alpha producing strain sPRO96 from Example 9.Figure 6: Averaged values of two experiments using strain sPRO96 from Example 9.Figure 7: Exemplary downstream purification routes for prostaglandins in relation to Example 10. Shown in figure 7 is a crystallization step as the last polishing step, which may be preferable at larger scales due to the cost of chromatography. Exemplary forms of prostaglandin salts that are stable in crystalline form are dinoprost tromethamine (a salt of PGF2a) and carboprost tromethamine (asynthetic analogue of PGF2a). Some prostaglandin APIs produced at commercial-scale utilize a chromatographic polishing step, in particular when isomers that are difficult to separate are produced. An exemplary chromatography step would be a reversed phase column such as a C18 preparative scale column, although SMB (simulated moving bed chromatography) may be desirable at large scales. SFC (supercritical fluid chromatography) has also been reported eg in US935O55B2.Figure 8: Overview of exemplary prostaglandin pathways through either ARA or DGLA. Dashed arrows indicate multiple steps may occur to remove the Co-A activated compounds required for the elongase / desaturase steps to produce the free fatty acid for the COX1 / COX2 enzymatic steps as shown in Figure 9.Figure 9: Simplified overview of prostaglandin pathway. One arrow can indicate more than one reaction. Arachidonic acid (ARA) and other fatty acids can be bound in and released from various lipid compounds including but not necessarily limited to various phospholipids, glycorolipids and sterol esters. Arachidonic acid can also be supplied exogenously or produced in other ways. The free and activated form of fatty acids (such as free arachidonic acid and arachidonoyl-CoA) are used interchangeably unless otherwise stated. The activated form of a fatty acid refers to when a fatty acid is in its coenzyme A thioester form (acyl-CoA). CoA; Coenzyme A. PA-CoA; Palmitoyl-CoA. SA-CoA; Stearoyl-Coa. OA-CoA; Oleoyl-CoA. LA-CoA; Linoleoyl-CoA. GLA-CoA; Gamma-linolenoyl-CoA. DGLA-CoA; Dihomo-gamma-linolenoyl-CoA. TAG; Triacylglycerol.Incorporation by reference

[0026] All publications, patents, and patent applications referred to herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict between a term herein and a term in an incorporated reference, the term herein prevails and controls.Detailed Description

[0027] Provided for herein are genetically modified host cells producing prostaglandins, to genetic constructs for expression of such mutants; to cultures of the genetically modified host cells and its use to produce the said products; to fermentation liquids comprising the said products resulting from such production; to compositions comprising the fermentation liquid; to pharmaceutical preparations made from such compositions and to the uses of such compositions and preparations.Definitions

[0028] Any EC numbers used herein refer to Enzyme Nomenclature 1992 from NC-IUBMB, AcademicPress, San Diego, California, including 30 supplements 1-5 published in Eur. J. Bio-chem. 1994, 223, 1-5; Eur. J. Biochem. 1995, 232, 1-6; Eur. J. Biochem. 1996, 237, 1-5; Eur. J. Biochem. 1997, 250, 1-6; and Eur. J. Biochem. 1999, 264, 610-650; respectively. The nomenclature is regularly supplemented and updated; see e.g., http: / / enzyme.expasy.org / .

[0029] The term "prostaglandins" or "PG" as used herein may be used interchangeably about the compound prostaglandins (PG), a group of physiologically active lipid compounds called eicosanoids that have diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid. Chemically prostaglandins contain 20 carbon atoms, including a 5-carbon ring.

[0030] The term "carbon feedstocks" as used herein covers glucose, sucrose, glycerol, methanol, fructose, xylose, lactose, cellobiose and complex carbohydrates. Preferred carbon feedstock is glucose.

[0031] The term "Delta 9-desaturase", also known as stearoyl-CoA desaturase-1 (SCD-1), plays a crucial role in fatty acid metabolism that catalyzes the rate-limiting step in the formation of monounsaturated fatty acids (MUFAs), specifically oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA. Oleate and palmitoleate are major components of membrane phospholipids, cholesterol esters and al kyl-diacylglycerol. In humans, the enzyme is present in two isoforms, encoded respectively by the SCD1 and SCD5 genes.

[0032] The term PGX covers the main enzymes involved in catalysis of prostaglandins including without being limited prostaglandin D synthase (PGDS), prostaglandin I synthase (PGIS), prostaglandin E2 synthase, 9-keto-prostaglandin E synthase, prostaglandin F synthase, and / or prostaglandin El synthase.

[0033] The term "delta 12-desaturase" also known as, Deltal2(omega6)-desaturase, oleoyl-CoA Deltal2 desaturase, Deltal2 desaturase, Deltal2-desaturase is an enzyme with systematic name acyl-CoA, hydrogen donor:oxygen Deltal2-oxidoreductase. This enzyme catalyses conversion of oleic acid 18:ln-9 into linolenic acid 18:2n-6;

[0034] The term "eicosanoids" includes but are not limited to the Prostaglandins PGF2-alpha, PGE2, PGEl and PGI2.

[0035] The term "delta 6-desaturase2 (D6D)"converting linolenic acid 18:2n-6 into Y-linolenic acid 18:3n-6;

[0036] The term "elongase" converting Y-linolenic acid 18:3n-6 into dihomo-Y-linolenic acid 20:3n-6;

[0037] The term "delta5-desaturase (D5D)" converting dihomo-Y-linolenic acid 20:4n-6 into Arachidonic acid 20:4n-6;

[0038] The term "cyclooxygenases (COX)" converting arachidonic acid and / or dihomo-gamma-linolenic acid (DGLA) into prostaglandin Hl or prostaglandin H2;

[0039] The term "prostaglandin D synthase (PGDS)" converting prostaglandin H2 (PGH2) into a prostaglandin D2;

[0040] The term "prostaglandin I synthase (PGIS)" converting prostaglandin H2 into a prostaglandin 12 and / or prostaglandin I into a prostaglandin 13;

[0041] The term "prostaglandin E2 synthase (PGES)" converting prostaglandin H2 into a prostaglandin E2;

[0042] The term "9-keto-prostaglandin E synthase" converting prostaglandin E2 into prostaglandin-F2-a;

[0043] The term "prostaglandin F synthase (PGFS)" converting prostaglandin H2 into prostaglandin-F2-a;

[0044] The term "prostaglandin El synthase" converting a prostaglandin Hl substrate into a prostaglandin El;

[0045] The term "host cell" refers to any cell type that is susceptible to transformation, transfection, transduction, or the like with a nucleic acid construct or expression vector comprising a polynucleotide of the present invention. The host cell encompasses any progeny of a parent cell that is not identical to the parent cell due to mutations that occur during replication.

[0046] The term "polynucleotide construct" refers to a polynucleotide, either single- or doublestranded, which is isolated from a naturally occurring gene or is modified to contain segments of nucleic acids in a manner that would not otherwise exist in nature, or which is synthetic, and which comprises a polynucleotide encoding a polypeptide and one or more control sequences.

[0047] The terms "nucleotide sequence" and "polynucleotide" are used herein interchangeably.

[0048] The term "coding sequence" refers to a nucleotide sequence, which directly specifies the amino acid sequence of a polypeptide. The boundaries of the coding sequence are generally determined by an open reading frame, which begins with a start codon such as ATG, GTG, or TTG and ends with a stop codon such as TAA, TAG, or TGA. The coding sequence may be a genomic DNA, cDNA, synthetic DNA, or a combination thereof.

[0049] The term "control sequence" as used herein refers to a nucleotide sequence necessary for expression of a polynucleotide encoding a polypeptide. A control sequence may be native (i.e., from the same gene or organism) or heterologous or foreign (i.e., from a different or organism) to the polynucleotide encoding the polypeptide. Control sequences include, but are not limited to leader sequences, polyadenylation sequences, pro-peptide coding sequences, promoter sequences, signal peptide coding sequences, translation terminator (stop) sequences and transcription terminator (stop) sequences. To be operational control sequences usually must include promoter sequences andtranscriptional and translational stop signals. Control sequences may be provided with linkers for the purpose of introducing specific restriction sites facilitating ligation of the control sequences with a coding region of a polynucleotide encoding a polypeptide.

[0050] The term "expression vector" refers to a DNA molecule, either single- or double-stranded, either linear or circular, which comprises a polynucleotide encoding a polypeptide and is operably linked to control sequences that provide for its expression. Expression vectors include expression cassettes for the integration of genes into a host cell as well as plasmids and / or chromosomes comprising such genes.

[0051] The term "expression" includes any step involved in the production of a polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion.

[0052] The term "over-expression" includes a situation when one or more components of the cell may be present at a higher-than-normal cellular level (i.e., higher than the concentration known to usually be present in the cell type exhibiting the gene and / or protein complex of interest). For example, the gene encoding a protein may begin to be overexpressed, or may be amplified (i. e., its gene copy number may be increased) in certain cells, leading to an increased number of component molecules within these cells.

[0053] The terms "heterologous" or "recombinant" or "genetically modified" and their grammatical equivalents as used herein interchangeably refer to entities "derived from a different species or cell". For example, a heterologous or recombinant polynucleotide gene is a gene in a host cell not naturally containing that gene, i.e., the gene is from a different species or cell type than the host cell. The terms as used herein about microbial host cells refer to microbial host cells comprising and expressing heterologous or recombinant polynucleotide genes.

[0054] The term "metabolic pathway" as used herein is intended to mean two or more enzymes acting sequentially in a live cell to convert chemical substrate(s) into chemical product(s). Enzymes are characterized by having catalytic activity, which can change the chemical structure of the substrate(s). An enzyme may have more than one substrate and produce more than one product. The enzyme may also depend on cofactors, which can be inorganic chemical compounds or organic compounds such as proteins for example enzymes (co-enzymes). A CPR that reduces certain cytochrome P450 enzymes is an example of an enzymatic co-factor. The term "operative biosynthetic metabolic pathway" refers to a metabolic pathway that occurs in a live recombinant host, as described herein. More specifically, the term "metabolic pathways capable of producing one or more prostaglandins" as used herein refers to a set of two or more enzymes that, when functionally expressed in a host cell, act sequentially to convert a precursor into a prostaglandin product. Such pathways may be comprised of nativepolypeptides, heterologous polypeptides, or a combination thereof, and typically include enzymes selected from the group consisting of fatty acid desaturases, fatty acid elongases, cyclooxygenases, and prostaglandin synthases. The precursor may be a simple carbon source, such as glucose, for de novo synthesis of prostaglandins, or a polyunsaturated fatty acid, such as arachidonic acid or dihomo-gamma-linolenic acid.

[0055] The term "in vivo", as used herein refers to within a living cell or organism, including, for example, animal, a plant or a microorganism.

[0056] The term "in vitro", as used herein refers to outside a living cell or organism, including, without limitation, for example, in a microwell plate, a tube, a flask, a beaker, a tank, a reactor and the like.

[0057] The term "substrate" or "precursor", as used herein refers to any compound that can be converted into a different compound. For example, Air can be a substrate for Phosphomethylpyrimidine synthase and can be converted into prostaglandin into hydroxymethylpyrimidine phosphate (HMP-P), a precursor of prostaglandin. For clarity, substrates and / or precursors include both compounds generated in situ by an enzymatic reaction in a cell or exogenously provided compounds, such as exogenously provided organic molecules which the host cell can metabolize into a desired compound.

[0058] The term "endogenous" or "native" as used herein refers to a gene or a polypeptide in a host cell which originates from the same host cell.

[0059] The term "deletion" as used herein refers to the manipulation of a gene so that it is no longer expressed in a host cell.

[0060] The term "attenuation" as used herein refers to the manipulation of a gene or any of the machinery participating in the expression of the gene so that the expression of the gene is reduced as compared to expression without the manipulation.

[0061] The terms "substantially" or "approximately" or "about", as used herein refer to a reasonable deviation around a value or parameter such that the value or parameter is not significantly changed. These terms of deviation from a value should be construed as including a deviation of the value where the deviation would not negate the meaning of the value deviated from. For example, in relation to a reference numerical value, the terms of degree can include a range of values plus or minus 10% from that value. For example, deviation from a value can include a specified value plus or minus a certain percentage from that value, such as plus or minus 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from the specified value.

[0062] The term "and / or" as used herein is intended to represent an inclusive "or". The wording X and / or Y is meant to mean both X or Y and X and Y. Further, the wording X, Y and / or Z is intended to mean X, Y and Z alone or any combination of X, Y, and Z.

[0063] The term "isolated" as used herein about a compound, refers to any compound, by means of human intervention, has been put in a form or environment that differs from the form or environment in which it is found in nature. Isolated compounds include but is no limited to compounds disclosed herein for which the ratio of the compounds relative to other constituents with which they are associated in nature is increased or decreased. In an important embodiment, the amount of compound is increased relative to other constituents with which the compound is associated in nature. In an embodiment, the compound disclosed herein may be isolated into a pure or substantially pure form. In this context, a substantially pure compound means that the compound is separated from other extraneous or unwanted material present from the onset of producing the compound or generated in the manufacturing process. Such a substantially pure compound preparation contains less than 10%, such as less than 8%, such as less than 6%, such as less than 5%, such as less than 4%, such as less than 3%, such as less than 2%, such as less than 1 %, such as less than 0.5% by weight of other extraneous or unwanted material usually associated with the compound when expressed natively or recombinantly. In an embodiment, the isolated compound is at least 90% pure, such as at least 91% pure, such as at least 92% pure, such as at least 93% pure, such as at least 94% pure, such as at least 95% pure, such as at least 96% pure, such as at least 97% pure, such as at least 98% pure, such as at least 99% pure, such as at least 99.5% pure, such as 100 % pure by weight.

[0064] The term "% identity" is used herein about the relatedness between two amino acid sequences or between two nucleotide sequences. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. "% identity" as used herein about amino acid sequences refers to the degree of identity in percent between two amino acid sequences obtained when using the Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, J. Mol. Biol. 48: 443-453) as implemented in the Needle program of the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice et al., 2000, Trends Genet. 16: 276-277), preferably version 5.0.0 or later. The parameters used are gap open penalty of 10, gap extension penalty of 0.5, and the EBLOSUM62 (EMBOSS version of BLOSUM62) substitution matrix. The output of Needle labeled "longest identity" (obtained using the -nobrief option) is used as the percent identity and is calculated as follows:identical amino acid residues- x 100 Length of alignment — total number of gaps in alignment

[0065] The term "% identity" as used herein about nucleotide sequences refers to the degree ofidentity in percent between two deoxyribonucleotide sequences obtained when using the Needleman-Wunsch algorithm (Needleman and Wunsch, 1970, supra) as implemented in the Needle program of the EMBOSS package (EMBOSS: The European Molecular Biology Open Software Suite, Rice et al., 2000, supra), preferably version 5.0.0 or later. The parameters used are gap open penalty of 10, gap extension penalty of 0.5, and the EDNAFULL (EMBOSS version of NCBI NUC4.4) substitution matrix. The output of Needle labeled "longest identity" (obtained using the -nobrief option) is used as the percent identity and is calculated as follows:identical amino acid residues- x 100 Length of alignment — total number of gaps in alignment

[0066] Other examples of algorithms that are suitable for determining percent sequence identity and sequence similarity include the BLAST and BLAST 2.0 algorithms, which are described in Altschul, et al. (1977) Nuc. Acids Res. 25: 3389-3402 and Altschul, et al. (1990) J.Mol. Biol. 215: 403-410, or the WU-BLAST-2 program (Altschul et al., Meth. Enzymol., 266: 460-480 (1996).

[0067] The protein sequences of the present invention can further be used as a "query sequence" to perform a search against sequence databases, for example, to identify other family members or related sequences. Such searches can be performed using the BLAST programs. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov). BLASTP is used for amino acid sequences and BLASTN for nucleotide sequences. The BLAST program uses as defaults:Cost to open gap: default= 5 for nucleotides / 11 for proteinsCost to extend gap: default = 2 for nucleotides / 1 for proteinsPenalty for nucleotide mismatch: default = -3Reward for nucleotide match: default= 1Expect value: default = 10Wordsize: default = 11 for nucleotides / 28 for megablast / 3 for proteins.

[0068] Furthermore, the degree of local identity between the amino acid sequence query or nucleic acid sequence query and the retrieved homologous sequences is determined by the BLAST program. However only those sequence segments are compared that give a match above a certain threshold. Accordingly, the program calculates the identity only for these matching segments. Therefore, the identity calculated in this way is referred to as local identity.

[0069] The term "mature polypeptide" or "mature enzyme" as used herein refers to a polypeptide in its final active form following translation and any post-translational modifications, such as N-terminal processing, C-terminal truncation, glycosylation, phosphorylation, etc. It is known in the art that a host cell may produce a mixture of two or more different mature polypeptides (i.e., with a different C-terminal and / or N-terminal amino acid) expressed by the same polynucleotide.

[0070] The term "cDNA" refers to a DNA molecule that can be prepared by reverse transcription from a mature, spliced, mRNA molecule obtained from a eukaryotic or prokaryotic cell. cDNA lacks intron sequences that may be present in the corresponding genomic DNA. The initial, primary RNA transcript is a precursor to mRNA that is processed through a series of steps, including splicing, before appearing as mature spliced mRNA.

[0071] The terms "comprise" and "include" as used throughout the specification and the accompanying items as well as variations such as "comprises", "comprising", "includes" and "including" are to be interpreted inclusively. These words are intended to convey the possible inclusion of other elements or integers not specifically recited, where the context allows.

[0072] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to one or at least one) of the grammatical object of the article. By way of example, "an element" may mean one element or more than one element.

[0073] Terms like "preferably", "commonly", "particularly", and "typically" are not utilized herein to limit the scope of the item's invention or to imply that certain features are critical, essential, or even important to the structure or function of the item invention. Rather, these terms are merely intended to highlight alternative or additional features that can or cannot be utilized in a particular embodiment of the present invention.

[0074] The term "cell culture" as used herein refers to a culture medium comprising a plurality of host cells disclosed herein. A cell culture may comprise a single strain of host cells or may comprise two or more distinct host cell strains. The culture medium may be any medium that may comprise a recombinant host, e.g., a liquid medium (i.e., a culture broth) or a semi-solid medium, and may comprise additional components, e.g., one or more of (i) trace metals; (ii) vitamins; (iii) salts (such as salts of phosphate, magnesium, potassium, zinc, iron); (iv) nitrogen sources (such as YNB, ammonium sulfate, urea, yeast extracts, ammonium nitrate, ammonium chloride, malt extract, peptone and / or amino acids); (v) carbon source (such as dextrose, sucrose, glycerol, glucose, maltose, molasses, starch, cellulose, xylan, pectin, lignocellolytic biomass hydrolysate, and / or acetate); (vi) nucleobases; (vii) aminoglycosides; and / or (viii) antibiotics (such as G418 and hygromycin B).

[0075] The terms "enhancing the yield" or "increased production" as used herein refer to a quantifiable increase in the final titer or concentration of a target prostaglandin, produced by agenetically modified host cell as defined herein compared to an unmodified parent host cell when both are cultured under substantially identical conditions. In certain embodiments, said increase is at least 5%, such as at least 10%, such as at least 25%, at least 50%, at least 100%, or at least 200%.

[0076] The term "reduced formation of byproducts" as used herein refers to a measurable decrease in the ratio of one or more undesired compounds to the desired target prostaglandin or prostaglandin precursor produced by a genetically modified host cell, as compared to the ratio produced by an unmodified parent host cell cultured under substantially identical conditions. In some embodiments, the ratio of byproduct to target product is decreased by at least 10%, such as at least 30%, at least 50%, or at least 75%.

[0077] The term "unwanted side-reaction" as used herein refers to any enzymatic or non-enzymatic conversion of a prostaglandin or a prostaglandin precursor that leads to the formation of a compound other than the intended target prostaglandin or an intermediate en route to the target prostaglandin.

[0078] The term "retards the catalytic activity" as used herein refers to a quantifiable reduction in the rate of an enzymatic reaction catalyzed by a polypeptide. This reduction is measured relative to the activity of the same polypeptide in an unmodified host cell under identical assay conditions.

[0079] The term "enhances folding or function" as used herein refers to the action of a polypeptide, such as an auxiliary polypeptide, that facilitates the correct three-dimensional conformation, stability, or catalytic activity of another target polypeptide, particularly a heterologous enzyme expressed in a host cell as defined herein.

[0080] The term "auxiliary gene" as used herein refers to a gene encoding a polypeptide that is not a direct enzymatic component of a given prostaglandin biosynthesis pathway but which enhances the overall production of the prostaglandin by supporting the expression, folding, stability, or catalytic function of one or more polypeptides within that pathway. Non-limiting examples of auxiliary genes include those encoding endoplasmic reticulum (ER) chaperones, protein disulfide isomerases, and proteins involved in electron transfer or cofactor supply.

[0081] The term "spontaneous conversion" as used herein refers to a non-enzymatic chemical transformation of a compound that occurs under relevant physiological or bioprocessing conditions, typically in an aqueous medium, without the requirement of a biological catalyst. For example, the conversion of prostaglandin 12 (PGI2) into 6-keto-prostaglandin-Fl-a is a spontaneous hydrolysis reaction.

[0082] As used herein, a "homolog," "ortholog," "paralog," or "variant" of a polypeptide or gene disclosed herein refers to a sequence that retains the activity of the referenced ("parent") polypeptide or gene. "Retains the activity" means that, when assayed under the conditions described herein (or substantially equivalent conditions), the homolog / ortholog / paralog / variant exhibits the samequalitative function and a measurable level of the relevant activity, which may be higher, lower, or the same as the parent. In some embodiments, retained activity is at least a detectable level above background; in some embodiments at least 1%, 5%, 10%, 20%, 25%, 50%, 75%, 90%, 95%, 99%, or 100% of the parent activity; in some embodiments >0.1x, >0.25x, >0.5x, >lx, >2x, >5x, or >10x the parent activity. Homologs / orthologs / paralogs / variants that do not retain the defined activity are excluded from these embodiments.

[0083]

[0084] "Variant" polypeptides include conservative substitutions, allelic variants, splice variants, domain swaps, truncations that maintain a functional domain (e.g., catalytic or binding domain), and fusion proteins (e.g., tags, localization signals) that do not abrogate activity. "Variant" nucleic acids include codon-optimized sequences, sequences encoding the foregoing polypeptide variants, complements, and sequences differing by silent substitutions. Unless stated otherwise, % identity is calculated over the full-length sequence (or over a functional domain) using a standard algorithm (e.g., BLAST or Needleman-Wunsch) as specified herein with default parameters. In some embodiments, homologs / orthologs / paralogs / variants have at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identity to the reference sequence (e.g., any SEQ. ID NO provided herein) and retain the activity as defined above. "Functional fragment" means a portion that retains the activity and may be, for example, >50, >75, >100, >150, or >200 amino acids or comprises the catalytic domain.

[0085] Activity can be demonstrated by any validated assay disclosed herein, including (by way of example) enzymatic turnover assays, substrate-to-product conversion rates, complementation of a loss-of-function phenotype, restoration of pathway flux, increased product titer in a host cell, or rescue of growth under selective conditions.

[0086] The term "modification enhancing the yield relative to the corresponding host cell without the modification" as used herein refers to a genetic modification as detailed herein that results in a quantifiable increase in the final titer or concentration of one or more prostaglandins or prostaglandin precursors. The "corresponding host cell without the modification" is the parent host cell from which the genetically modified host cell was derived, prior to the introduction of said modification. The increase in yield is determined when both the modified host cell and the parent host cell are cultured under substantially identical conditions. In certain embodiments, said increase in yield is at least 10%, such as at least 25%, at least 50%, at least 100%, or at least 200%. This enhancement is achieved through at least one of the specific technical modifications disclosed herein, such as the attenuation of endogenous competing pathways, the overexpression of precursor-supplying genes, or the expression of auxiliary genes that support the prostaglandin biosynthesis pathway.Host cells

[0087] Accordingly, in a first aspect the present invention discloses a genetically modified host cell comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor.

[0088] In some embodiments, a genetically modified host cell is provided comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, wherein the host cell is further genetically modified by at least one modification enhancing the yield of one or more prostaglandins or prostaglandin precursors. In some embodiments, a genetically modified host cell is provided comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, wherein the host cell is further genetically modified by at least one modification as defined herein.

[0089] In some embodiments, a genetically modified host cell is provided comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, and wherein the host cell is further genetically modified by at least one modification enhancing the yield of one or more prostaglandins or prostaglandin precursors relative to the corresponding host cell without the modification; and wherein the host cell is of a genus selected from the group consisting of: Saccharomyces, Aspergillus, Kluyveromyces, Candida, Komagataella (formerly Pichia), Debaromyces, Hansenula, Zygosaccharomyces, and Schizosaccharomyces.

[0090] In some embodiments, a genetically modified host cell is provided comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, wherein the host cell is further genetically modified by at least one modification selected from the group consisting of:i) the attenuation, disruption or deletion of one or more endogenous genes encoding a polypeptide that catalyzes an unwanted side-reaction on one or more prostaglandin precursors and / or retards the catalytic activity of one or more of the polypeptides of the metabolic pathways capable of producing one or more prostaglandins, optionally wherein the one or more endogenous genes are selected from the group consisting of a glutathione S-transferase, an esterase, a thioredoxin peroxidase, and an oxidoreductase;ii) the overexpression of a gene that increases the supply of one or more prostaglandin precursors, optionally wherein said gene is selected from the group consisting of: a gene encoding a mutant acetyl-CoA carboxylase (ACC1) and an endogenous delta-9 desaturase gene; andiii) the expression or overexpression of an auxiliary gene encoding a polypeptide that enhances folding or function of one or more of the polypeptides of the metabolic pathways capable of producing one or more prostaglandins, optionally wherein said polypeptide is selected from the group consisting ofan endoplasmic reticulum (ER) chaperone, a protein disulfide isomerase, and a cytochrome bS-like polypeptide.

[0091] In some embodiments, the host cell is further genetically modified by at least one modification selected from the group consisting of:i) the attenuation, disruption or deletion of one or more endogenous genes encoding a polypeptide that catalyzes an unwanted side-reaction on one or more prostaglandin precursors and / or retards the catalytic activity of one or more of the polypeptides of the metabolic pathways capable of producing one or more prostaglandins, optionally wherein the one or more endogenous genes are selected from the group consisting of a glutathione S-transferase, an esterase, a thioredoxin peroxidase, and an oxidoreductase;ii) the overexpression of a gene that increases the supply of one or more prostaglandin precursors, optionally wherein said gene is selected from the group consisting of: a gene encoding a mutant acetyl-CoA carboxylase (ACC1) and an endogenous delta-9 desaturase gene; andiii) expressing or overexpressing one or more auxiliary genes encoding polypeptides selected from at least one of the following functional groups:a) polypeptides involved in the unfolded protein response or protein degradation pathway; b) polypeptides involved in the oxidative stress response;c) polypeptides involved in heme oxidoreductase activity or electron transfer; andd) polypeptides involved in fatty acid and / or lipid production.

[0092] In some embodiments, the modification is the expression or overexpression of one or more auxiliary genes encoding polypeptides according to (iii)(a), wherein the polypeptides are selected from the group consisting of an endoplasmic reticulum (ER) chaperone, a protein disulfide isomerase, and a peptidyl-prolyl cis-trans isomerase.

[0093] In some embodiments, the modification is the expression or overexpression of one or more auxiliary genes encoding polypeptides according to (iii)(b), wherein the polypeptides are selected from the group consisting of a catalase, a glutathione peroxidase, and a glucose-6-phosphate dehydrogenase, optionally wherein the catalase is fused to an ER-directing signal sequence.

[0094] In some embodiments, the modification is the expression or overexpression of one or more auxiliary genes encoding polypeptides according to (iii)(c) or (iii)(d), wherein the polypeptides are selected from the group consisting of a membrane steroid-binding protein (MSBP), a NADP-cytochrome P450 reductase, a cytochrome b5, a cytochrome b5 reductase, and a phospholipase A2.

[0095] In some embodiments, the host cell is modified by at least two modifications selected from the group consisting of (i), (ii), and (iii).

[0096] In some embodiments, the host cell is modified by attenuating or deleting an endogenous geneaccording to (i) and by expressing or overexpressing one or more auxiliary genes according to (iii).

[0097] In some embodiments, the host cell is capable of producing prostaglandins via arachidonic acid (ARA) from a carbon feedstock.

[0098] In some embodiments, the host cell is capable of producing prostaglandins via arachidonic acid (ARA) and / or DGLA, such as via DGLA from a carbon feedstock.

[0099] In particular the cell of the invention may be a eukaryote cell selected from the group consisting of mammalian, insect, plant, or fungal cells. In another embodiment the cell is a fungal cell selected from the phylas consisting of Ascomycota, Basidiomycota, Neocallimastigomycota, Glomeromycota, Blastocladiomycota, Chytridiomycota, Zygomycota, Oomycota and Microsporidia. A particularly useful fungal cell is a yeast cell selected from the group consisting of ascosporogenous yeast (Endomycetales), basidiosporogenous yeast, and Fungi Imperfecti yeast (Blastomycetes). Such yeast cells may further be selected from the genera consisting of Saccharomyces, Kluveromyces, Candida, Pichia, Komagataella, Debaromyces, Hansenula, Yarrowia, Zygosaccharomyces, and Schizosaccharomyces. More specifically the yeast cell may be selected from the species consisting of Kluyveromyces lactis, Saccharomyces carlsbergensis, Saccharomyces cerevisiae, Saccharomyces diastaticus, Saccharomyces douglasii, Saccharomyces kluyveri, Saccharomyces norbensis, Saccharomyces oviformis, Pichia pastoris (Komagataella phaffii) and Yarrowia lipolytica.

[0100] An alternative fungal host cell of the invention is a filamentous fungal cell. Such filamentous fungal cell may be selected from the phylas consisting of Ascomycota, Eumycota and Oomycota, more specifically selected from the genera consisting of Acremonium, Aspergillus, Aureobasidium, Bjerkandera, Ceriporiopsis, Chrysosporium, Coprinus, Corio / us, Cryptococcus, Filibasidium, Fusarium, Humicola, Magnaporthe, Mucor, Myceliophthora, Neocallimastix, Neurospora, Paecilomyces, Penicillium, Phanerochaete, Phlebia, Piromyces, Pleurotus, Schizophyllum, Talaromyces, Thermoascus, Thielavia, Tolypocladium, Trametes, and Trichoderma. In important embodiments the filamentous fungal cell may be selected from the species consisting of Aspergillus awamori, Aspergillus foetidus, Aspergillus fumigatus, Aspergillus japonicus, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Bjerkandera adusta, Ceriporiopsis aneirina, Ceriporiopsis caregiea, Ceriporiopsis gilvescens, Ceriporiopsis pannocinta, Ceriporiopsis rivulosa, Ceriporiopsis subrufa, Ceriporiopsis subvermispora, Chrysosporiuminops, Chrysosporiumkeratinophilum, Chrysosporium lucknowense, Chrysosporium merdarium, Chrysosporium pannicola, Chrysosporium queenslandicum, Chrysosporium tropicum, Chrysosporium zonatum, Coprinus cinereus, Coriolus hirsutus, Fusarium bactridioides, Fusarium cerealis, Fusarium crookwellense, Fusarium culmorum, Fusarium graminearum, Fusarium graminum, Fusarium heterosporum, Fusarium negundi, Fusarium oxysporum, Fusarium reticulatum, Fusarium roseum, Fusarium sambucinum, Fusarium sarcochroum,Fusarium sporotrichioides, Fusarium sulphureum, Fusarium torulosum, Fusarium trichothecioides, Fusarium venenatum, Humicola insolens, Humicola lanuginosa, Mucor miehei, Myceliophthora thermophila, Neurospora crassa, Penicillium purpurogenum, Phanerochaete chrysosporium, Phlebia radiata, Pleurotus eryngii, Thielavia terrestris, Trametes villosa, Trametes versicolor, Trichoderma harzianum, Trichoderma koningii, Trichoderma longibrachiatum, Trichoderma reesei, and Trichoderma viride.

[0101] In some embodiments, the eukaryote cell is a fungal cell.

[0102] One skilled in the art will recognize that some fungal host cells produce polysaturated fatty acids (PUFAs) such as arachidonic acid naturally and would not require the upstream engineering steps of desaturases and elongases. Exemplary fungal host cells capable of producing PUFAs include Mortierella alpina and Pythium irregulare.

[0103] In some embodiments, the host cell is a fungal cell selected from the phyla consisting of Ascomycota and / or Basidiomycota.

[0104] In some embodiments, the fungal cell is a yeast selected from the genera consisting of Ascomycota (Saccharomyces, Aspergillus, Yarrowia, Candida & Komagataella (formerly Pichia)), Mucoromycota (Mortierella), ascosporogenous yeast (Endomycetales), basidiosporogenous yeast, and Fungi Imperfecti yeast (Blastomycetes).

[0105] In some embodiments, the yeast cell is of a genus selected from the group consisting of Saccharomyces, Aspergillus, Mortierella, Kluyveromyces, Candida, Komagataella (formerly Pichia), Debaromyces, Hansenula, Yarrowia, Zygosaccharomyces, and Schizosaccharomyces.

[0106] In some embodiments, the yeast cell is of a species selected from the group consisting of Kluyveromyces lactis, Saccharomyces carlsbergensis, Saccharomyces cerevisiae, Saccharomyces diastaticus, Saccharomyces douglasii, Saccharomyces kluyveri, Saccharomyces norbensis, Saccharomyces oviformis, Mortierella alpina, Komagataella phaffii (syn. Pichia pastoris), and / or Yarrowia lipolytica.

[0107] In some embodiments, the host cell is of a genus selected from the group consisting of Saccharomyces, Yarrowia, and Komagataella.

[0108] In some embodiments, the host cell is Saccharomyces cerevisiae, Yarrowia lipolytica, or Komagataella phaffii.

[0109] In one embodiment the host cell further genetically modified to exhibit increased tolerance towards one or more substrates, intermediates, or product molecules from the prostaglandin pathway.

[0110] In another aspect the host cell is a prokaryote cell, an eukaryote cell or an archaeal cell.

[0111] In one embodiment, the eukaryote cell is a fungal cell.

[0112] In one embodiment, the host cell is a fungal cell selected from the phyla consisting of Ascomycota and / or Basidiomycota.

[0113] In one embodiment of the host cell the fungal cell is a yeast selected from the genera consisting of Ascomycota (Saccharomyces, Aspergillus, Yarrowia, Candida & Pichia) Mucoromycota (Mortierella), ascosporogenous yeast (Endomycetales), basidiosporogenous yeast, and Fungi Imperfecti yeast (Blastomycetes).

[0114] In one embodiment of the host cell the yeast cell is of a genus selected from the group consisting of Saccharomyces, Aspergillus, Mortierella, Kluyveromyces, Candida, Pichia, Debaromyces, Hansenula, Yarrowia, Zygosaccharomyces, and Schizosaccharomyces.

[0115] In a particular embodiment of the host cell the yeast cell is of a species selected from the group consisting of Kluyveromyces lactis, Saccharomyces carlsbergensis, Saccharomyces cerevisiae, Saccharomyces diastaticus, Saccharomyces douglasii, Saccharomyces kluyveri, Saccharomyces norbensis, Saccharomyces oviformis, Mortierella alpina, Pichia pastoris (Komagataella phaffii) and Yarrowia lipolytica.

[0116] In a specific embodiment the host cell is Saccharomyces cerevisiae, and comprisesa) genes MrD9D (SEQ ID NO: 80), MrD12D (SEQ ID NO: 81), MaD6D (SEQ ID NO: 82), MaD5D (SEQ ID NO: 83) and or MaD6Elo (SEQ ID NO: 84); and isb) for the production of arachidonic acid, and / orc) for the production of prostaglandin.

[0117] In another specific embodiment the host cell is Saccharomyces cerevisiae, and comprises a) genes RnCOX2 (SEQ ID NO: 21) and PGF2_1 to PGF-12 (SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69); and isb) for the production of arachidonic acid; and / orc) for the production of prostaglandin.

[0118] In a specific embodiment, the fungal cell is a filamentous fungus.

[0119] In one embodiment the host cell the filamentous fungal cell is of a phylum selected from group consisting of Ascomycota.

[0120] In one embodiment, the filamentous fungal cell is of a genus selected from the group consisting of Aspergillus.

[0121] In a specific embodiment the host cell the filamentous fungal cell is of species selected from group consisting of Aspergillus niger.

[0122] In a specific embodiment the host cell the bacterial cell is of a phylum selected from group consisting of Escherichia coli.Genetic modifications

[0123] It is to be understood that the nature of the genetic modification, whether it involves the expression of a heterologous gene or the overexpression of an endogenous gene, is dependent on the genetic background of the selected host cell. For a given enzymatic function required by a metabolic pathway, if the chosen host cell naturally contains a gene encoding a polypeptide with that function, the genetic modification may comprise overexpressing this endogenous gene. Overexpression can be achieved by methods known in the art, such as integrating additional copies of the endogenous gene into the host genome or replacing its native promoter with a stronger, constitutive or inducible promoter. The present disclosure also details throughout the examples way of overexpressing endogenous genes as well as ways of introducing heterologous genes. Conversely, if the host cell lacks a suitable endogenous gene for a desired function, or possesses one with low efficiency, the genetic modification may comprise introducing and expressing a heterologous gene from a different source organism. The use of "and / or" throughout the present disclosure signifies that the host cell of the disclosure may be modified using either strategy exclusively or, in many embodiments, a combination of both, wherein some pathway steps are enhanced by heterologous gene expression and others by endogenous gene overexpression.

[0124] In some embodiments, the host cell has been genetically modified to express one or more heterologous genes and / or overexpress one or more endogenous genes each independently selected from the group consisting of:a) a gene encoding a prostaglandin D2 synthase (prostaglandin-H2 D-isomerase) (PGD) converting prostaglandin H2 into a prostaglandin D2;b) a gene encoding a NADH-cytochrome B5 reductase (NCB5R), transferring electrons from NADH to other molecules in fatty acid biosynthesis pathways;c) a gene encoding a cytochrome B5 (CYB5) hemoprotein cofactor supporting transfer of electrons in fatty acid biosynthesis pathways;d) a gene encoding an elongase (ELO) adding two-carbon units to the end of a fatty acid-CoA chain using malonyl CoA);e) a gene encoding a delta-6 desaturase (D6D) converting linoleoyl-CoA to gamma-linolenoyl-CoA;f) a gene encoding a delta-12-fatty acid desaturase (D12D) converting oleoyl-CoA to linoleoyl-CoA;g) a gene encoding a polyunsaturated fatty acid elongation enzyme (D6Elo) adding two-carbon units to the end of a polyunsaturated fatty acid-coA substrate;h) a gene encoding a delta-5 desaturase (D5D) converting dihomo-gamma-linolenoyl-CoA to Arachidonoyl-CoA;i) a gene encoding a stearoyl-CoA-9 desaturase (Ole, D9D) converting stearoyl-CoA to oleoyl-CoA;j) a gene encoding a cyclooxygenase (COX)_enzyme converting arachidonic acid to Prostaglanding G2 (PGG2) and / or converts PGG2 to prostaglandin H2 (PGH2);k) a gene encoding a prostaglandin F synthase (PGF2) converting prostaglandin H2 to prostaglandin F2;l) a gene encoding a prostaglandin E synthase (PGES) converting prostaglandin H2 into prostaglandin E2;m) a gene encoding an ATPase acting as a chaperone to mediate protein folding in the ER; n) a gene encoding a protein disulfide isomerase (PDI) acting as an oxidoreductase in the ER lumen;o) a gene encoding a cytosolic or peroxisomal catalase (CT) enzyme that decomposes hydrogen peroxide and protects from oxidative damage;p) a gene encoding a Peptidyl-prolyl cis-trans isomerase of the ER;q) a gene encoding an Integral ER membrane protein (ICE2) with type-III transmembrane domains and promotes ER membrane expansion;r) a gene encoding a NADP-cytochrome P450 reductase assisting in electron transfer of associated P450 enzymes;s) a gene encoding a nuclear RNA-binding protein (GRP7);t) a gene encoding a UDP-glucose pyrophosphorylase (UGPase); catalyses the reversible formation of UDP-GIc from glucose 1-phosphate and UTP (UGP1);u) a gene encoding a Glucose-6-phosphate dehydrogenase (G6PD) catalyzing the first step of the pentose phosphate pathway;v) a gene encoding a protein involved in homologous recombination (RAD52);w) a gene encoding a Phospholipid hydroperoxide glutathione peroxidase involved in the antioxidant system that decreases mitochondrial ROS production and preserves electron transport chain (ETC) function (GPX2);x) a gene encoding a 3'-5' exonuclease specific for poly-A RNAs (NGL3);y) a gene encoding an L119A mutant of a component of the cleavage and polyadenylation factor I (INO2);z) a gene encoding a Component of the cleavage and polyadenylation factor I (RNA15); aa) a gene encoding a yeast RNA annealing protein (YRA2);bb) a gene encoding a phospholipase A2, membrane associated precursor (PA2GA);cc) a gene encoding a transcription factor in oxidative stress response (STB5);dd) a gene encoding a mutant (R206) heat shock transcription factor (HSF1);ee) a gene encoding an alcohol dehydrogenase (ADH1) converting acetaldehyde to ethanol; ff) a gene encoding a Mitochondrial NADH kinase (POS5);gg) a gene encoding a Bifunctional alcohol dehydrogenase and formaldehyde dehydrogenase (SFA1) involved in formaldehyde detoxification and long chain alcohols;hh) a gene encoding a Transcription factor involved in phospholipid synthesis (INO4);ii) a gene encoding a Plasma membrane protein involved in maintaining membrane organization (HSP12);jj) a gene encoding a Membrane-bound peptidyl-prolyl cis-trans isomerase (PPIase);kk) a gene encoding a Cytosolic copper-zinc superoxide dismutase / sulfide oxidase (sodl) acting to detoxify superoxide and hydrogen sulfide;II) a gene encoding an Aminolevulinate dehydratase (HEM2) converting 5-aminolevulinate to porphobilinogen;mm) a gene encoding a Lanosterol 14-alpha-demethylase (ERG11) catalyzes C-14 demethylation of lanosterol to form 4,4"-dimethyl cholesta-8,14,24-triene-3-beta-ol;nn) a gene encoding a Damage resistance protein (DAP1) Heme-binding protein involved in regulation of cytochrome P450 protein Ergllp and damage response protein; andoo) a gene encoding a membrane steroid binding protein (MSBP).

[0125] In some embodiments, the host cell has been genetically modified to express one or more heterologous genes and / or overexpress one or more endogenous genes each independently selected from the group consisting of:a) a gene encoding a MmPGD, wherein the gene encoding said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 96, and / or wherein the polypeptide encoded by said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 95, or any of its orthologs or paralogs;b) a gene encoding a NCB5R_MORAP_GA, wherein the gene encoding said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 98, and / or wherein the polypeptide encoded by said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as atleast 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 97, or any of its orthologs or paralogs;c) a gene encoding a CYB5_MORAP_GA, wherein the gene encoding said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 100, and / or wherein the polypeptide encoded by said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 99, or any of its orthologs or paralogs;d) a gene encoding a McELO, wherein the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs;e) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs;f) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs;g) a gene encoding a MaD12D_2, wherein the gene encoding said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 108, and / or wherein the polypeptide encoded by said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 107, or any of its orthologs or paralogs;h) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%,such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109, or any of its orthologs or paralogs;i) a gene encoding a MaD6Elo_2, wherein the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111, or any of its orthologs or paralogs;j) a gene encoding a MaD5D_2, wherein the gene encoding said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 114, and / or wherein the polypeptide encoded by said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 113, or any of its orthologs or paralogs;k) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115, or any of its orthologs or paralogs;l) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs;m) a gene encoding a ScOLE1, wherein the gene encoding said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 120, and / or wherein the polypeptide encoded by said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 119, or any of its orthologs or paralogs;n) a gene encoding an RnCOX2_GS_YALI, wherein the gene encoding said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 121, or any of its orthologs or paralogs;o) a gene encoding a PGF2_12_GS_YALI, wherein the gene encoding said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 123, or any of its orthologs or paralogs;p) a gene encoding a HsPGES-1_GS_YALI, wherein the gene encoding said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 126, and / or wherein the polypeptide encoded by said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 125, or any of its orthologs or paralogs;q) a gene encoding a D6D_YALI, wherein the gene encoding said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 128, and / or wherein the polypeptide encoded by said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 127, or any of its orthologs or paralogs;r) a gene encoding a D6Elo_YALI, wherein the gene encoding said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 130, and / or wherein the polypeptide encoded by said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 129, or any of its orthologs or paralogs;s) a gene encoding a D5D_YALI, wherein the gene encoding said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 132, and / or wherein the polypeptide encoded by said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as atleast 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 131, or any of its orthologs or paralogs;t) a gene encoding a KAR2, wherein the gene encoding said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 134, and / or wherein the polypeptide encoded by said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, or any of its orthologs or paralogs;u) a gene encoding a PDI1, wherein the gene encoding said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 136, and / or wherein the polypeptide encoded by said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, and SEQ ID NO: 314, or any of its orthologs or paralogs;v) a gene encoding a CTT1_prepro, wherein the gene encoding said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 138, and / or wherein the polypeptide encoded by said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 137, SEQ ID NO: 319, SEQ ID NO: 320, SEQ ID NO: 321, or any of its orthologs or paralogs;w) a gene encoding a CTA1_prepro, wherein the gene encoding said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 140, and / or wherein the polypeptide encoded by said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 139, or any of its orthologs or paralogs;x) a gene encoding a CPR5, wherein the gene encoding said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 142, and / or wherein the polypeptide encoded by said CPR5 has atleast 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%,such as at least 99%, such as at least 100% identity to SEQ ID NO: 141, or any of its orthologs or paralogs;y) a gene encoding an ICE2, wherein the gene encoding said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 144, and / or wherein the polypeptide encoded by said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 143, or any of its orthologs or paralogs; z) a gene encoding an NCP1, wherein the gene encoding said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 146, and / or wherein the polypeptide encoded by said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 145, or any of its orthologs or paralogs; aa) a gene encoding an AtMSBP1, wherein the gene encoding said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 148, and / or wherein the polypeptide encoded by said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 147, or any of its orthologs or paralogs;bb) a gene encoding an AtGRP7, wherein the gene encoding said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 150, and / or wherein the polypeptide encoded by said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 149, or any of its orthologs or paralogs;cc) a gene encoding an UGP1, wherein the gene encoding said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 152, and / or wherein the polypeptide encoded by said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 151, or any of its orthologs or paralogs;dd) a gene encoding a ZWF1, wherein the gene encoding said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 154, and / or wherein the polypeptide encoded by said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, suchas at least 99%, such as at least 100% identity to any of SEQ ID NO: 153, SEQ ID NO: 326, SEQ ID NO: 327, SEQ ID NO: 328, and SEQ ID NO: 329, or any of its orthologs or paralogs;ee) a gene encoding a HaCPR5hom_7, wherein the gene encoding said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 156, and / or wherein the polypeptide encoded by said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 155, or any of its orthologs or paralogs;ff) a gene encoding a RAD52, wherein the gene encoding said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 158, and / or wherein the polypeptide encoded by said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 157, or any of its orthologs or paralogs;gg) a gene encoding a GPX2, wherein the gene encoding said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 160, and / or wherein the polypeptide encoded by said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 159, or any of its orthologs or paralogs; hh) a gene encoding an NGL3, wherein the gene encoding said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 162, and / or wherein the polypeptide encoded by said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 161, or any of its orthologs or paralogs;ii) a gene encoding an INO2_L119A, wherein the gene encoding said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 164, and / or wherein the polypeptide encoded by said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 163, or any of its orthologs or paralogs;jj) a gene encoding an RNA15, wherein the gene encoding said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 166, and / or wherein the polypeptide encoded by said RNA15has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 165, or any of its orthologs or paralogs;kk) a gene encoding a YRA2, wherein the gene encoding said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 168, and / or wherein the polypeptide encoded by said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 167, SEQ ID NO: 315, SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, or any of its orthologs or paralogs;II) a gene encoding an RnPA2GA, wherein the gene encoding said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 170, and / or wherein the polypeptide encoded by said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 169, SEQ ID NO: 322, SEQ ID NO: 323, or any of its orthologs or paralogs;mm) a gene encoding a STB5, wherein the gene encoding said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 172, and / or wherein the polypeptide encoded by said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 171, SEQ ID NO: 330, SEQ ID NO: 331, SEQ ID NO: 332, or any of its orthologs or paralogs;nn) a gene encoding a HSF1_R206S, wherein the gene encoding said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 174, and / or wherein the polypeptide encoded by said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 173, or any of its orthologs or paralogs;oo) a gene encoding an ADH1, wherein the gene encoding said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 176, and / or wherein the polypeptide encoded by said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 175, or any of its orthologs or paralogs;pp) a gene encoding a HvCPR5hom_6, wherein the gene encoding said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 178, and / or wherein the polypeptide encoded by said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 177, or any of its orthologs or paralogs;qq) a gene encoding a POS5, wherein the gene encoding said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 180, and / or wherein the polypeptide encoded by said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 179, SEQ ID NO: 324, SEQ ID NO: 325, or any of its orthologs or paralogs;rr) a gene encoding a SFA1, wherein the gene encoding said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 182, and / or wherein the polypeptide encoded by said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 181, or any of its orthologs or paralogs; ss) a gene encoding an INO4, wherein the gene encoding said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 184, and / or wherein the polypeptide encoded by said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 183, or any of its orthologs or paralogs; tt) a gene encoding an HSP12, wherein the gene encoding said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 186, and / or wherein the polypeptide encoded by said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 185, or any of its orthologs or paralogs;uu) a gene encoding an FPR2, wherein the gene encoding said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 188, and / or wherein the polypeptide encoded by said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 187, or any of its orthologs or paralogs;vv) a gene encoding an MSBP_40, wherein the gene encoding said MSBP_40 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 190, and / or wherein the polypeptide encoded by said MSBP_40 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 189, or any of its orthologs or paralogs;ww) a gene encoding an MSBP_56, wherein the gene encoding said MSBP_56 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 192, and / or wherein the polypeptide encoded by said MSBP_56 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 191, or any of its orthologs or paralogs;xx) a gene encoding an MSBP_22, wherein the gene encoding said MSBP_22 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 194, and / or wherein the polypeptide encoded by said MSBP_22 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 193, or any of its orthologs or paralogs;yy) a gene encoding a DAP1_9, wherein the gene encoding said DAP1_9 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 196, and / or wherein the polypeptide encoded by said DAP1_9 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 195, or any of its orthologs or paralogs;zz) a gene encoding an MSBP_21, wherein the gene encoding said MSBP_21 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 198, and / or wherein the polypeptide encoded by said MSBP_21 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 197, or any of its orthologs or paralogs;aaa) a gene encoding an MSBP_62, wherein the gene encoding said MSBP_62 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 200, and / or wherein the polypeptide encoded by said MSBP_62 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as atleast 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 199, or any of its orthologs or paralogs;bbb) a gene encoding an MSBP_26, wherein the gene encoding said MSBP_26 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 202, and / or wherein the polypeptide encoded by said MSBP_26 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 201, or any of its orthologs or paralogs;ccc) a gene encoding an MSBP_35, wherein the gene encoding said MSBP_35 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 204, and / or wherein the polypeptide encoded by said MSBP_35 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 203, or any of its orthologs or paralogs;ddd) a gene encoding an MSBP_17, wherein the gene encoding said MSBP_17 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 206, and / or wherein the polypeptide encoded by said MSBP_17 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 205, or any of its orthologs or paralogs; andeee) a gene encoding an MSBP_79, wherein the gene encoding said MSBP_79 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 208, and / or wherein the polypeptide encoded by said MSBP_79 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 207, or any of its orthologs or paralogs.

[0126] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes selected from the group consisting of:a) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs;b) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs;c) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 107, or any of its orthologs or paralogs;d) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115, or any of its orthologs or paralogs; ande) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs.a) a gene encoding a MmPGD, wherein the gene encoding said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 96, and / or wherein the polypeptide encoded by said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 95, or any of its orthologs or paralogs;b) a gene encoding a NCB5R_MORAP_GA, wherein the gene encoding said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 98, and / or wherein the polypeptide encoded by said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as atleast 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 97, or any of its orthologs or paralogs;c) a gene encoding a CYB5_MORAP_GA, wherein the gene encoding said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 100, and / or wherein the polypeptide encoded by said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 99, or any of its orthologs or paralogs;d) a gene encoding a McELO, wherein the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs;e) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs;f) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs;g) a gene encoding a MaD12D_2, wherein the gene encoding said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 108, and / or wherein the polypeptide encoded by said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 107, or any of its orthologs or paralogs;h) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%,such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109, or any of its orthologs or paralogs;i) a gene encoding a MaD6Elo_2, wherein the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111, or any of its orthologs or paralogs;j) a gene encoding a MaD5D_2, wherein the gene encoding said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 114, and / or wherein the polypeptide encoded by said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 113, or any of its orthologs or paralogs;k) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115, or any of its orthologs or paralogs;l) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs;m) a gene encoding a ScOLE1, wherein the gene encoding said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 120, and / or wherein the polypeptide encoded by said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 119, or any of its orthologs or paralogs;n) a gene encoding an RnCOX2_GS_YALI, wherein the gene encoding said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 121, or any of its orthologs or paralogs;o) a gene encoding a PGF2_12_GS_YALI, wherein the gene encoding said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 123, or any of its orthologs or paralogs;p) a gene encoding a HsPGES-1_GS_YALI, wherein the gene encoding said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 126, and / or wherein the polypeptide encoded by said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 125, or any of its orthologs or paralogs;q) a gene encoding a D6D_YALI, wherein the gene encoding said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 128, and / or wherein the polypeptide encoded by said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 127, or any of its orthologs or paralogs;r) a gene encoding a D6Elo_YALI, wherein the gene encoding said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 130, and / or wherein the polypeptide encoded by said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 129, or any of its orthologs or paralogs;s) a gene encoding a D5D_YALI, wherein the gene encoding said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 132, and / or wherein the polypeptide encoded by said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as atleast 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 131, or any of its orthologs or paralogs;t) a gene encoding a KAR2, wherein the gene encoding said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 134, and / or wherein the polypeptide encoded by said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, or any of its orthologs or paralogs;u) a gene encoding a PDI1, wherein the gene encoding said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 136, and / or wherein the polypeptide encoded by said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, and SEQ ID NO: 314, or any of its orthologs or paralogs;v) a gene encoding a CTT1_prepro, wherein the gene encoding said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 138, and / or wherein the polypeptide encoded by said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 137, SEQ ID NO: 319, SEQ ID NO: 320, SEQ ID NO: 321, or any of its orthologs or paralogs;w) a gene encoding a CTA1_prepro, wherein the gene encoding said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 140, and / or wherein the polypeptide encoded by said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 139, or any of its orthologs or paralogs;x) a gene encoding a CPR5, wherein the gene encoding said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 142, and / or wherein the polypeptide encoded by said CPR5 has atleast 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%,such as at least 99%, such as at least 100% identity to SEQ ID NO: 141, or any of its orthologs or paralogs;y) a gene encoding an ICE2, wherein the gene encoding said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 144, and / or wherein the polypeptide encoded by said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 143, or any of its orthologs or paralogs; z) a gene encoding an NCP1, wherein the gene encoding said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 146, and / or wherein the polypeptide encoded by said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 145, or any of its orthologs or paralogs; aa) a gene encoding an AtMSBP1, wherein the gene encoding said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 148, and / or wherein the polypeptide encoded by said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 147, or any of its orthologs or paralogs;bb) a gene encoding an AtGRP7, wherein the gene encoding said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 150, and / or wherein the polypeptide encoded by said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 149, or any of its orthologs or paralogs;cc) a gene encoding an UGP1, wherein the gene encoding said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 152, and / or wherein the polypeptide encoded by said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 151, or any of its orthologs or paralogs;dd) a gene encoding a ZWF1, wherein the gene encoding said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 154, and / or wherein the polypeptide encoded by said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, suchas at least 99%, such as at least 100% identity to any of SEQ ID NO: 153, SEQ ID NO: 326, SEQ ID NO: 327, SEQ ID NO: 328, and SEQ ID NO: 329, or any of its orthologs or paralogs;ee) a gene encoding a HaCPR5hom_7, wherein the gene encoding said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 156, and / or wherein the polypeptide encoded by said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 155, or any of its orthologs or paralogs;ff) a gene encoding a RAD52, wherein the gene encoding said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 158, and / or wherein the polypeptide encoded by said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 157, or any of its orthologs or paralogs;gg) a gene encoding a GPX2, wherein the gene encoding said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 160, and / or wherein the polypeptide encoded by said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 159, or any of its orthologs or paralogs; hh) a gene encoding an NGL3, wherein the gene encoding said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 162, and / or wherein the polypeptide encoded by said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 161, or any of its orthologs or paralogs;ii) a gene encoding an INO2_L119A, wherein the gene encoding said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 164, and / or wherein the polypeptide encoded by said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 163, or any of its orthologs or paralogs;jj) a gene encoding an RNA15, wherein the gene encoding said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 166, and / or wherein the polypeptide encoded by said RNA15has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 165, or any of its orthologs or paralogs;kk) a gene encoding a YRA2, wherein the gene encoding said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 168, and / or wherein the polypeptide encoded by said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 167, SEQ ID NO: 315, SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, or any of its orthologs or paralogs;II) a gene encoding an RnPA2GA, wherein the gene encoding said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 170, and / or wherein the polypeptide encoded by said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 169, SEQ ID NO: 322, SEQ ID NO: 323, or any of its orthologs or paralogs;mm) a gene encoding a STB5, wherein the gene encoding said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 172, and / or wherein the polypeptide encoded by said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 171, SEQ ID NO: 330, SEQ ID NO: 331, SEQ ID NO: 332, or any of its orthologs or paralogs;nn) a gene encoding a HSF1_R206S, wherein the gene encoding said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 174, and / or wherein the polypeptide encoded by said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 173, or any of its orthologs or paralogs;oo) a gene encoding an ADH1, wherein the gene encoding said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 176, and / or wherein the polypeptide encoded by said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 175, or any of its orthologs or paralogs;pp) a gene encoding a HvCPR5hom_6, wherein the gene encoding said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 178, and / or wherein the polypeptide encoded by said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 177, or any of its orthologs or paralogs;qq) a gene encoding a POS5, wherein the gene encoding said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 180, and / or wherein the polypeptide encoded by said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 179, SEQ ID NO: 324, SEQ ID NO: 325, or any of its orthologs or paralogs;rr) a gene encoding a SFA1, wherein the gene encoding said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 182, and / or wherein the polypeptide encoded by said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 181, or any of its orthologs or paralogs; ss) a gene encoding an INO4, wherein the gene encoding said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 184, and / or wherein the polypeptide encoded by said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 183, or any of its orthologs or paralogs; tt) a gene encoding an HSP12, wherein the gene encoding said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 186, and / or wherein the polypeptide encoded by said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 185, or any of its orthologs or paralogs;uu) a gene encoding an FPR2, wherein the gene encoding said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 188, and / or wherein the polypeptide encoded by said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 187, or any of its orthologs or paralogs;vv) a gene encoding an MSBP_40, wherein the gene encoding said MSBP_40 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 190, and / or wherein the polypeptide encoded by said MSBP_40 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 189, or any of its orthologs or paralogs;ww) a gene encoding an MSBP_56, wherein the gene encoding said MSBP_56 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 192, and / or wherein the polypeptide encoded by said MSBP_56 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 191, or any of its orthologs or paralogs;xx) a gene encoding an MSBP_22, wherein the gene encoding said MSBP_22 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 194, and / or wherein the polypeptide encoded by said MSBP_22 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 193, or any of its orthologs or paralogs;yy) a gene encoding a DAP1_9, wherein the gene encoding said DAP1_9 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 196, and / or wherein the polypeptide encoded by said DAP1_9 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 195, or any of its orthologs or paralogs;zz) a gene encoding an MSBP_21, wherein the gene encoding said MSBP_21 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 198, and / or wherein the polypeptide encoded by said MSBP_21 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 197, or any of its orthologs or paralogs;aaa) a gene encoding an MSBP_62, wherein the gene encoding said MSBP_62 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 200, and / or wherein the polypeptide encoded by said MSBP_62 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as atleast 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 199, or any of its orthologs or paralogs;bbb) a gene encoding an MSBP_26, wherein the gene encoding said MSBP_26 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 202, and / or wherein the polypeptide encoded by said MSBP_26 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 201, or any of its orthologs or paralogs;ccc) a gene encoding an MSBP_35, wherein the gene encoding said MSBP_35 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 204, and / or wherein the polypeptide encoded by said MSBP_35 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 203, or any of its orthologs or paralogs;ddd) a gene encoding an MSBP_17, wherein the gene encoding said MSBP_17 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 206, and / or wherein the polypeptide encoded by said MSBP_17 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 205, or any of its orthologs or paralogs; andeee) a gene encoding an MSBP_79, wherein the gene encoding said MSBP_79 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 208, and / or wherein the polypeptide encoded by said MSBP_79 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 207, or any of its orthologs or paralogs.

[0127] In some embodiments:a) the gene encoding said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 96, and / or wherein the polypeptide encoded by said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 95, or any of its orthologs or paralogs;b) the gene encoding said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity toSEQ ID NO: 98, and / or wherein the polypeptide encoded by said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 97, or any of its orthologs or paralogs; c) the gene encoding said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 100, and / or wherein the polypeptide encoded by said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 99, or any of its orthologs or paralogs; d) the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs;e) the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs;f) the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs;g) the gene encoding said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 108, and / or wherein the polypeptide encoded by said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 107, or any of its orthologs or paralogs;h) the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109, or any of its orthologs or paralogs;i) the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111, or any of its orthologs or paralogs;j) the gene encoding said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 114, and / or wherein the polypeptide encoded by said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 113, or any of its orthologs or paralogs;k) the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115, or any of its orthologs or paralogs;l) the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs;m) the gene encoding said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 120, and / or wherein the polypeptide encoded by said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 119, or any of its orthologs or paralogs;n) the gene encoding said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 121, or any of its orthologs or paralogs;o) the gene encoding said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12_GS_YALI has at least70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 123, or any of its orthologs or paralogs; p) the gene encoding said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 126, and / or wherein the polypeptide encoded by said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 125, or any of its orthologs or paralogs; q) the gene encoding said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 128, and / or wherein the polypeptide encoded by said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 127, or any of its orthologs or paralogs;r) the gene encoding said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 130, and / or wherein the polypeptide encoded by said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 129, or any of its orthologs or paralogs;s) the gene encoding said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 132, and / or wherein the polypeptide encoded by said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 131, or any of its orthologs or paralogs;t) the gene encoding said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 134, and / or wherein the polypeptide encoded by said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, or any of its orthologs or paralogs;u) the gene encoding said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 136, and / or wherein the polypeptide encoded by said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least100% identity to any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, and SEQ ID NO: 314, or any of its orthologs or paralogs;v) the gene encoding said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 138, and / or wherein the polypeptide encoded by said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 137, SEQ ID NO: 319, SEQ ID NO: 320, SEQ ID NO: 321, or any of its orthologs or paralogs;w) the gene encoding said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 140, and / or wherein the polypeptide encoded by said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 139, or any of its orthologs or paralogs;x) the gene encoding said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 142, and / or wherein the polypeptide encoded by said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 141, or any of its orthologs or paralogs;y) the gene encoding said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 144, and / or wherein the polypeptide encoded by said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 143, or any of its orthologs or paralogs;z) the gene encoding said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 146, and / or wherein the polypeptide encoded by said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 145, or any of its orthologs or paralogs;aa) the gene encoding said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 148, and / or wherein the polypeptide encoded by said AtMSBP1 has at least 70%, such as atleast 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 147, or any of its orthologs or paralogs;bb) the gene encoding said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 150, and / or wherein the polypeptide encoded by said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 149, or any of its orthologs or paralogs;cc) the gene encoding said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 152, and / or wherein the polypeptide encoded by said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 151, or any of its orthologs or paralogs;dd) the gene encoding said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 154, and / or wherein the polypeptide encoded by said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 153, SEQ ID NO: 326, SEQ ID NO: 327, SEQ ID NO: 328, and SEQ ID NO: 329, or any of its orthologs or paralogs;ee) the gene encoding said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 156, and / or wherein the polypeptide encoded by said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 155, or any of its orthologs or paralogs;ff) the gene encoding said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 158, and / or wherein the polypeptide encoded by said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 157, or any of its orthologs or paralogs;gg) the gene encoding said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 160, and / or wherein the polypeptide encoded by said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 159, or any of its orthologs or paralogs;hh) the gene encoding said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 162, and / or wherein the polypeptide encoded by said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 161, or any of its orthologs or paralogs;ii) the gene encoding said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 164, and / or wherein the polypeptide encoded by said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 163, or any of its orthologs or paralogs;jj) the gene encoding said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 166, and / or wherein the polypeptide encoded by said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 165, or any of its orthologs or paralogs;kk) the gene encoding said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 168, and / or wherein the polypeptide encoded by said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 167, SEQ ID NO: 315, SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, or any of its orthologs or paralogs;II) the gene encoding said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 170, and / or wherein the polypeptide encoded by said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 169, SEQ ID NO: 322, SEQ ID NO: 323, or any of its orthologs or paralogs;mm) the gene encoding said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 172, and / or wherein the polypeptide encoded by said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 171, SEQ ID NO: 330, SEQ ID NO: 331, SEQ ID NO: 332, or any of its orthologs or paralogs;nn) the gene encoding said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 174, and / or wherein the polypeptide encoded by said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 173, or any of its orthologs or paralogs;oo) the gene encoding said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 176, and / or wherein the polypeptide encoded by said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 175, or any of its orthologs or paralogs;pp) the gene encoding said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 178, and / or wherein the polypeptide encoded by said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 177, or any of its orthologs or paralogs;qq) the gene encoding said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 180, and / or wherein the polypeptide encoded by said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 179, SEQ ID NO: 324, SEQ ID NO: 325, or any of its orthologs or paralogs;rr) the gene encoding said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 182, and / or wherein the polypeptide encoded by said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 181, or any of its orthologs or paralogs;ss) the gene encoding said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 184, and / or wherein the polypeptide encoded by said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 183, or any of its orthologs or paralogs;tt) the gene encoding said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 186, and / or wherein the polypeptide encoded by said HSP12 has at least 70%, such as at least 75%,such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 185, or any of its orthologs or paralogs;uu) the gene encoding said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 188, and / or wherein the polypeptide encoded by said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 187, or any of its orthologs or paralogs;vv) the gene encoding said MSBP_40 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 190, and / or wherein the polypeptide encoded by said MSBP_40 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 189, or any of its orthologs or paralogs;ww) the gene encoding said MSBP_56 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 192, and / or wherein the polypeptide encoded by said MSBP_56 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 191, or any of its orthologs or paralogs;xx) the gene encoding said MSBP_22 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 194, and / or wherein the polypeptide encoded by said MSBP_22 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 193, or any of its orthologs or paralogs;yy) the gene encoding said DAP1_9 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 196, and / or wherein the polypeptide encoded by said DAP1_9 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 195, or any of its orthologs or paralogs;zz) the gene encoding said MSBP_21 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 198, and / or wherein the polypeptide encoded by said MSBP_21 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 197, or any of its orthologs or paralogs;aaa) the gene encoding said MSBP_62 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 200, and / or wherein the polypeptide encoded by said MSBP_62 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 199, or any of its orthologs or paralogs;bbb) the gene encoding said MSBP_26 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 202, and / or wherein the polypeptide encoded by said MSBP_26 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 201, or any of its orthologs or paralogs;ccc) the gene encoding said MSBP_35 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 204, and / or wherein the polypeptide encoded by said MSBP_35 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 203, or any of its orthologs or paralogs;ddd) the gene encoding said MSBP_17 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 206, and / or wherein the polypeptide encoded by said MSBP_17 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 205, or any of its orthologs or paralogs; and / oreee) the gene encoding said MSBP_79 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 208, and / or wherein the polypeptide encoded by said MSBP_79 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 207, or any of its orthologs or paralogs.

[0128] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes selected from the group consisting of:a) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs;b) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs;c) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 107, or any of its orthologs or paralogs;d) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115, or any of its orthologs or paralogs; ande) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs.

[0129] In some embodiments, the host cell has been genetically modified to express one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding an RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22 or SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21 or SEQ ID NO: 121, or any of its orthologs or paralogs;b) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, suchas at least 100% identity to SEQ ID NO: 69 or SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54 or SEQ ID NO: 123, or any of its orthologs or paralogs;h) a gene encoding an ACC1 mutant, wherein the gene encoding said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71, and / or wherein the polypeptide encoded by said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 56, or any of its orthologs or paralogs;i) a gene encoding an McELO, wherein the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs; andj) optionally a gene encoding an ScOLE1, wherein the gene encoding said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 120, and / or wherein the polypeptide encoded by said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 119, or any of its orthologs or paralogs.

[0130] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding a MaD12D_2, wherein the gene encoding said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 108, and / or wherein the polypeptide encoded by said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 107;b) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109;c) a gene encoding a MaD6Elo_2, wherein the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111; andd) a gene encoding a MaD5D_2, wherein the gene encoding said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 114, and / or wherein the polypeptide encoded by said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 113.

[0131] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103;b) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105;c) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109;d) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115; ande) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, suchas at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117.

[0132] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs; b) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs;c) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109, or any of its orthologs or paralogs;d) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115, or any of its orthologs or paralogs;e) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs;f) a gene encoding an RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21, or any of its orthologs or paralogs;g) a gene encoding an McELO, wherein the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs;h) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 69 or SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54 or SEQ ID NO: 123, or any of its orthologs or paralogs; andi) a gene encoding an ACC1 mutant, wherein the gene encoding said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71; and / or wherein the polypeptide encoded by said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 56, or any of its orthologs or paralogs.

[0133] In some embodiments, the host cell further comprises a gene encoding an ACC1 mutant.

[0134] In some embodiments, the gene encoding the ACC1 mutant has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polynucleotide of SEQ ID NO: 71, such as wherein the gene comprises or consists of SEQ ID NO: 71; and / or wherein the ACC1 mutant has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polypeptide of SEQ ID NO: 56.

[0135] In some embodiments, the host cell is genetically modified by expressing an optionally heterologous gene encoding an ACC1 mutant, wherein the gene encoding said ACC1 mutant has atleast 70% identity to SEQ ID NO: 71 and / or wherein the polypeptide encoded by said ACC1 mutant has at least 70% identity to SEQ ID NO: 56.

[0136] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes encoding one or more copies of RnCOX2, such as two copies of RnCOX2, wherein the one or more genes encoding said one or more copies of RnCOX2 has at least 60% identity to SEQ ID NO: 22 or SEQ ID NO: 122, and / or wherein the polypeptide(s) encoded by said one or more RnCOX2 has at least 60% identity to SEQ ID NO: 21 or SEQ ID NO: 121.

[0137] In some embodiments, the host cell is genetically modified to express genes encoding two copies of RnCOX2, such as encoding a copy of RnCOX2 having at least 60% identity to SEQ ID NO: 21 and a copy of RnCOX2_GS_YALI having at least 60% identity to SEQ ID NO: 121.

[0138] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes encoding one or more copies of PGF2_12, such as two copies of PGF2_12, wherein the one or more genes encoding said one or more copies of PGF2_12 has at least 60% identity to SEQ ID NO: 69 or SEQ ID NO: 124, and / or wherein the polypeptide(s) encoded by said one or more PGF2_12 has at least 60% identity to SEQ ID NO: 54 or SEQ ID NO: 123.

[0139] In some embodiments, the host cell is genetically modified to express genes encoding two copies of PGF2_12, such as encoding a copy of PGF2_12 having at least 60% identity to SEQ ID NO: 54 and a copy of PGF2_12_GS_YALI having at least 60% identity to SEQ ID NO: 123.

[0140] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding a RnCOX2_GS_YALI, wherein the gene encoding said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 121; andb) a gene encoding a HsPGES-1_GS_YALI, wherein the gene encoding said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 126, and / or wherein the polypeptide encoded by said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 125.

[0141] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:a) a gene encoding a RnCOX2_GS_YALI, wherein the gene encoding said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 121; andb) a gene encoding a PGF2_12_GS_YALI, wherein the gene encoding said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 123.

[0142] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding a D6D_YALI, wherein the gene encoding said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 128, and / or wherein the polypeptide encoded by said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 127;b) a gene encoding a D6Elo_YALI, wherein the gene encoding said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 130, and / or wherein the polypeptide encoded by said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 129; andc) a gene encoding a D5D_YALI, wherein the gene encoding said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 132, and / or wherein the polypeptide encoded by said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 131.

[0143] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6Dhas at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103;b) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105;c) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115;d) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117;e) a gene encoding a RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21;f) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 69, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54;g) a gene encoding an ACC1_S659A_S1157A, wherein the gene encoding said ACC1_S659A_S1157A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71, and / or wherein the polypeptide encoded by said ACC1_S659A_S1157A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71; andh) a gene encoding a ScOLE1, wherein the gene encoding said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 120, and / or wherein the polypeptide encoded by said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 119.

[0144] In some embodiments, the host cell has been genetically modified to produce one or more prostaglandins from a carbon source, such as wherein the carbon source is glucose.

[0145] In some embodiments, the host cell has been genetically modified to produce arachidonic acid (ARA) and / or dihomo-gamma-linolenic acid (DGLA).

[0146] In some embodiments, the host cell has been genetically modified to produce prostaglandin Hl (PGH1) from dihomo-gamma-linolenic acid (DGLA), optionally by expressing COXI and / or COX2.

[0147] In some embodiments, the host cell has been genetically modified to express one or more extra copies of one or more genes as defined herein, and / or overexpress one or more of said genes.

[0148] In some embodiments, the host cell has been genetically modified to express a heterologous membrane-associated progesterone receptor (MAPR) family polypeptide, said polypeptide comprising a cytochrome b5-like heme / steroid-binding domain.

[0149] In some embodiments, the expressed MAPR family polypeptide further comprises:(i) a single-pass transmembrane segment;(ii) a cytosolic MAPR / PGRMC-like cytochrome b5-fold structured for heme and / or steroid binding; and(iii) a polypeptide sequence selected from the group consisting of:(a) a polypeptide having at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to any one of SEQ ID NO: 189 (MSBP_40), SEQ ID NO: 191 (MSBP_56), SEQ ID NO: 193 (MSBP_22), SEQ ID NO: 197 (MSBP_21), SEQ ID NO: 199 (MSBP_62), SEQ ID NO: 201 (MSBP_26), SEQ ID NO: 203 (MSBP_35), SEQ ID NO: 205 (MSBP_17), or SEQ ID NO: 207 (MSBP_79), and exhibiting membrane-associated progesterone receptor (MAPR) activity;(b) a polypeptide having at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to SEQ ID NO: 195 (DAP1_9), and exhibiting membrane-associated progesterone receptor (MAPR) activity; and(c) a variant polypeptide of any of (a) or (b) having at least 50%, such as at least 60%, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to the respective SEQ ID NO and exhibiting membrane-associated progesterone receptor (MAPR) activity.

[0150] In some embodiments, the host cell has been genetically modified to introduce one or more heterologous genes encoding a polypeptide having enzymatic activity in a prostaglandin biosynthesis pathway, and / or to increase the expression of one or more endogenous genes encoding a polypeptide having enzymatic activity in a prostaglandin biosynthesis pathway.

[0151] In some embodiments, the gene encodes an oxidoreductase polypeptide selected from the group consisting of:(i) a polypeptide comprising the amino acid sequence of SEQ ID NO: 135; and(ii) a variant polypeptide, such as a paralog or ortholog thereof, having at least 50%, such as at least 60%, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to SEQ ID NO: 135 and retaining protein disulfide isomerase activity.Auxiliary genes

[0152] The present disclosure further provides means for enhancing pathway performance via auxiliary polypeptides encoded by auxiliary genes.

[0153] The present disclosure recognizes that the core pathway enzymes may be supported by expressing or overexpressing specific "helper" or "auxiliary" polypeptides as set out herein.

[0154] As demonstrated in Example 7, it was surprisingly discovered that the overall production of prostaglandins can be systematically and significantly improved by expressing or overexpressing auxiliary polypeptides that support the core biosynthetic pathway. These auxiliary genes can be categorized into distinct functional groups based on the specific cellular bottleneck they resolve. In certain embodiments, the host cell is genetically modified to express or overexpress one or more auxiliary genes selected from one or more of these functional groups.

[0155] In some embodiments, the auxiliary genes are selected from a protein folding and degradation pathway group. Without wishing to be bound by theory, this group addresses the challenge of correctly folding and maintaining the stability of complex heterologous enzymes, such as cyclooxygenases, within the endoplasmic reticulum. This group comprises genes encoding polypeptides such as an endoplasmic reticulum (ER) chaperone (e.g., KAR2), a protein disulfide isomerase (e.g., PDI1), and a peptidyl-prolyl cis-trans isomerase (e.g., CPR5).

[0156] In some embodiments, the auxiliary genes are selected from an oxidative stress response group. Without wishing to be bound by theory, this group protects the prostaglandin pathway enzymes and their sensitive fatty acid intermediates from oxidative damage. This group comprises genes encoding polypeptides such as a catalase (e.g., CTT1 or CTA1), a glutathione peroxidase (e.g., GPX2), and a glucose-6-phosphate dehydrogenase (e.g., ZWF1). It was further discovered thattargeting these protective enzymes to the site of the pathway, for example by expressing a catalase fused with an ER-directing signal sequence, provides a particularly effective strategy for increasing production.

[0157] In some embodiments, the auxiliary genes are selected from a heme oxidoreductase and electron transfer group. Without wishing to be bound by theory, this group enhances the function of critical cytochrome P450 enzymes within the pathway by ensuring an efficient supply of cofactors and electrons. This group comprises genes encoding polypeptides such as a membrane steroid-binding protein (MSBP), a NADP-cytochrome P450 reductase (e.g., NCP1), and a phospholipase A2. It was found that combining these strategies, for instance by modifying the host cell with genes from two or more of these functional groups, can provide synergistic improvements to prostaglandin production.

[0158] In some embodiments, the host cell has been genetically modified to express and / or overexpress one or more auxiliary genes, such as auxiliary genes capable of increasing production of one or more prostaglandins and / or intermediates in a biosynthetic prostaglandin pathway.

[0159] In some embodiments, the host cell has been genetically modified by one or more modifications independently selected from the group consisting of:a) expressing one or more heterologous auxiliary genes; andb) overexpressing one or more endogenous auxiliary genes;wherein said auxiliary genes are capable of increasing production of one or more prostaglandins or intermediates in a prostaglandin biosynthetic pathway.

[0160] In some embodiments, the one or more genes encodes an oxidoreductase, such as an ER-luminal protein disulfide isomerase (PDI), for example encoding a PDI1 or PDIA1, a paralog or ortholog thereof.

[0161] In some embodiments, the host cell has been genetically modified to express a gene encoding an endoplasmic reticulum (ER) chaperone of the HSP70 family comprising an ATP-binding domain.

[0162] In some embodiments, the ER chaperone is selected from the group consisting of:(i) a polypeptide comprising the amino acid sequence of SEQ ID NO: 133; and(ii) a variant polypeptide, such as a paralog or ortholog thereof, having at least 50%, such as at least 60%, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to SEQ ID NO: 133 and retaining endoplasmic reticulum chaperone activity.

[0163] In some embodiments, the gene encodes a KAR2 having at least 60% identity to SEQ ID NO: 134, or any of its orthologs or paralogs.

[0164] In some embodiments, the host cell is genetically modified by a) expressing one or more heterologous auxiliary genes, and / or b) overexpressing one or more endogenous auxiliary genes, wherein said gene(s) is / are independently selected from the group consisting of:a) a gene encoding an ATPase involved in protein import into the ER and acting as a chaperone to mediate protein folding (KAR2), or any of its orthologs or paralogs;b) a gene encoding a Membrane steroid-binding protein (MSBP);c) a gene encoding a NADP-cytochrome P450 reductase associated with Ergllp (NCP1), or any of its orthologs or paralogs;d) a gene encoding a protein disulfide isomerase (PDI) of the ER lumen with multifunctional oxidoreductase activity;e) a gene encoding a cytosolic or peroxisomal catalase (CT) which acts on hydrogen peroxide to degrade it;g) a gene encoding a nuclear RNA-binding protein from Arabidopsis thaliana (AtGRP7), or any of its orthologs or paralogs;h) a gene encoding Peptidyl-prolyl cis-trans isomerase located in the ER (CPR5), or any of its orthologs or paralogs;i) a gene encoding Integral ER membrane protein with type-III transmembrane domain (ICE2), , or any of its orthologs or paralogs;j) a gene encoding a UDP-glucose pyrophosphorylase (UGPase); catalysing the reversible formation of UDP-GIc from glucose 1-phosphate and UTP;k) a gene encoding Glucose-6-phosphate dehydrogenase (G6PD) (ZWF1), or any of its orthologs or paralogs;l) a gene encoding a cytochrome P450 reductase (CPR) acting with P450 enzymes to transfer electrons from cofactors;m) a gene encoding a Protein involved in homologous recombination; attenuating resection of DNA double-strand break ends (RAD52), or any of its orthologs or paralogs;n) a gene encoding Phospholipid hydroperoxide glutathione peroxidase (GPX2), or any of its orthologs or paralogs;o) a gene encoding a 3'-5' exonuclease specific for poly-A RNAs;p) a gene encoding a transcription factor involved in derepression of phospholipid biosynthetic genes;q) a gene encoding a Component of the cleavage and polyadenylation factor I (CF I);r) a gene encoding RNA and export factor binding proteins involed in export of polyA;s) a gene encoding Phospholipase A2, group IIA type acting to hydrolyze phospholipids to free fatty acids;t) a gene encoding a Transcription factor involved in regulating multidrug resistance and the oxidative stress response (STB5), or any of its orthologs or paralogs;u) a gene encoding a modified Trimeric heat shock transcription factor (HSF1_R206S), or any of its orthologs or paralogs;v) a gene encoding alcohol dehydrogenase (ADH) converting acetaldehyde to ethanol;x) a gene encoding a Mitochondrial NADH kinase; acting to phosphorylate NADH during oxidative stress (POS5);y) a gene encoding a Bifunctional alcohol dehydrogenase and formaldehyde dehydrogenase involved in detoxification of formaldehyde;z) a gene encoding a Transcription factor involved in phospholipid synthesis (INO4), or any of its orthologs or paralogs;aa) a gene encoding a heat shock protein (HSP12), a plasma membrane protein involved in maintaining membrane organization, or any of its orthologs or paralogs;bb) a gene encoding a Membrane-bound peptidyl-prolyl cis-trans isomerase (PPIase ), and cc) a gene encoding a Lanosterol 14-alpha-demethylase (ERG11) catalyzes C-14 demethylation of lanosterol to form 4,4"-dimethyl cholesta-8,14,24-triene-3-beta-ol;dd) a gene encoding a Cytosolic copper-zinc superoxide dismutase / sulfide oxidase (sodl) acting to detoxify superoxide and hydrogen sulfide; andee) a gene encoding an Aminolevulinate dehydratase (HEM2) converting 5-aminolevulinate to porphobilinogen.

[0165] In some embodiments, the host cell is genetically modified by a) expressing one or more heterologous auxiliary genes, and / or b) overexpressing one or more endogenous auxiliary genes, wherein said gene(s) is / are independently selected from the group consisting of:a) a gene encoding KAR2, wherein the gene encoding said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 134, and / or wherein the polypeptide encoded by said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, or any of its orthologs or paralogs;b) a gene encoding AtMSBP1, wherein the gene encoding said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 148, and / or wherein the polypeptide encoded by said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 147, or any of its orthologs or paralogs;c) a gene encoding NCP1, wherein the gene encoding said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 146, and / or wherein the polypeptide encoded by said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 145, or any of its orthologs or paralogs; d) a gene encoding PDI1, wherein the gene encoding said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 136, and / or wherein the polypeptide encoded by said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, SEQ ID NO: 314, or any of its orthologs or paralogs;e) a gene encoding CTT1_prepro, wherein the gene encoding said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 138, and / or wherein the polypeptide encoded by said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 137, SEQ ID NO: 319, SEQ ID NO: 320, SEQ ID NO: 321, or any of its orthologs or paralogs;f) a gene encoding CTA1_prepro, wherein the gene encoding said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 140, and / or wherein the polypeptide encoded by said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 139, or any of its orthologs or paralogs;g) a gene encoding AtGRP7, wherein the gene encoding said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 150, and / or wherein the polypeptide encoded by saidAtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 149, or any of its orthologs or paralogs;h) a gene encoding CPR5, wherein the gene encoding said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 142, and / or wherein the polypeptide encoded by said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 141, or any of its orthologs or paralogs; i) a gene encoding ICE2, wherein the gene encoding said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 144, and / or wherein the polypeptide encoded by said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 143, or any of its orthologs or paralogs; j) a gene encoding UGP1, wherein the gene encoding said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 152, and / or wherein the polypeptide encoded by said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 151, or any of its orthologs or paralogs; k) a gene encoding ZWF1, wherein the gene encoding said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 154, and / or wherein the polypeptide encoded by said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 153, SEQ ID NO: 326, SEQ ID NO: 327, SEQ ID NO: 328, SEQ ID NO: 329, or any of its orthologs or paralogs;l) a gene encoding HaCPR5hom_7, wherein the gene encoding said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 156, and / or wherein the polypeptide encoded by said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 155, or any of its orthologs or paralogs;m) a gene encoding RAD52, wherein the gene encoding said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 158, and / or wherein the polypeptide encoded by said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%,such as at least 99%, such as at least 100% identity to SEQ ID NO: 157, or any of its orthologs or paralogs;n) a gene encoding GPX2, wherein the gene encoding said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 160, and / or wherein the polypeptide encoded by said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 159, or any of its orthologs or paralogs; o) a gene encoding NGL3, wherein the gene encoding said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 162, and / or wherein the polypeptide encoded by said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 161, or any of its orthologs or paralogs; p) a gene encoding INO2_L119A, wherein the gene encoding said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 164, and / or wherein the polypeptide encoded by said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 163, or any of its orthologs or paralogs;q) a gene encoding RNA15, wherein the gene encoding said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 166, and / or wherein the polypeptide encoded by said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 165, or any of its orthologs or paralogs;r) a gene encoding YRA2, wherein the gene encoding said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 168, and / or wherein the polypeptide encoded by said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 167, SEQ ID NO: 315, SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, or any of its orthologs or paralogs;s) a gene encoding RnPA2GA, wherein the gene encoding said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 170, and / or wherein the polypeptide encoded by said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as atleast 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 169, SEQ ID NO: 322, SEQ ID NO: 323, or any of its orthologs or paralogs;t) a gene encoding STB5, wherein the gene encoding said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 172, and / or wherein the polypeptide encoded by said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 171, SEQ ID NO: 330, SEQ ID NO: 331, SEQ ID NO: 332, or any of its orthologs or paralogs;u) a gene encoding HSF1_R206S, wherein the gene encoding said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 174, and / or wherein the polypeptide encoded by said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 173, or any of its orthologs or paralogs;v) a gene encoding ADH1, wherein the gene encoding said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 176, and / or wherein the polypeptide encoded by said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 175, or any of its orthologs or paralogs; w) a gene encoding HvCPR5hom_6, wherein the gene encoding said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 178, and / or wherein the polypeptide encoded by said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 177, or any of its orthologs or paralogs;x) a gene encoding POS5, wherein the gene encoding said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 180, and / or wherein the polypeptide encoded by said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 179, SEQ ID NO: 324, SEQ ID NO: 325, or any of its orthologs or paralogs;y) a gene encoding SFA1, wherein the gene encoding said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 182, and / or wherein the polypeptide encoded by said SFA1 has atleast 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 181, or any of its orthologs or paralogs; z) a gene encoding INO4, wherein the gene encoding said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 184, and / or wherein the polypeptide encoded by said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 183, or any of its orthologs or paralogs; aa) a gene encoding HSP12, wherein the gene encoding said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 186, and / or wherein the polypeptide encoded by said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 185, or any of its orthologs or paralogs;bb) a gene encoding FPR2, wherein the gene encoding said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 188, and / or wherein the polypeptide encoded by said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 187, or any of its orthologs or paralogs; cc) a gene encoding ERG11, wherein the gene encoding said ERG11 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 262, and / or wherein the polypeptide encoded by said ERG11 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 261, or any of its orthologs or paralogs;dd) a gene encoding SOD1, wherein the gene encoding said SOD1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 264, and / or wherein the polypeptide encoded by said SOD1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 263, or any of its orthologs or paralogs; andee) a gene encoding HEM2, wherein the gene encoding said HEM2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 266, and / or wherein the polypeptide encoded by said HEM2 has atleast 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 265, or any of its orthologs or paralogs.

[0166] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding KAR2, wherein the gene encoding said KAR2 has at least 70% identity to SEQ ID NO: 134 and / or wherein the polypeptide encoded by said KAR2 has at least 70% identity to any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, for example SEQ ID NO: 133.

[0167] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding AtMSBP1, wherein the gene encoding said AtMSBP1 has at least 70% identity to SEQ ID NO: 148 and / or wherein the polypeptide encoded by said AtMSBP1 has at least 70% identity to SEQ ID NO: 147.

[0168] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding NCP1, wherein the gene encoding said NCP1 has at least 70% identity to SEQ ID NO: 146 and / or wherein the polypeptide encoded by said NCP1 has at least 70% identity to SEQ ID NO: 145.

[0169] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding PDI1, wherein the gene encoding said PDI1 has at least 70% identity to SEQ ID NO: 136 and / or wherein the polypeptide encoded by said PDI1 has at least 70% identity to any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, SEQ ID NO: 314, for example SEQ ID NO: 135.

[0170] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding CTT1_prepro, wherein the gene encoding said CTT1_prepro has at least 70% identity to SEQ ID NO: 138 and / or wherein the polypeptide encoded by said CTT1_prepro has at least 70% identity to any of SEQ ID NO: 137, SEQ ID NO: 319, SEQ ID NO: 320, SEQ ID NO: 321, for example SEQ ID NO: 137.

[0171] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding CTA1_prepro, wherein the gene encoding said CTA1_prepro has at least 70% identity to SEQ ID NO: 140 and / or wherein the polypeptide encoded by said CTA1_prepro has at least 70% identity to SEQ ID NO: 139.

[0172] In some embodiments, the host cell is genetically modified by expressing a heterologous gene encoding AtGRP7, wherein the gene encoding said AtGRP7 has at least 70% identity to SEQ ID NO: 150 and / or wherein the polypeptide encoded by said AtGRP7 has at least 70% identity to SEQ ID NO: 149.

[0173] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding CPR5, wherein the gene encoding said CPR5 has at least 70% identity to SEQ ID NO: 142 and / or wherein the polypeptide encoded by said CPR5 has at least 70% identity to SEQ ID NO: 141.

[0174] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding ICE2, wherein the gene encoding said ICE2 has at least 70% identity to SEQ ID NO: 144 and / or wherein the polypeptide encoded by said ICE2 has at least 70% identity to SEQ ID NO: 143.

[0175] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding UGP1, wherein the gene encoding said UGP1 has at least 70% identity to SEQ ID NO: 152 and / or wherein the polypeptide encoded by said UGP1 has at least 70% identity to SEQ ID NO: 151.

[0176] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding ZWF1, wherein the gene encoding said ZWF1 has at least 70% identity to SEQ ID NO: 154 and / or wherein the polypeptide encoded by said ZWF1 has at least 70% identity to any of SEQ ID NO: 153, SEQ ID NO: 326, SEQ ID NO: 327, SEQ ID NO: 328, SEQ ID NO: 329, for example SEQ ID NO: 153.

[0177] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding HaCPR5hom_7, wherein the gene encoding said HaCPR5hom_7 has at least 70% identity to SEQ ID NO: 156 and / or wherein the polypeptide encoded by said HaCPR5hom_7 has at least 70% identity to SEQ ID NO: 155.

[0178] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding RAD52, wherein the gene encoding said RAD52 has at least 70% identity to SEQ ID NO: 158 and / or wherein the polypeptide encoded by said RAD52 has at least 70% identity to SEQ ID NO: 157.

[0179] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding GPX2, wherein the gene encoding said GPX2 has at least 70% identity to SEQ ID NO: 160 and / or wherein the polypeptide encoded by said GPX2 has at least 70% identity to SEQ ID NO: 159.

[0180] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding NGL3, wherein the gene encoding said NGL3 has at least 70% identity to SEQ ID NO: 162 and / or wherein the polypeptide encoded by said NGL3 has at least 70% identity to SEQ ID NO: 161.

[0181] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding INO2_L119A, wherein the gene encoding said INO2_L119A has at least 70% identity to SEQ ID NO: 164 and / or wherein the polypeptide encoded by said INO2_L119A has at least 70% identity to SEQ ID NO: 163.

[0182] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding RNA15, wherein the gene encoding said RNA15 has at least 70% identity to SEQ ID NO: 166 and / or wherein the polypeptide encoded by said RNA15 has at least 70% identity to SEQ ID NO: 165.

[0183] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding YRA2, wherein the gene encoding said YRA2 has at least 70% identity to SEQ ID NO: 168 and / or wherein the polypeptide encoded by said YRA2 has at least 70% identity to any of SEQ ID NO: 167, SEQ ID NO: 315, SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, for example SEQ ID NO: 167.

[0184] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding RnPA2GA, wherein the gene encoding said RnPA2GA has at least 70% identity to SEQ ID NO: 170 and / or wherein the polypeptide encoded by said RnPA2GA has at least 70% identity to any of SEQ ID NO: 169, SEQ ID NO: 322, and SEQ ID NO: 323, for example SEQ ID NO: 169.

[0185] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding STB5, wherein the gene encoding said STB5 has at least 70% identity to SEQ ID NO: 172 and / or wherein the polypeptide encoded by said STB5 has at least 70% identity to any of SEQ ID NO: 171, SEQ ID NO: 330, SEQ ID NO: 331, and SEQ ID NO: 332, for example SEQ ID NO: 171.

[0186] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding HSF1_R206S, wherein the gene encoding said HSF1_R206S has at least 70% identity to SEQ ID NO: 174 and / or wherein the polypeptide encoded by said HSF1_R206S has at least 70% identity to SEQ ID NO: 173.

[0187] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding ADH1, wherein the gene encoding said ADH1has at least 70% identity to SEQ ID NO: 176 and / or wherein the polypeptide encoded by said ADH1 has at least 70% identity to SEQ ID NO: 175.

[0188] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding HvCPR5hom_6, wherein the gene encoding said HvCPR5hom_6 has at least 70% identity to SEQ ID NO: 178 and / or wherein the polypeptide encoded by said HvCPR5hom_6 has at least 70% identity to SEQ ID NO: 177.

[0189] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding POS5, wherein the gene encoding said POS5 has at least 70% identity to SEQ ID NO: 180 and / or wherein the polypeptide encoded by said POS5 has at least 70% identity to any of SEQ ID NO: 179, SEQ ID NO: 324, and SEQ ID NO: 325, for example SEQ ID NO: 179.

[0190] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding SFA1, wherein the gene encoding said SFA1 has at least 70% identity to SEQ ID NO: 182 and / or wherein the polypeptide encoded by said SFA1 has at least 70% identity to SEQ ID NO: 181.

[0191] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding INO4, wherein the gene encoding said INO4 has at least 70% identity to SEQ ID NO: 184 and / or wherein the polypeptide encoded by said INO4 has at least 70% identity to SEQ ID NO: 183.

[0192] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding HSP12, wherein the gene encoding said HSP12 has at least 70% identity to SEQ ID NO: 186 and / or wherein the polypeptide encoded by said HSP12 has at least 70% identity to SEQ ID NO: 185.

[0193] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding FPR2, wherein the gene encoding said FPR2 has at least 70% identity to SEQ ID NO: 188 and / or wherein the polypeptide encoded by said FPR2 has at least 70% identity to SEQ ID NO: 187.

[0194] In some embodiments, the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding ScOLE1, wherein the gene encoding said ScOLE1 has at least 70% identity to SEQ ID NO: 120 and / or wherein the polypeptide encoded by said ScOLE1 has at least 70% identity to SEQ ID NO: 119.

[0195] In some embodiments, the host cell has been genetically modified to comprise a gene encoding a cytochrome b5 (CYB5) enzyme and / or a cytochrome b5 reductase.

[0196] In some embodiments, the gene encoding the cytochrome b5 enzyme and the gene encoding the cytochrome b5 reductase are heterologous to the host cell.

[0197] In some embodiments, the gene encoding the cytochrome b5 (CYB5) enzyme has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polynucleotide of SEQ ID NO: 100; and / or wherein the cytochrome b5 (CYB5) enzyme has at least 60%, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polypeptide of SEQ ID NO: 99.

[0198] In some embodiments, the gene encoding the cytochrome b5 reductase has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polynucleotide of SEQ ID NO: 98, such as wherein the gene comprises or consists of SEQ ID NO: 98; and / or wherein the cytochrome b5 reductase has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polypeptide of SEQ ID NO: 97.

[0199] In some embodiments, the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding a RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21;b) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 69, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54;c) a gene encoding an ACC1_S659A_S1157A, wherein the gene encoding said ACC1_S659A_S1157A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71, and / or wherein the polypeptide encoded by said ACC1_S659A_S1157A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71;d) a gene encoding a NCB5R_MORAP_GA, wherein the gene encoding said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 98, and / or wherein the polypeptide encoded by said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 97; ande) a gene encoding a CYB5_MORAP_GA, wherein the gene encoding said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 100, and / or wherein the polypeptide encoded by said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 99.

[0200] In some embodiments, the host cell is further genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding an RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21, or any of its orthologs or paralogs;b) a gene encoding an McELO, wherein the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs;c) a gene encoding an HsPGES1, wherein the gene encoding said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 126 or SEQ ID NO: 40, and / or wherein the polypeptide encoded by said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 125 or SEQ ID NO: 39, or any of its orthologs or paralogs;

[0201] In some embodiments, the host cell is further genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:a) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 69, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54, or any of its orthologs or paralogs; andb) a gene encoding an ACC1 mutant, wherein the gene encoding said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71, and / or wherein the polypeptide encoded by said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 56, or any of its orthologs or paralogs.

[0202] In some embodiments, the host cell is provided for producing prostaglandin El, wherein the host cell has been genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:a) a gene encoding a RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22 or SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21 or SEQ ID NO: 121, or any of its orthologs or paralogs;b) a gene encoding a HsPGES1, wherein the gene encoding said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 40, and / or wherein the polypeptide encoded by said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 39, or any of its orthologs or paralogs;c) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs;d) a gene encoding an RmD12D, wherein the gene encoding said aRmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said aRmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs; ande) a gene encoding a MaD6Elo_2, wherein the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111, or any of its orthologs or paralogs.

[0203] In some embodiments, the host cell is provided for producing prostaglandin E2, wherein the host cell has been genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:a) a gene encoding a RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22 or SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21 or SEQ ID NO: 121, or any of its orthologs or paralogs;b) a gene encoding a HsPGES1, wherein the gene encoding said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 40, and / or wherein the polypeptide encoded by said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 39, or any of its orthologs or paralogs;c) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs;d) a gene encoding an RmD12D, wherein the gene encoding said aRmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said aRmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs; ande) a gene encoding a MaD6Elo_2, wherein the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111, or any of its orthologs or paralogs, andf) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs

[0204] In some embodiments, the host cell has been genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of: a) a gene encoding an MmPGD, wherein the gene encoding said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 96, and / or wherein the polypeptide encoded by said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 95, or any of its orthologs or paralogs; andb) a gene encoding a RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22 or SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21 or SEQ ID NO: 121.

[0205] In some embodiments, the gene encoding a catalase is fused to a signal sequence that directs the polypeptide to the endoplasmic reticulum, thereby providing targeted protection from oxidativedamage within the ER.Gene knockout, disruption or attenuation

[0206] The present disclosure documents that native host cell enzymes, previously unrecognized as problematic, catalyze unwanted side-reactions and provides means to attenuate, disrupt, or delete the endogenous genes encoding these enzymes to significantly improve the specificity and / or yield of the target prostaglandin.

[0207] In some embodiments, the host cell has been genetically modified by attenuating, disrupting and / or deleting, for example deleting, one or more endogenous genes of the host cell.

[0208] In some embodiments, the attenuating, disrupting and / or deleting one or more endogenous genes of the host cell provides for reduced formation of byproducts and / or increased production of one or more prostaglandins.

[0209] In some embodiments, the one or more endogenous genes are selected from the group consisting of:a) gtt2;b) yprl;c) gre3;d) gcyl;e) gre2;f) ydr541c;g) gtt1;h) ecm4;i) adh6;j) aril;k) ycrl07w;l) adh7;m) aral;n) gpxl;o) gpx2;p) gpx3;q) ithl;r) ydll24w;s) yjl068c;t) prxl;u) tsa1;v) oye2;w) oye3;x) bdhl;y) bdh2;z) ccpl; andany paralogs, and any orthologs thereof.

[0210] In some embodiments, the one or more endogenous genes are selected from the group consisting of:a) a gene encoding a GTT2, wherein the gene encoding said GTT2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 210, and / or wherein the polypeptide encoded by said GTT2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 209, or any of its orthologs or paralogs;b) a gene encoding a YPR1, wherein the gene encoding said YPR1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 212, and / or wherein the polypeptide encoded by said YPR1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 211, or any of its orthologs or paralogs;c) a gene encoding a GRE3, wherein the gene encoding said GRE3 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 214, and / or wherein the polypeptide encoded by said GRE3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 213, or any of its orthologs or paralogs;d) a gene encoding a GCY1, wherein the gene encoding said GCY1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 216, and / or wherein the polypeptide encoded by said GCY1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 215, or any of its orthologs or paralogs;e) a gene encoding a GRE2, wherein the gene encoding said GRE2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 218, and / or wherein the polypeptide encoded by said GRE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 217, or any of its orthologs or paralogs;f) a gene encoding a YDR541C, wherein the gene encoding said YDR541C has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 220, and / or wherein the polypeptide encoded by said YDR541C has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 219, or any of its orthologs or paralogs;g) a gene encoding a GTT1, wherein the gene encoding said GTT1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 222, and / or wherein the polypeptide encoded by said GTT1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 221, or any of its orthologs or paralogs;h) a gene encoding an ECM4, wherein the gene encoding said ECM4 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 224, and / or wherein the polypeptide encoded by said ECM4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 223, or any of its orthologs or paralogs;i) a gene encoding an ADH6, wherein the gene encoding said ADH6 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 226, and / or wherein the polypeptide encoded by said ADH6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 225, or any of its orthologs or paralogs;j) a gene encoding an ARI1, wherein the gene encoding said ARI1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 228, and / or wherein the polypeptide encoded by said ARI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 227, or any of its orthologs or paralogs;k) a gene encoding a YCR107W, wherein the gene encoding said YCR107W has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 230, and / or wherein the polypeptide encoded by said YCR107W has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 229, or any of its orthologs or paralogs;l) a gene encoding an ADH7, wherein the gene encoding said ADH7 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 232, and / or wherein the polypeptide encoded by said ADH7 has at least 70%, such as at least75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 231, or any of its orthologs or paralogs;m) a gene encoding an ARA1, wherein the gene encoding said ARA1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 234, and / or wherein the polypeptide encoded by said ARA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 233, or any of its orthologs or paralogs;n) a gene encoding a GPX1, wherein the gene encoding said GPX1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 236, and / or wherein the polypeptide encoded by said GPX1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 235, or any of its orthologs or paralogs;o) a gene encoding a GPX2, wherein the gene encoding said GPX2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 238, and / or wherein the polypeptide encoded by said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 237, or any of its orthologs or paralogs;r) a gene encoding a YDL124W, wherein the gene encoding said YDL124W has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 244, and / or wherein the polypeptide encoded by said YDL124W has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 243, or any of its orthologs or paralogs;s) a gene encoding a YJL068C, wherein the gene encoding said YJL068C has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 246, and / or wherein the polypeptide encoded by said YJL068C has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 245, or any of its orthologs or paralogs;t) a gene encoding a PRX1, wherein the gene encoding said PRX1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 248, and / or wherein the polypeptide encoded by said PRX1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 247, or any of its orthologs or paralogs;u) a gene encoding a TSA1, wherein the gene encoding said TSA1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ IDNO: 250, and / or wherein the polypeptide encoded by said TSA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 249, or any of its orthologs or paralogs;v) a gene encoding an OYE2, wherein the gene encoding said OYE2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 252, and / or wherein the polypeptide encoded by said OYE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 251, or any of its orthologs or paralogs;w) a gene encoding an OYE3, wherein the gene encoding said OYE3 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 254, and / or wherein the polypeptide encoded by said OYE3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 253, or any of its orthologs or paralogs;x) a gene encoding a BDH1, wherein the gene encoding said BDH1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 256, and / or wherein the polypeptide encoded by said BDH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 255, or any of its orthologs or paralogs;y) a gene encoding a BDH2, wherein the gene encoding said BDH2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 258, and / or wherein the polypeptide encoded by said BDH2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 257, or any of its orthologs or paralogs; andz) a gene encoding a CCP1, wherein the gene encoding said CCP1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 260, and / or wherein the polypeptide encoded by said CCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 259, or any of its orthologs or paralogs.

[0211] In some embodiments, the one or more endogenous genes are selected from the group consisting of:a) GTT1;b) YJL068C;c) GRE2;d) ARI1;e) YDL124W;f) TSA1;g) OYE3; andany paralogs, and any orthologs thereof.

[0212] In some embodiments, the one or more endogenous genes are selected from the group consisting of:a) a gene encoding a GTT1, wherein the gene encoding said GTT1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 222, and / or wherein the polypeptide encoded by said GTT1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 221, or any of its orthologs or paralogs;b) a gene encoding a YJL068C, wherein the gene encoding said YJL068C has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 246, and / or wherein the polypeptide encoded by said YJL068C has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 245, or any of its orthologs or paralogs;c) a gene encoding a GRE2, wherein the gene encoding said GRE2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 218, and / or wherein the polypeptide encoded by said GRE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 217, or any of its orthologs or paralogs;d) a gene encoding an ARI1, wherein the gene encoding said ARI1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 228, and / or wherein the polypeptide encoded by said ARI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 227, or any of its orthologs or paralogs;e) a gene encoding a YDL124W, wherein the gene encoding said YDL124W has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 244, and / or wherein the polypeptide encoded by said YDL124W has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 243, or any of its orthologs or paralogs;f) a gene encoding a TSA1, wherein the gene encoding said TSA1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 250, and / or wherein the polypeptide encoded by said TSA1 has at least 70%, such as at least75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 249, or any of its orthologs or paralogs;g) a gene encoding an OYE3, wherein the gene encoding said OYE3 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 254, and / or wherein the polypeptide encoded by said OYE3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 253, or any of its orthologs or paralogs.

[0213] In some embodiments, the host cell is Saccharomyces cerevisiae, Yarrowia lipolytica, or Komagataella phaffii, for example Saccharomyces cerevisiae.

[0214] In some embodiments, the host cell is configured for producing prostaglandin E2, characterized in that the endogenous gene GTT1, a paralog or ortholog thereof, is attenuated or deleted.

[0215] In some embodiments, the host cell is a Komagataella phaffii host cell, and the endogenous gene GTT1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 268, and / or wherein the polypeptide encoded by said gene has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 267; orthe host cell is a Yarrowia lipolytica host cell, and the endogenous gene GTT1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to any one of SEQ ID NOs: 270, 272, 274, 276, or 278, and / or wherein the polypeptide encoded by said gene has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any one of SEQ ID NOs: 269, 271, 273, 275, or 277.

[0216] In some embodiments, the host cell is configured for producing prostaglandin F2a, characterized in that the endogenous gene TSA1, a paralog or ortholog thereof, is attenuated or deleted.

[0217] In some embodiments, the host cell is a Komagataella phaffii host cell, and the endogenous gene TSA1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 282, and / or wherein the polypeptide encoded by said gene has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 281; orthe host cell is a Yarrowia lipolytica host cell, and the endogenous gene TSA1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 280, and / or wherein the polypeptide encoded by said gene has at least 70%,such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ. ID NO: 279.Further modifications involving ACC1

[0218] In some embodiments, a genetically modified host cell is provided for the production of prostaglandins, wherein the host cell comprises one or more metabolic pathways for producing said prostaglandins, and wherein the host cell is modified to express a gene encoding a mutant acetyl-CoA carboxylase (ACC1) having enhanced catalytic activity, such as a gene encoding the ACC1 mutant disclosed herein, characterised in that the host cell is further modified by attenuating or deleting an endogenous gene selected from the group consisting of:a) a gene encoding a glutathione S-transferase (GTT1), thereby increasing the production specificity for prostaglandin E2 or D2; andb) a gene encoding a thioredoxin peroxidase (TSA1), thereby increasing the production of prostaglandin F2a.

[0219] In some embodiments, a genetically modified host cell is provided for the production of prostaglandins, wherein the host cell comprises one or more metabolic pathways for producing said prostaglandins, and wherein the host cell is modified to express a gene encoding a mutant acetyl-CoA carboxylase (ACC1) having enhanced catalytic activity, such as a gene encoding the ACC1 mutant as disclosed herein, characterised in that the host cell is further modified to express or overexpress one or more auxiliary genes selected from the group consisting of:a) a gene encoding an endoplasmic reticulum (ER) chaperone;b) a gene encoding a protein disulfide isomerase; andc) a gene encoding a phospholipase A2.Polynucleotide constructs and expression vectors

[0220] Also provided for herein are polynucleotide constructs harbouring one or more gene(s) encoding native or mutated 9-desaturase (D9D), delta 12-desaturase (D12D), delta 6-desaturase (D6D), delta 6-elongase (D6Elo), delta 5-desaturase (D5D), fatty acyl thioesterase I, NADPH-cytochrome P450 reductase (POR), prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2), prostaglandin D synthase (PGDS), prostacyclin synthase (PGIS), prostaglandin E2 synthase (PGES), prostaglandin F synthase (PGFS) and / or 9-keto-prostaglandin E synthasegenes operably linked to one or more control sequences, said polynucleotide constructs comprising mutations to delete, disrupt, and / or an attenuate the gene transcription or translation or the activity and / or function of the encoded genes. The control sequences direct the expression of the encoded one or more of 9-desaturase (D9D), delta 12-desaturase (D12D), delta 6-desaturase (D6D), delta 6-elongase (D6Elo), delta 5-desaturase (D5D), fatty acyl thioesterase I, NADPH-cytochrome P450 reductase (POR), prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2), prostaglandin D synthase (PGDS), prostacyclin synthase (PGIS), prostaglandin E2 synthase (PGES), prostaglandin F synthase (PGFS) and / or 9-keto-prostaglandin E synthasein the host cell harbouring the polynucleotide construct. Conditions for the expression should be compatible with the control sequences. The control sequence may be heterologous or native to the gene(s) encoding the 9-desaturase (D9D), delta 12-desaturase (D12D), delta 6-desaturase (D6D), delta 6-elongase (D6Elo), delta 5-desaturase (D5D), fatty acyl thioesterase I, NADPH-cytochrome P450 reductase (POR), prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2), prostaglandin D synthase (PGDS), prostacyclin synthase (PGIS), prostaglandin E2 synthase (PGES), prostaglandin F synthase (PGFS) and / or 9-keto-prostaglandin E synthase genes and / or to the host cell. In some embodiments, both the control sequence and the gene(s) encoding 9-desaturase (D9D), delta 12-desaturase (D12D), delta 6-desaturase (D6D), delta 6-elongase (D6Elo), delta 5-desaturase (D5D), fatty acyl thioesterase I, NADPH-cytochrome P450 reductase (POR), prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2), prostaglandin D synthase (PGDS), prostacyclin synthase (PGIS), prostaglandin E2 synthase (PGES), prostaglandin F synthase (PGFS) and / or 9-keto-prostaglandin E synthase are heterologous to the host cell and optionally also to each other. In one embodiment the polynucleotide construct is an expression vector, comprising the gene(s) encoding the 9-desaturase (D9D), delta 12-desaturase (D12D), delta 6-desaturase (D6D), delta 6-elongase (D6Elo), delta 5-desaturase (D5D), fatty acyl thioesterase I, NADPH-cytochrome P450 reductase (POR), prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2), prostaglandin D synthase (PGDS), prostacyclin synthase (PGIS), prostaglandin E2 synthase (PGES), prostaglandin F synthase (PGFS) and / or 9-keto-prostaglandin E synthase operably linked to the one or more control sequences.

[0221] Polynucleotides may be manipulated in a variety of ways to modify the expression of the 9-desaturase (D9D), delta 12-desaturase (D12D), delta 6-desaturase (D6D), delta 6-elongase (D6Elo), delta 5-desaturase (D5D), fatty acyl thioesterase I, NADPH-cytochrome P450 reductase (POR), prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2), prostaglandin D synthase (PGDS), prostacyclin synthase (PGIS), prostaglandin E2 synthase (PGES), prostaglandin F synthase (PGFS) and / or 9-keto-prostaglandin E synthase. Manipulation of the polynucleotide prior to its insertion into an expression vector may be desirable or necessary depending on the expression vector. The techniques for modifying polynucleotides utilizing recombinant DNA methods are well known in the art.

[0222] The control sequence may be a promoter, which is a polynucleotide that is recognized by ahost cell for expression of a polynucleotide. The promoter contains transcriptional control sequences that mediate the expression of the polypeptide. The promoter may be any polynucleotide that shows transcriptional activity in the host cell including mutant, truncated, and hybrid promoters, and may be obtained from genes encoding extracellular or intracellular polypeptides either homologous or heterologous to the host cell. The promoter may also be an inducible promoter. Selecting a suitable promoter for expression in yeast is well-known and is well understood by persons skilled in the art.

[0223] The control sequence may also be a transcription terminator, which is recognized by a host cell to terminate transcription. The terminator is operably linked to the 3'-terminus of the polynucleotide encoding the polypeptide. Any terminator that is functional in the host cell may be used. The control sequence may also be an mRNA stabilizer region downstream of a promoter and upstream of the coding sequence of a gene which increases the expression of the gene.

[0224] The control sequence may also be a leader, a non-translated region of an mRNA that is important for translation by the host cell. The leader is operably linked to the 5'-terminus of the polynucleotide encoding the polypeptide. Any leader that is functional in the host cell may be used.

[0225] The control sequence may also be a polyadenylation sequence; a sequence operably linked to the 3'-terminus of the polynucleotide and, when transcribed, is recognized by the host cell as a signal to add polyadenosine residues to transcribed mRNA. Any polyadenylation sequence that is functional in the host cell may be used.

[0226] It may also be desirable to add regulatory sequences that regulate the expression of the 9-desaturase (D9D), delta 12-desaturase (D12D), delta 6-desaturase (D6D), delta 6-elongase (D6Elo), delta 5-desaturase (D5D), fatty acyl thioesterase I, NADPH-cytochrome P450 reductase (POR), prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2), prostaglandin D synthase (PGDS), prostacyclin synthase (PGIS), prostaglandin E2 synthase (PGES), prostaglandin F synthase (PGFS) and / or 9-keto-prostaglandin E synthase genes relative to the growth of the host cell. Examples of regulatory systems are those that cause expression of the gene to be turned on or off in response to a chemical or physical stimulus, including the presence of a regulatory compound.

[0227] Various nucleotide sequences in addition to the polynucleotide construct disclosed herein may be joined together to produce a recombinant expression vector, which may include one or more convenient restriction sites to allow for insertion or substitution of the polynucleotide sequence encoding the 9-desaturase (D9D), delta 12-desaturase (D12D), delta 6-desaturase (D6D), delta 6-elongase (D6Elo), delta 5-desaturase (D5D), fatty acyl thioesterase I, NADPH-cytochrome P450 reductase (POR), prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2), prostaglandin D synthase (PGDS), prostacyclin synthase (PGIS), prostaglandin E2 synthase (PGES), prostaglandin F synthase (PGFS) and / or 9-keto-prostaglandin E synthase genes at such sites. Therecombinant expression vector may be any vector (e.g., a plasmid or virus or chromosomal) that can be conveniently subjected to recombinant DNA procedures and can bring about expression of the 9-desaturase (D9D), delta 12-desaturase (D12D), delta 6-desaturase (D6D), delta 6-elongase (D6Elo), delta 5-desaturase (D5D), fatty acyl thioesterase I, NADPH-cytochrome P450 reductase (POR), prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2), prostaglandin D synthase (PGDS), prostacyclin synthase (PGIS), prostaglandin E2 synthase (PGES), prostaglandin F synthase (PGFS) and / or 9-keto-prostaglandin E synthase. The choice of the vector will typically depend on the compatibility of the vector with the host cell into which the vector is to be introduced. The vector may be an autonomously replicating vector, i.e., a vector that exists as an extrachromosomal entity, the replication of which is independent of chromosomal replication, e.g., a plasmid (linear or closed circular plasmid), an extrachromosomal element, a mini-chromosome, or an artificial chromosome. The vector may contain any means for assuring self-replication. Alternatively, the vector may, when introduced into the host cell, integrate into the genome, and replicate together with the chromosome(s) into which it has been integrated. Furthermore, a single vector or plasmid or two or more vectors or plasmids that together contain the total DNA to be introduced into the genome of the host cell, or a transposon, may be used.

[0228] The vector may contain one or more selectable markers that permit easy selection of transformed, transfected, transduced, or the like cells. A selectable marker is a gene from which the product provides for biocide or viral resistance, resistance to heavy metals, prototrophy to auxotrophs, and the like.

[0229] The vector may further contain element(s) that permits integration of the vector into genome (being a vector in itself) of the host cell or permits autonomous replication of the vector in the cell independent of the genome. Alternatively, the vector may contain additional polynucleotides for directing integration by homologous recombination into the genome of the host cell at a precise location(s) in the chromosome(s). To increase the likelihood of integration at a precise location, the integrational elements should contain a sufficient number of nucleic acids, such as 100 to 10,000 base pairs, such as 400 to 10,000 base pairs, and such as 800 to 10,000 base pairs, which have a high degree of sequence identity to the corresponding target sequence to enhance the probability of homologous recombination. The integrational elements may be any sequence that is homologous with the target sequence in the genome of the host cell. Furthermore, the integrational elements may be nonencoding or encoding polynucleotides. On the other hand, the vector may be integrated into the genome of the host cell by non-homologous recombination.

[0230] For autonomous replication, the vector may further comprise an origin of replication enabling the vector to replicate autonomously in the host cell in question. The origin of replication may be anyplasmid replicator mediating autonomous replication that functions in a cell. The term "origin of replication" or "plasmid replicator" refers to a polynucleotide that enables a plasmid or vector to replicate in vivo.

[0231] As mentioned, supra, more than one copy of a gene encoding pathway elements for prostaglandin may be inserted into a host cell to increase the production of the prostaglandin. An increase in the gene copy number can be obtained by integrating one or more additional copies of a gene into the host cell genome or by including an amplifiable selectable marker gene with the gene so that cells containing amplified copies of the selectable marker gene - and thereby additional copies of the polynucleotide - can be selected by cultivating the cells in the presence of the appropriate selectable agent. The procedures used to ligate the elements described above to construct the recombinant expression vectors of the present disclosure are well known to one skilled in the art (see, e.g., Sambrook et al., 1989, supra).In a separate embodiment, the host cell comprises the polynucleotide constructs and / or vectors as disclosed herein.

[0232] In one embodiment the host cell is capable of producing prostaglandins via arachidonic acid (ARA) from a carbon feedstock and comprises one or more pathways expressing one or more heterologous genes selected from:a) a gene encoding a delta 9-desaturase (D9D) converting stearic acid 18:0-CoA into oleic acid 18:ln-9-CoA;b) a gene encoding a delta 12-desaturase (D12D) converting oleic acid 18:ln-9-CoA into linolenic acid 18:2n-6 -CoA;c) a gene encoding a delta 6-desaturase (D6D) converting linolenic acid 18:2n-6 -CoA into Y- linolenic acid 18:3n-6-CoA;d) a gene encoding a delta 6-elongase (D6Elo) converting gamma-linolenic acid 18:3n-6-CoA into dihomo-gamma-linolenic acid 20:3n-6-CoA (DGLA-CoA);e) a gene encoding a delta 5-desaturase (D5D) converting dihomo-gamma-linolenic acid 20:4n-6- CoA into arachidonic acid 20:4n-6-CoA (ARA-CoA);f) a gene encoding fatty acyl thioesterase I catalyzing hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH;g) a gene encoding NADPH-cytochrome P450 reductase (POR) catalyzing electron transfer from NADP to cytochrome P450;h) a gene encoding a prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 into prostaglandin H2 (PGH2);i) a gene encoding a prostaglandin D synthase (PGDS) converting prostaglandin H2 (PGH2) into a prostaglandin D2 (PGD2);j) a gene encoding a prostacyclin synthase (PGIS) converting prostaglandin H2 into a prostaglandin 12 (PGI2);k) a gene encoding a prostaglandin E2 synthase (PGES) converting prostaglandin H2 into a prostaglandin E2 (PGE2);l) a gene encoding a prostaglandin F synthase (PGFS) converting prostaglandin H2 into prostaglandin-F2-a (PGF2a) and / orm) a gene encoding a 9-keto-prostaglandin E synthase converting prostaglandin E2 into prostaglandin-F2-a(PGF2a).

[0233] In one embodiment the host is further capable of spontaneous conversion of prostaglandin 12 into a 6-keto-prostaglandin-Fl-a.

[0234] In one embodiment the host cell produces arachidonic acid (ARA) from a carbon feedstock and comprises one or more pathways expressing one or more heterologous genes selected from:a) a gene encoding a delta 9-desaturase (D9D) converting stearic acid 18:0-CoA into oleic acid 18:ln-9-CoA;b) a gene encoding a delta 12-desaturase (D12D) converting oleic acid 18:ln-9-CoA into linolenic acid 18:2n-6-CoA;c) a gene encoding a delta 6-desaturase (D6D) converting linolenic acid 18:2n-6-CoA into gamma-linolenic acid 18:3n-6-CoA;d) a gene encoding a delta 6-elongase (D6Elo) converting Y-linolenic acid 18:3n-6-CoA into dihomo-gamma-linolenic acid 20:3n-6-CoA;e) a gene encoding a delta 5-desaturase (D5D) converting dihomo-gamma-linolenic acid 20:4n- 6-CoA into arachidonic acid 20:4n-6-CoA (ARA-CoA) andf) a gene encoding fatty acyl thioesterase I catalyzing hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH.

[0235] In one embodiment the host cell produces prostaglandin (PGI2) from arachidonic acid and comprises one or more pathways expressing one or more heterologous genes selected from: a) a gene encoding NADPH-cytochrome P450 reductase (POR) catalyzing electron transfer from NADP to cytochrome P450;b) a gene encoding a prostaglandin G / H synthase 2 or cyclooxygenase 1 or 2 (COX 1 or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 to prostaglandin H2 (PGH2); and / orc) a gene encoding a prostacyclin synthase (PGIS) converting prostaglandin H2 into a prostaglandin 12 (PGI2).

[0236] In one embodiment the host cell produces prostaglandin E2 from arachidonic acid (ARA) and comprises one or more pathways expressing one or more heterologous genes selected from:a) a gene encoding a prostaglandin G / H synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 into prostaglandin H2 (PGH2); and / orb) a gene encoding a prostaglandin E synthase (PGES) converting prostaglandin H2 into a prostaglandin E2 (PGE2).

[0237] In one embodiment the host cell produces prostaglandin D2 (PGD2) and / or 15-deoxy-A12,14-prostaglandin J2 (5d-PGJ2) from arachidonic acid (ARA) and comprises one or more pathways expressing one or more heterologous genes selected from:a) a gene encoding NADPH-cytochrome P450 reductase (POR) catalyzing electron transfer from NADP to cytochrome P450;b) a gene encoding a prostaglandin G / H synthase 2 or cyclooxygenase 1 or 2 (COX 1 or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 into prostaglandin H2 (PGH2); and / orc) a gene encoding a prostaglandin D synthase (PGDS) converting prostaglandin H2 into a prostaglandin D2 (PGD2).

[0238] In one embodiment the host cell produces PGF2-a from an arachidonic acid (ARA) feedstock and comprises one or more pathways expressing one or more heterologous genes selected from: a) a gene encoding NADPH-cytochrome P450 reductase (POR) catalyzing electron transfer from NADP to cytochrome P450;b) a gene encoding a prostaglandin G / H synthase 2 or cyclooxygenase 1 or 2 (COX 1 or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 into prostaglandin H2 (PGH2)c) a gene encoding a prostaglandin F synthase (PGFS) converting prostaglandin H2 into a prostaglandin F2-a (PGF2- a).

[0239] In one embodiment the cyclooxygenase is a cyclooxygenase-2.

[0240] In one embodiment the cyclooxygenase-2 is a mammalian cyclooxygenase-2.

[0241] In one embodiment the cyclooxygenase is a mutant cyclooxygenase comprising one or more mutations in a signal sequence.

[0242] In one embodiment the cyclooxygenase is a chimeric or fused enzyme wherein a signal sequence has been wholly or partially replaced by a signal sequence from another enzyme.

[0243] In one embodiment the prostaglandin I synthase is a mammalian prostaglandin I synthase.

[0244] In one embodiment the prostaglandin I synthase is a rat prostaglandin I synthase.

[0245] In one embodiment the prostaglandin I synthase is a mutant prostaglandin I synthase comprising one or more mutations in a signal sequence.

[0246] In one embodiment the prostaglandin I synthase is a chimeric or fused enzyme wherein a signal sequence has been wholly or partially replaced by a signal sequence from another enzyme.

[0247] In one embodiment the prostaglandin E synthase is a mammalian prostaglandin E synthase.

[0248] In one embodiment the prostaglandin E synthase is a Homo sapiens prostaglandin E synthase.

[0249] In one embodiment the prostaglandin E synthase is a mutant prostaglandin E synthase comprising one or more mutations in a signal sequence.

[0250] In one embodiment the prostaglandin E synthase is a chimeric or fused enzyme wherein a signal sequence has been wholly or partially replaced by a signal sequence from another enzyme.

[0251] In one embodiment the prostaglandin F synthase is a bacterial prostaglandin F synthase.

[0252] In one embodiment the prostaglandin F synthase is a mammalian prostaglandin F synthase.

[0253] In one embodiment the prostaglandin F synthase is a mutant prostaglandin F synthase comprising one or more mutations in a signal sequence.

[0254] In one embodiment the prostaglandin F synthase is a chimeric or fused enzyme wherein a signal sequence has been wholly or partially replaced by a signal sequence from another enzyme.

[0255] In one embodiment of the host cell is provided, wherein:a) the delta 9-desaturase (D9D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 9-desaturase (D9D) comprised in SEQ ID NO: 1 and / or 80;b) the delta 12-desaturase (D12D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 12-desaturase (D12D) comprised in SEQ ID NO: 3 and / or 81;c) the delta 6-desaturase (D6D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 6-desaturase (D6D) comprised in SEQ ID NO: 5, 7, and / or 82;d) the delta 6-elongase (D6Elo) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 6-elongase (D6Elo) comprised in SEQ ID NO: 9, 84 and / or 11;e) the fatty acyl thioesterase I has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the fatty acyl thioesterase I comprised in SEQ ID NO: 17;f) the delta 5-desaturase (D5D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 5-desaturase (D5D) comprised in SEQ ID NO: 13, 15, and / or 55;g) the NADPH-cytochrome P450 reductase (POR) such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH-cytochrome P450 reductase (POR) comprised in SEQ ID NO: 32, 34, 36 and / or 38; h) the prostaglandin G / H2 or cyclooxygenase 2 (COX2) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin G / H2 or cyclooxygenase 2 (COX2) comprised in SEQ ID NO: 19, 21 85,87, 89, 91 and / or 93;i) the prostaglandin D synthase (PGDS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin D synthase (PGDS) comprised in SEQ ID NO: 41 and / or 79;j) the prostaglandin I synthase (PGIS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin I synthase (PGIS) comprised in SEQ ID NO: 23, 25, 27 and / or 29;k) the prostaglandin E2 synthase (PGES) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin E2 synthase comprised in SEQ ID NO: 39; and / orl) the prostaglandin F synthase synthase (PGFS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin F synthase comprised in SEQ ID NO: 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 and / or 54.

[0256] In one embodiment of the host cell is provided, wherein:the NADPH-cytochrome P450 reductase (POR) has at least 70%, such as at least 75%, such as 80%, such as 85%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH-cytochrome P450 reductase (POR) comprised in SEQ ID NO: 32, 34, 36 and / or 38;

[0257] In one embodiment of the host cell is provided, wherein:the prostaglandin G / H2 or cyclooxygenase 2 (COX2) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin G / H2 or cyclooxygenase 2 (COX2) comprised in SEQ ID NO: 19, 21 85,87, 89, 91 and / or 93;

[0258] In one embodiment of the host cell is provided, wherein:a) the NADPH-cytochrome P450 reductase (POR) such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH-cytochrome P450 reductase (POR) comprised in SEQ ID NO: 32, 34, 36 and / or 38; and / orb) the prostaglandin I synthase (PGIS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin I synthase (PGIS) comprised in SEQ ID NO: 23, 25, 27, 29.e

[0259] In one embodiment of host cell is provided, wherein:the prostaglandin E2 synthase (PGES) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin E2 synthase comprised in SEQ ID NO: 39.

[0260] In one embodiment of the host cell is provided, wherein:the prostaglandin F synthase (PGFS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin F synthase comprised in SEQ ID NO: 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 and / or 54.

[0261] In one embodiment of the host cell is provided, wherein:a) the gene encoding the delta 9-desaturase (D9D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 9-desaturase (D9D) gene comprised in SEQ ID NO: 2 and / or 73 or any of its paralogs or orthologs;b) the gene encoding the delta 12-desaturase (D12D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 12-desaturase (D12D) gene comprised in SEQ ID NO: 4 and / or 74 or any of its paralogs or orthologs;c) the gene encoding the delta 6-desaturase (D6D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 6-desaturase (D6D) gene comprised in SEQ ID NO: 6, 8 and / or 75 or any of its paralogs or orthologs;d) the gene encoding the delta 6-elongase (D6Elo) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 6-elongase (D6Elo) gene comprised in SEQ ID NO: 10, 77 and / or 12 or any of its paralogs or orthologs;e) the gene encoding the fatty acyl thioesterase I has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100%identity to the fatty acyl thioesterase I gene comprised in SEQ ID NO: 18 or any of its paralogs or orthologs;f) the gene encoding the delta 5-desaturase (D5D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 5-desaturase (D5D) gene comprised in SEQ ID NO: 14, 16, 70, and / or 76 or any of its paralogs or orthologs;g) the gene encoding the NADPH-cytochrome P450 reductase (POR) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH-cytochrome P450 reductase (POR) gene comprised in SEQ ID NO: 31, 33, 35 and / or 37;h) the gene encoding the prostaglandin G / H2 synthase or cyclooxygenase 2 (COX2) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin G / H2 synthase or cyclooxygenase 2 (COX2) gene comprised in SEQ ID NO: 20, 22, 86, 88, 90, 92 and / or 94 or any of its paralogs or orthologs;i) the gene encoding the prostaglandin D synthase (PGDS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin D synthase (PGDS) gene comprised in SEQ ID NO: 42 and / or 78 or any of its paralogs or orthologs;j) the gene encoding the prostaglandin I synthase (PGIS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin I synthase (PGIS) gene comprised in SEQ ID NO: 24, 26, 28, and / or 30, or any of its paralogs or orthologs;k) the gene encoding the prostaglandin E2 synthase (PGES) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin E2 synthase gene comprised in SEQ ID NO: 40 or any of its paralogs or orthologs; and / orl) the gene encoding the prostaglandin F synthase (PGFS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin F synthase gene comprised in SEQ ID NO:, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 and / or 69 or any of its paralogs or orthologs.

[0262] In one embodiment of the host cell is provided, wherein:a) the gene encoding the NADPH-cytochrome P450 reductase (POR) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%,such as 100% identity to the NADPH-cytochrome P450 reductase (POR) gene comprised in SEQ ID NO: 31, 33, 35 and / or 37 or any of its paralogs or orthologs.

[0263] In one embodiment of the host cell is provided, wherein:the gene encoding the prostaglandin G / H2 synthase or cyclooxygenase 2 (COX2) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin G / H2 synthase or cyclooxygenase 2 (COX2) gene comprised in SEQ ID NO: 20, 22, 86, 88, 90, 92 and / or 94 or any of its paralogs or orthologs.

[0264] In one embodiment of the host cell is provided, wherein:the gene encoding the prostaglandin I synthase (PGIS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin I synthase (PGIS) gene comprised in SEQ ID NO: 24, 26, 28, 30, 32, 34, 36 and / or 38 or any of its paralogs or orthologs.

[0265] In one embodiment of the host cell is provided, wherein:the gene encoding the prostaglandin E2 synthase (PGES) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin E2 synthase gene comprised in SEQ ID NO: 40 or any of its paralogs or orthologs.

[0266] In one embodiment of the host cell is provided, wherein:the gene encoding the prostaglandin F synthase (PGFS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin F synthase gene comprised in SEQ ID NO: 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 and / or 69 or any of its paralogs or orthologs.

[0267] In one embodiment of the host cell the prostaglandin is selected from prostaglandin Hl, prostaglandin H2, prostaglandin I, prostaglandin D2, prostaglandin 12, prostaglandin 13, prostaglandin E2, prostaglandin-F2-a and / or prostaglandin El.

[0268] In one embodiment of the host cell the sequence identity to any sequence is at least 90 %.

[0269] In one embodiment the host cell is further modified to increase Acetyl-CoA, NADPH, and / or malonyl-CoA, optionally byoverexpressing one or more of pyruvate decarboxylase, aldehyde dehydrogenase, acetyl-CoA synthetase, ATP-citrate lyase, malic enzyme, FAS complex proteins, pentose phosphate enzymes (glucose-6-dehydrogenase, 6-phosphogluconate dehydrogenase, and NADPH- dependent isocitrate dehydrogenase).In one embodiment the host cell further comprising at least 2 copies of one or more genes in the prostaglandin pathway.

[0270] In one embodiment of the host cell one or more genes of the arachidonic precursor pathway are overexpressed.

[0271] In one embodiment the host cell is further genetically modified to provide an increased amount of a substrate for at least one step of the prostaglandin pathway.Cultures

[0272] Further provided for herein are cell cultures comprising the genetically modified host cells disclosed herein and a growth medium. Suitable growth mediums for relevant prokaryotic or eukaryotic host cells are widely known in the art.

[0273] In a further aspect is comprised a polynucleotide construct comprising a polynucleotide sequence encoding a heterologous enzyme operably linked to one or more control sequences.

[0274] In a further aspect is comprised the host cell culture and a growth medium.Methods of producing compounds

[0275] This disclosure also describes a method for producing prostaglandin comprisinga) culturing the cell culture disclosed herein at conditions allowing the host cells to produce the prostaglandin; andb) optionally recovering and / or isolating the prostaglandin.

[0276] The cell culture can be cultivated in a nutrient medium and at conditions suitable for the production of the prostaglandin disclosed herein and / or for propagating cell count using methods known in the art. For example, the culture may be cultivated by shake flask cultivation, or small-scale or large-scale fermentation (including continuous, batch, fed-batch, or solid state fermentations) in a laboratory or industrial fermenters in a suitable medium and under conditions allowing the host cells to grow and / or propagate, optionally to be recovered and / or isolated.

[0277] The cultivation can take place in a suitable nutrient medium comprising carbon and nitrogen sources and inorganic salts, using procedures known in the art. Suitable media are available from commercial suppliers or may be prepared according to published recipes (e.g., from catalogues of the American Type Culture Collection). The selection of the appropriate medium may be based on the choice of host cell and / or based on the regulatory requirements for the host cell. Such media are available in the art. The medium may, if desired, contain additional components favouring the transformed expression hosts over other potentially contaminating microorganisms. Accordingly, in an embodiment a suitable nutrient medium can include one or more of (i) trace metals; (ii) vitamins; (iii) salts (such as salts of phosphate, magnesium, potassium, zinc, iron); (iv) nitrogen sources (such as YNB, ammonium sulfate, urea, yeast extracts, ammonium nitrate, ammonium chloride, malt extract,peptone and / or amino acids); (v) carbon source (such as dextrose, sucrose, glycerol, glucose, maltose, molasses, starch, cellulose, xylan, pectin, lignocellolytic biomass hydrolysate, and / or acetate); (vi) nucleobases; (vii) aminoglycosides; and / or (viii) antibiotics (such as G418 and hygromycin B).

[0278] The cultivation of the host cell may be performed over a period of from about 0.5 to about 30 days. The cultivation process may be a batch process, continuous or fed-batch process, suitably performed at a temperature in the range of 0-100 °C or 0-80 °C, for example, from about 0 °C to about 50 °C and / or at a pH, for example, from about 2 to about 10. Preferred fermentation conditions are a temperature in the range of from about 25 °C to about 55 °C and at a pH of from about 3 to about 9. The appropriate conditions are usually selected based on the choice of host cell. Accordingly, in some embodiments the method disclosed herein comprises one or more elements selected from:a) culturing the cell culture under aerobic or anaerobic conditionsb) cultivating the host cells under mixing;c) cultivating the host cells at a temperature of between 25°C to 50°C;d) cultivating the host cells at a pH of between 3-9; ande) cultivating the host cells for between 10 hours to 120 days.

[0279] The cell culture disclosed herein may be recovered and or isolated using methods known in the art. For example, the compound(s) may be recovered from the nutrient medium by conventional procedures including, but not limited to, centrifugation, filtration, spray-drying, or lyophilization. In a particular embodiment the method includes a recovery and / or isolation step comprising separating a liquid phase of the cell culture from a solid phase of the cell culture to obtain a supernatant comprising the prostaglandin and subjecting the supernatant to one or more steps selected from:a) contacting the supernatant with one or more adsorbent resins to obtain at least a portion of the produced prostaglandin, then optionally recovering the prostaglandin from the resin in a concentrated solution prior to isolation of the prostaglandin by crystallisation or solvent evaporation;b) contacting the supernatant with one or more ion exchange or reversed-phase chromatography columns to obtain at least a portion of the prostaglandin, then optionally recovering the prostaglandin from the resin in a concentrated solution prior to isolation of the prostaglandin by crystallisation or solvent evaporation;c) extracting the prostaglandin from the supernatant, such as by liquid-liquid extraction into an immiscible solvent, then optionally isolating the prostaglandin by crystallisation or solvent evaporation; andthereby recovering and / or isolating the prostaglandin.

[0280] The prostaglandin yield provided by the method disclosed herein is typically higher than whenproducing prostaglandin by methods employing host cells without reduced CRP-cAMP complex formation and / or increased degradation and / or decreased binding of cAMP, in some embodiments at least 10% higher such as at least 50%, such as at least 100%, such as least 150%, such as at least 200% higher.

[0281] The method disclosed herein may further comprise one or more steps of mixing the prostaglandin with one or more carriers, agents, adjuvants, additives and / or excipients, optionally pharmaceutical grade carriers, agents, adjuvants, additives and / or excipients.

[0282] The method disclosed herein may further comprise one or more in vitro steps in the process of producing the prostaglandin. It may also comprise one or more in vivo steps performed in another cell than the host cell disclosed herein. For example, precursors for and / or intermediates in the pathway for the prostaglandin may be produced in another cell and isolated therefrom and then fed to a cell culture disclosed herein for conversion into the prostaglandin. Accordingly, in one embodiment the method disclosed herein further comprises feeding one or more exogenous prostaglandin precursors to the host cell culture.

[0283] In a further aspect is disclosed a method for producing a prostaglandin comprising:a) culturing the host cell culture t conditions allowing the host cell to produce the prostaglandin; and / orb) optionally recovering and / or isolating the prostaglandin.

[0284] In one embodiment the recovering and / or isolation step comprises one or more steps selected from:a) Sol id: liquid separation (e.g. centrifugation or microfiltration)b) Adsorptionc) Ultrafiltration or nanofiltrationd) Precipitatione) Crystallizationf) Dryingg) Chromatographyh) Extraction, andi) Distillation.

[0285] In some embodiments, the recovering and / or isolating step comprises:a) performing a solid:liquid separation to provide a cell-containing solid phase and a cell-free liquid phase; andb) extracting the prostaglandin from the solid phase and / or the liquid phase using a solvent.

[0286] In some embodiments, the prostaglandin is extracted from the cell-containing solid phase using an alcohol, such as ethanol.

[0287] In some embodiments, the prostaglandin is extracted from the cell-free liquid phase or from the entire cell culture via liquid-liquid extraction.

[0288] In some embodiments, the liquid-liquid extraction is performed using ethanol, such as in a batch, cross-current, or counter-current mode.

[0289] In some embodiments, the recovering and / or isolating step further comprises a chromatography step.

[0290] In some embodiments, the chromatography is performed using a non-polar porous resin.

[0291] In some embodiments, the non-polar porous resin is a styrene-divinylbenzene resin.

[0292] In some embodiments, the chromatography step comprises:a) loading an aqueous mixture containing the prostaglandin onto a column comprising the resin; b) washing the column with water; andc) eluting the prostaglandin from the column using an alcohol, such as methanol or ethanol.

[0293] In some embodiments, the method further comprising a step of reducing the concentration of an organic solvent from a prostaglandin-containing mixture by evaporation prior to loading the mixture onto the column.

[0294] In some embodiments, the recovering and / or isolating step comprises:a) performing dialysis on the cell culture or a fraction thereof at a first pH, such as about pH 8; and b) extracting the prostaglandin at a second pH, such as about pH 3, using a solvent, such as a chlorinated solvent, for example chloroform; wherein the second pH is lower than the first pH.

[0295] In some embodiments, the method further comprising adding a reducing agent, such as glutathione, during the culturing, recovering, and / or isolating steps.

[0296] In one embodiment the method further comprising one or more elements selected from: a) culturing the host cell culture in a nutrient medium;b) culturing the host cell culture under aerobic conditionsc) culturing the host cell culture under agitation;d) culturing the host cell culture at a temperature of between 18 to 40 °C;e) culturing the host cell culture at a pH of between 3-9; andf) culturing the host cell culture for between 10 hours to 30 days.

[0297] In one embodiment the method further comprising one or more steps wherein production of the prostaglandin is performed in vitro.

[0298] In some embodiments, the method comprises producing the prostaglandin de novo, for example from a carbon source, such as from glucose.

[0299] In some embodiments, the culturing is performed as a fed-batch process.

[0300] In some embodiments, the fed-batch process comprises a batch phase followed by one or more fed-batch phases.

[0301] In some embodiments, the batch phase comprises culturing the host cell in a minimal medium containing a carbon source, such as glucose, for example at an initial fill volume of one-third to one-half of the total final working volume.

[0302] In some embodiments, the one or more fed-batch phases comprise a glucose-limited exponential growth phase targeting a predefined growth rate of for example about 0.08 h-1to 0.1 h-1, followed by one or more phases with constant feed rates of a carbon source.

[0303] In some embodiments, the growth medium comprises a carbon source, a nitrogen source, a phosphate source, and optionally one or more supplements selected from the group consisting of a vitamin solution and a trace elements solution.

[0304] In some embodiments, the carbon source is glucose.

[0305] In some embodiments, the vitamin solution comprises one or more components selected from the group consisting of d-biotin, Ca-pantothenate, Nicotinic acid, Thiamine-HCI, Pyridoxine-HCI, 4-aminobenzoic acid, and Myo-inositol.

[0306] In some embodiments, the trace elements solution comprises one or more components selected from the group consisting of Iron (III) citrate hydrate, ZnSO4·7H2O, MnCl2·4H2O, and CuSO4·5H2O.

[0307] In some embodiments, the method comprises using a feed solution during the fed-batch phases comprises one or more of: glucose, (NH4)2SO4, KH2PO4, MgSO4·7H2O, K2SO4, and Na2SO4.

[0308] In some embodiments, the culturing comprises controlling one or more physical parameters selected from the group consisting of temperature, pH, aeration rate, and stirring rate.

[0309] In some embodiments, the one or more physical parameters are controlled such that: a) the temperature is maintained at about 30 °C;b) the pH is controlled to about 5.5;c) the aeration rate is maintained at about 1.5 vvm; and / ord) the stirring rate is maintained at about 1100 rpm.

[0310] In some embodiments, the method further comprising a step selected from the group consisting of:a) limiting a nitrogen source after a biomass accumulation phase;b) adding an antioxidant, such as a carotenoid, to the growth medium; andc) adding an additional nitrogen source, such as yeast extract or one or more amino acids, to the growth medium.

[0311] In some embodiments, the method further comprising a stabilizing step for stabilizing the prostaglandin and / or an arachidonic acid precursor against oxidation.

[0312] In some embodiments, the stabilizing step comprises adding a stabilizing agent, such as an antioxidant to the cell culture or to a solution containing the prostaglandin or arachidonic acid precursor.

[0313] In some embodiments, the stabilizing agent is selected from the group consisting of glutathione, nordihydroguaiaretic acid, butylated hydroxyanisole, N-acetylcysteine, citric acid, and cysteine.

[0314] In some embodiments, the stabilizing step comprises storing a solution containing arachidonic acid or a precursor thereof under non-oxidizing conditions prior to or during the culturing step.

[0315] In some embodiments, storing under non-oxidizing conditions comprises purging the solution with an inert gas, such as argon or nitrogen.

[0316] In some embodiments, the method further comprising minimizing exposure of the cell culture, a solution containing arachidonic acid, or the prostaglandin to UV light.

[0317] In some embodiments, the step of feeding the host cell culture with arachidonic acid or one or more arachidonic acid precursors is performed over time to prevent accumulation of arachidonic acid in the growth medium.

[0318] In some embodiments, the culturing step is controlled to minimize accumulation of arachidonic acid, wherein said control comprises regulating the dissolved oxygen set point.

[0319] In some embodiments, the recovering and / or isolating step further comprises a packaging step of packaging the prostaglandin in a protective container.

[0320] In some embodiments, the packaging step comprises degassing the prostaglandin and enclosing it in a non-gas permeable capsule or a hermetically-sealed container.Fermentation composition

[0321] This disclosure also describes a fermentation composition comprising the cell culture disclos...

Claims

1. Claims1. A genetically modified host cell comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, and wherein the host cell is further genetically modified by at least one modification enhancing the yield of one or more prostaglandins or prostaglandin precursors relative to the corresponding host cell without the modification; and wherein the host cell is of a genus selected from the group consisting of: Saccharomyces, Aspergillus, Kluyveromyces, Candida, Komagataella (formerly Pichia), Debaromyces, Hansenula, Zygosaccharomyces, and Schizosaccharomyces.

2. The host cell of claim 1, wherein the host cell is further genetically modified by at least one modification selected from the group consisting of:4.i) the attenuation, disruption or deletion of one or more endogenous genes encoding a polypeptide that catalyzes an unwanted side-reaction on one or more prostaglandin precursors and / or retards the catalytic activity of one or more of the polypeptides of the metabolic pathways capable of producing one or more prostaglandins, optionally wherein the one or more endogenous genes are selected from the group consisting of a glutathione S-transferase, an esterase, a thioredoxin peroxidase, and an oxidoreductase;5.ii) the overexpression of a gene that increases the supply of one or more prostaglandin precursors, optionally wherein said gene is selected from the group consisting of: a gene encoding a mutant acetyl-CoA carboxylase (ACC1) and an endogenous delta-9 desaturase gene; and6.iii) expressing or overexpressing one or more auxiliary genes encoding polypeptides selected from at least one of the following functional groups:7.a) polypeptides involved in the unfolded protein response or protein degradation pathway; b) polypeptides involved in the oxidative stress response;8.c) polypeptides involved in heme oxidoreductase activity or electron transfer; and d) polypeptides involved in fatty acid and / or lipid production.

3. The host cell of any one of claims 1-2, wherein the modification is the expression or overexpression of one or more auxiliary genes encoding polypeptides according to (iii)(a), wherein the polypeptides are selected from the group consisting of an endoplasmic reticulum (ER) chaperone, a protein disulfide isomerase, and a peptidyl-prolyl cis-trans isomerase.

4. The host cell of any one of claims 1-3, wherein the modification is the expression or overexpression of one or more auxiliary genes encoding polypeptides according to (iii)(b), whereinthe polypeptides are selected from the group consisting of a catalase, a glutathione peroxidase, and a glucose-6-phosphate dehydrogenase, optionally wherein the catalase is fused to an ER-directing signal sequence.

5. The host cell of any one of claims 1-4, wherein the modification is the expression or overexpression of one or more auxiliary genes encoding polypeptides according to (iii)(c) or (iii)(d), wherein the polypeptides are selected from the group consisting of a membrane steroid-binding protein (MSBP), a NADP-cytochrome P450 reductase, a cytochrome b5, a cytochrome b5 reductase, and a phospholipase A2.

6. The host cell of any one of claims 2-5, wherein the host cell is modified by at least two modifications selected from the group consisting of (i), (ii), and (iii).

7. The host cell of any of claims 2-6, wherein the host cell is modified by attenuating or deleting an endogenous gene according to (i) and by expressing or overexpressing one or more auxiliary genes according to (iii).

8. The host cell of any preceding claims, wherein the host cell is capable of producing prostaglandins via arachidonic acid (ARA) and / or dihomo-gamma-linolenic acid (DGLA) from a carbon feedstock.

9. The host cell of any preceding claims, wherein the host cell is capable of producing prostaglandins via arachidonic acid (ARA) from a carbon feedstock and comprises one or more pathways expressing one or more heterologous genes selected from:16.a) a gene encoding a delta 9-desaturase (D9D) converting stearic acid 18:0-CoA into oleic acid 18:ln-9-CoA;17.b) a gene encoding a delta 12-desaturase (D12D) converting oleic acid 18:ln-9-CoA into linolenic acid 18:2n-6 -CoA;18.c) a gene encoding a delta 6-desaturase (D6D) converting linolenic acid 18:2n-6 -CoA into Y- linolenic acid 18:3n-6-CoA;19.d) a gene encoding a delta 6-elongase (D6Elo) converting gamma-linolenic acid 18:3n-6-CoA into dihomo-gamma-linolenic acid 20:3n-6-CoA (DGLA-CoA);20.e) a gene encoding a delta 5-desaturase (D5D) converting dihomo-gamma-linolenic acid 20:4n-6- CoA into arachidonic acid 20:4n-6-CoA (ARA-CoA);21.f) a gene encoding fatty acyl thioesterase I catalyzing hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH; g) a gene encoding NADPH-cytochrome P450 reductase (POR) catalyzing electron transfer from NADP to cytochrome P450;22.h) a gene encoding a prostaglandin G / H2 synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 into prostaglandin H2 (PGH2);23.i) a gene encoding a prostaglandin D synthase (PGDS) converting prostaglandin H2 (PGH2) into a prostaglandin D2 (PGD2);24.j) a gene encoding a prostacyclin synthase (PGIS) converting prostaglandin H2 into a prostaglandin 12 (PGI2);25.k) a gene encoding a prostaglandin E2 synthase (PGES) converting prostaglandin H2 into a prostaglandin E2 (PGE2);26.l) a gene encoding a prostaglandin F synthase (PGFS) converting prostaglandin H2 into prostaglandin-F2-a (PGF2a) and / or27.m) a gene encoding a 9-keto-prostaglandin E synthase converting prostaglandin E2 into prostaglandin-F2-a(PGF2a).

10. The host cell of any preceding claims, further capable of spontaneous conversion of prostaglandin 12 into a 6-keto-prostaglandin-Fl-a.

11. The host cell of any preceding claims, wherein the host cell produces arachidonic acid (ARA) from a carbon feedstock and comprises one or more pathways expressing one or more heterologous genes selected from:30.a) a gene encoding a delta 9-desaturase (D9D) converting stearic acid 18:0-CoA into oleic acid 18:ln-9-CoA;31.b) a gene encoding a delta 12-desaturase (D12D) converting oleic acid 18:ln-9-CoA into linolenic acid 18:2n-6-CoA;32.c) a gene encoding a delta 6-desaturase (D6D) converting linolenic acid 18:2n-6-CoA into gammalinolenic acid 18:3n-6-CoA;33.d) a gene encoding a delta 6-elongase (D6Elo) converting Y-linolenic acid 18:3n-6-CoA into dihomo-gamma-linolenic acid 20:3n-6-CoA;34.e) a gene encoding a delta 5-desaturase (D5D) converting dihomo-gamma-linolenic acid 20:4n-6- CoA into arachidonic acid 20:4n-6-CoA (ARA-CoA) and35.f) a gene encoding fatty acyl thioesterase I catalyzing hydrolysis of fatty acyl-CoAs to free fatty acids and CoA-SH.

12. The host cell of any preceding claims, wherein the host cell produces prostaglandin (PGI2) from arachidonic acid and comprises one or more pathways expressing one or more heterologous genes selected from:36.a) a gene encoding NADPH-cytochrome P450 reductase (POR) catalyzing electron transfer from NADP to cytochrome P450;37.b) a gene encoding a prostaglandin G / H synthase 2 or cyclooxygenase 1 or 2 (COX 1 or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 to prostaglandin H2 (PGH2); and / or38.c) a gene encoding a prostacyclin synthase (PGIS) converting prostaglandin H2 into a prostaglandin 12 (PGI2).

13. The host cell of any preceding claims, wherein the host cell produces prostaglandin E2 from arachidonic acid (ARA) and comprises one or more pathways expressing one or more heterologous genes selected from:40.a) a gene encoding a prostaglandin G / H synthase 2 or cyclooxygenase 1 or 2 (COXI or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 into prostaglandin H2 (PGH2); and / or41.b) a gene encoding a prostaglandin E synthase (PGES) converting prostaglandin H2 into a prostaglandin E2 (PGE2).

14. The host cell of any preceding claims, wherein the host cell produces prostaglandin D2 (PGD2) and / or 15-deoxy-A12,14-prostaglandin J2 (5d-PGJ2) from arachidonic acid (ARA) and comprises one or more pathways expressing one or more heterologous genes selected from:43.a) a gene encoding NADPH-cytochrome P450 reductase (POR) catalyzing electron transfer from NADP to cytochrome P450;44.b) a gene encoding a prostaglandin G / H synthase 2 or cyclooxygenase 1 or 2 (COX 1 or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 into prostaglandin H2 (PGH2); and / or45.c) a gene encoding a prostaglandin D synthase (PGDS) converting prostaglandin H2 into a prostaglandin D2 (PGD2).

15. The host cell of any preceding claims, wherein the host cell produces PGF2-a from an arachidonic acid (ARA) feedstock and comprises one or more pathways expressing one or more heterologous genes selected from:46.a) a gene encoding NADPH-cytochrome P450 reductase (POR) catalyzing electron transfer from NADP to cytochrome P450;47.b) a gene encoding a prostaglandin G / H synthase 2 or cyclooxygenase 1 or 2 (COX 1 or COX2) converting arachidonic acid into prostaglandin G2(PGG2) and further converting PGG2 into prostaglandin H2 (PGH2)48.c) a gene encoding a prostaglandin F synthase (PGFS) converting prostaglandin H2 into a prostaglandin F2-a (PGF2- a).

16. The host cell of any of the preceding claim, wherein the cyclooxygenase is a cyclooxygenase-2.

17. The host cell of any of claim 16, wherein the cyclooxygenase-2 is a mammalian cyclooxygenase-2.

18. The host cell of any of the claim 16 to 17, wherein the cyclooxygenase is a mutant cyclooxygenase comprising one or more mutations in a signal sequence.

19. The host cell of any of the claim 16 to 18, wherein the cyclooxygenase is a chimeric or fused enzyme wherein a signal sequence has been wholly or partially replaced by a signal sequence from another enzyme.

20. The host cell of any of the preceding claim, wherein the prostaglandin I synthase is a mammalian prostaglandin I synthase.

21. The host cell of claim 20, wherein the prostaglandin I synthase is a rat prostaglandin I synthase.

22. The host cell of claim 20 to 21, wherein the prostaglandin I synthase is a mutant prostaglandin I synthase comprising one or more mutations in a signal sequence.

23. The host cell of claim 20 to 22, wherein the prostaglandin I synthase is a chimeric or fused enzyme wherein a signal sequence has been wholly or partially replaced by a signal sequence from another enzyme.

24. The host cell of any of the preceding claim, wherein the prostaglandin E synthase is a mammalian prostaglandin E synthase.

25. The host cell of claim 24, wherein the prostaglandin E synthase is a Homo sapiens prostaglandin E synthase.

26. The host cell of claim 24 to 25, wherein the prostaglandin E synthase is a mutant prostaglandin E synthase comprising one or more mutations in a signal sequence.

27. The host cell of any of the claim 24 to 26, wherein the prostaglandin E synthase is a chimeric or fused enzyme wherein a signal sequence has been wholly or partially replaced by a signal sequence from another enzyme.

28. The host cell of any of the preceding claim, wherein the prostaglandin F synthase is a bacterial prostaglandin F synthase.

29. The host cell of any of the preceding claim, wherein the prostaglandin F synthase is a mammalian prostaglandin F synthase.

30. The host cell of claim 28 to 29, wherein the prostaglandin F synthase is a mutant prostaglandin F synthase comprising one or more mutations in a signal sequence.

31. The host cell of any of the claims 28 to 30, wherein the prostaglandin F synthase is a chimeric or fused enzyme wherein a signal sequence has been wholly or partially replaced by a signal sequence from another enzyme.

32. The host cell of any of the preceding claims, wherein:65.a) the delta 9-desaturase (D9D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 9-desaturase (D9D) comprised in SEQ ID NO: 1 and / or 80;66.b) the delta 12-desaturase (D12D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 12-desaturase (D12D) comprised in SEQ ID NO: 3 and / or 81; c) the delta 6-desaturase (D6D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 6-desaturase (D6D) comprised in SEQ ID NO: 5, 7, and / or 82;67.d) the delta 6-elongase (D6Elo) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 6-elongase (D6Elo) comprised in SEQ ID NO: 9, 84 and / or 11;68.e) the fatty acyl thioesterase I has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the fatty acyl thioesterase I comprised in SEQ ID NO: 17;69.f) the delta 5-desaturase (D5D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 5-desaturase (D5D) comprised in SEQ ID NO: 13, 15, and / or 55;70.g) the NADPH-cytochrome P450 reductase (POR) such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH- cytochrome P450 reductase (POR) comprised in SEQ ID NO: 32, 34, 36 and / or 38;71.h) the prostaglandin G / H2 or cyclooxygenase 2 (COX2) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin G / H2 or cyclooxygenase 2 (COX2) comprised in SEQ ID NO: 19, 21 85, 87, 89, 91 and / or 93;72.i) the prostaglandin D synthase (PGDS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin D synthase (PGDS) comprised in SEQ ID NO: 41 and / or 79;73.j) the prostaglandin I synthase (PGIS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin I synthase (PGIS) comprised in SEQ ID NO: 23, 25, 27 and / or 29;74.k) the prostaglandin E2 synthase (PGES) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin E2 synthase comprised in SEQ ID NO: 39; and / or75.l) the prostaglandin F synthase synthase (PGFS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin F synthase comprised in SEQ ID NO: 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 and / or 54.

33. The host cell of claim 32, wherein:the NADPH-cytochrome P450 reductase (POR) has at least 70%, such as at least 75%, such as 80%, such as 85%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH-cytochrome P450 reductase (POR) comprised in SEQ ID NO: 32, 34, 36 and / or 38.

34. The host cell of claim 32, wherein:78.the prostaglandin G / H2 or cyclooxygenase 2 (COX2) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin G / H2 or cyclooxygenase 2 (COX2) comprised in SEQ ID NO: 19, 21 85,87, 89, 91 and / or 93.

35. The host cell of claim 32, wherein:80.a) the NADPH-cytochrome P450 reductase (POR) has at least 70%, such as at least 75%, such as 80%, such as 85%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH-cytochrome P450 reductase (POR) comprised in SEQ ID NO: 32, 34, 36 and / or 38; and / or81.b) the prostaglandin I synthase (PGIS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin I synthase (PGIS) comprised in SEQ ID NO: 23, 25, 27, 29.

36. The host cell of claim 32, wherein:83.the prostaglandin E2 synthase (PGES) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin E2 synthase comprised in SEQ ID NO: 39.

37. The host cell of claim 32, wherein:85.the prostaglandin F synthase (PGFS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin F synthase comprised in SEQ ID NO: 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 and / or 54.

38. The host cell of any of the preceding claim wherein:87.a) the gene encoding the delta 9-desaturase (D9D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 9-desaturase (D9D) gene comprised in SEQ ID NO: 2 and / or 73 or any of its paralogs or orthologs; b) the gene encoding the delta 12-desaturase (D12D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 12-desaturase (D12D) gene comprised in SEQ ID NO: 4 and / or 74 or any of its paralogs or orthologs;88.c) the gene encoding the delta 6-desaturase (D6D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 6-desaturase (D6D) gene comprised in SEQ ID NO: 6, 8 and / or 75 or any of its paralogs or orthologs;89.d) the gene encoding the delta 6-elongase (D6Elo) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 6-elongase (D6Elo) gene comprised in SEQ ID NO: 10, 77 and / or 12 or any of its paralogs or orthologs;90.e) the gene encoding the fatty acyl thioesterase I has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the fatty acyl thioesterase I gene comprised in SEQ ID NO: 18 or any of its paralogs or orthologs;91.f) the gene encoding the delta 5-desaturase (D5D) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the delta 5-desaturase (D5D) gene comprised in SEQ ID NO: 14, 16, 70, and / or 76 or any of its paralogs or orthologs;92.g) the gene encoding the NADPH-cytochrome P450 reductase (POR) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH-cytochrome P450 reductase (POR) gene comprised in SEQ ID NO: 31, 33, 35 and / or 37;93.h) the gene encoding the prostaglandin G / H2 synthase or cyclooxygenase 2 (COX2) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin G / H2 synthase or cyclooxygenase 2 (COX2) gene comprised in SEQ ID NO: 20, 22, 86, 88, 90, 92 and / or 94 or any of its paralogs or orthologs;94.i) the gene encoding the prostaglandin D synthase (PGDS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin D synthase (PGDS) gene comprised in SEQ ID NO: 42 and / or 78 or any of its paralogs or orthologs;95.j) the gene encoding the prostaglandin I synthase (PGIS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin I synthase (PGIS) gene comprised in SEQ ID NO: 24, 26, 28, and / or 30, or any of its paralogs or orthologs;96.k) the gene encoding the prostaglandin E2 synthase (PGES) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin E2 synthase gene comprised in SEQ ID NO: 40 or any of its paralogs or orthologs; and / or97.l) the gene encoding the prostaglandin F synthase (PGFS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin F synthase gene comprised in SEQ ID NO:, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 and / or 69 or any of its paralogs or orthologs.

39. The host cell of claim 38 wherein:99.a) the gene encoding the NADPH-cytochrome P450 reductase (POR) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH-cytochrome P450 reductase (POR) gene comprised in SEQ ID NO: 31, 33, 35 and / or 37 or any of its paralogs or orthologs.

40. The host cell of claim 38 wherein:101.the gene encoding the prostaglandin G / H2 synthase or cyclooxygenase 2 (COX2) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin G / H2 synthase or cyclooxygenase 2 (COX2) gene comprised in SEQ ID NO: 20, 22, 86, 88, 90, 92 and / or 94 or any of its paralogs or orthologs.

41. The host cell of claim 38 wherein:103.a) the gene encoding the NADPH-cytochrome P450 reductase (POR) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the NADPH-cytochrome P450 reductase (POR) gene comprised in SEQ ID NO: 31, 33, 35 and / or 37 or any of its paralogs or orthologs; and / or104.b) the gene encoding the prostaglandin I synthase (PGIS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin I synthase (PGIS) gene comprised in SEQ ID NO: 24, 26, 28, 30, 32, 34, 36 and / or 38 or any of its paralogs or orthologs.

42. The host cell of claim 38 wherein:105.the gene encoding the prostaglandin E2 synthase (PGES) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin E2 synthase gene comprised in SEQ ID NO: 40 or any of its paralogs or orthologs.

43. The host cell of claim 38 wherein:107.the gene encoding the prostaglandin F synthase (PGFS) has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to the prostaglandin F synthase gene comprised in SEQ ID NO: 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 and / or 69 or any of its paralogs or orthologs.

44. The host cell of any preceding claims wherein the prostaglandin is selected from prostaglandin Hl, prostaglandin H2, prostaglandin I, prostaglandin D2, prostaglandin 12, prostaglandin 13, prostaglandin E2, prostaglandin-F2-a and / or prostaglandin El.

45. The host cell of claim 44 wherein the sequence identity to any sequence is at least 90 %.

46. The host cell of any of the preceding claims, wherein the host cell is further modified to increase Acetyl-CoA, NADPH, and / or malonyl-CoA, optionally by111.a) overexpressing one or more of pyruvate decarboxylase, aldehyde dehydrogenase, acetyl-CoA synthetase, ATP-citrate lyase, malic enzyme, FAS complex proteins, pentose phosphate enzymes (glucose-6-dehydrogenase, 6-phosphogluconate dehydrogenase, and NADPH- dependent isocitrate dehydrogenase).

47. The host cell of any of the preceding claims, further comprising at least 2 copies of one or more genes in the prostaglandin pathway.

48. The host cell of any of the preceding claims, wherein one or more genes of the arachidonic precursor pathway are overexpressed.

49. The host cell of any of the preceding claims further genetically modified to provide an increased amount of a substrate for at least one step of the prostaglandin pathway.

50. The host cell of any of the preceding claims further genetically modified to exhibit increased tolerance towards one or more substrates, intermediates, or product molecules from the prostaglandin pathway.

51. The host cell of any preceding claims, wherein the yeast cell is of a species selected from the group consisting of Kluyveromyces lactis, Saccharomyces carlsbergensis, Saccharomyces cerevisiae, Saccharomyces diastaticus, Saccharomyces douglasii, Saccharomyces kluyveri, Saccharomyces norbensis, Saccharomyces oviformis, and / or Pichia pastoris.

52. The host cell of claim 51 wherein the host cell is Saccharomyces cerevisiae, and comprises a) genes MrD9D (SEQ ID NO: 80), MrD12D (SEQ ID NO: 81), MaD6D (SEQ ID NO: 82), MaD5D (SEQ ID NO: 83) and / or MaD6Elo (SEQ ID NO: 84); and is117.b) for the production of arachidonic acid; and / or118.c) for the production of a prostaglandin.

53. The host cell of claim 51 wherein the host cell is Saccharomyces cerevisiae, and comprises a) genes RnCOX2 (SEQ ID NO: 21) and PGF2_1 to PGF-12 (SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO:120.60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, and SEQ ID NO: 69); and is121.b) for the production of arachidonic acid; and / or122.c) for the production of prostaglandin.

54. The host cell of any preceding claims, wherein the yeast cell is of a species selected from the group consisting of Kluyveromyces lactis, Saccharomyces carlsbergensis, Saccharomyces cerevisiae, Saccharomyces diastaticus, Saccharomyces douglasii, Saccharomyces kluyveri, Saccharomyces norbensis, Saccharomyces oviformis, Mortierella alpina, Komagataella phaffii (syn. Pichia pastoris), and / or Yarrowia lipolytica.

55. The host cell of any preceding claims, wherein the host cell is of a genus selected from the group consisting of Saccharomyces, and Komagataella.

56. The host cell of claim 55, wherein the host cell is Saccharomyces cerevisiae, or Komagataella phaffii.

57. The host cell of any preceding claims, wherein the host cell has been genetically modified to express one or more heterologous genes and / or overexpress one or more endogenous genes each independently selected from the group consisting of:126.a) a gene encoding a prostaglandin D2 synthase (prostaglandin-H2 D-isomerase) (PGD) converting prostaglandin H2 into a prostaglandin D2;127.b) a gene encoding a NADH-cytochrome B5 reductase (NCB5R), transferring electrons from NADH to other molecules in fatty acid biosynthesis pathways;128.c) a gene encoding a cytochrome B5 (CYB5) hemoprotein cofactor supporting transfer of electrons in fatty acid biosynthesis pathways;129.d) a gene encoding an elongase (ELO) adding two-carbon units to the end of a fatty acid-CoA chain using malonyl CoA);130.e) a gene encoding a delta-6 desaturase (D6D) converting linoleoyl-CoA to gamma-linolenoyl-CoA; f) a gene encoding a delta-12-fatty acid desaturase (D12D) converting oleoyl-CoA to linoleoyl-CoA; g) a gene encoding a polyunsaturated fatty acid elongation enzyme (D6Elo) adding two-carbon units to the end of a polyunsaturated fatty acid-coA substrate;131.h) a gene encoding a delta-5 desaturase (D5D) converting dihomo-gamma-linolenoyl-CoA to Arachidonoyl-CoA;132.i) a gene encoding a stearoyl-CoA-9 desaturase (Ole, D9D) converting stearoyl-CoA to oleoyl-CoA; j) a gene encoding a cyclooxygenase (COX)_enzyme converting arachidonic acid to Prostaglanding G2 (PGG2) and / or converts PGG2 to prostaglandin H2 (PGH2);133.k) a gene encoding a prostaglandin F synthase (PGF2) converting prostaglandin H2 to prostaglandin F2;134.l) a gene encoding a prostaglandin E synthase (PGES) converting prostaglandin H2 into prostaglandin E2;135.m) a gene encoding an ATPase acting as a chaperone to mediate protein folding in the ER;136.n) a gene encoding a protein disulfide isomerase (PDI) acting as an oxidoreductase in the ER lumen; o) a gene encoding a cytosolic or peroxisomal catalase (CT) enzyme that decomposes hydrogen peroxide and protects from oxidative damage;137.p) a gene encoding a Peptidyl-prolyl cis-trans isomerase of the ER;138.q) a gene encoding an Integral ER membrane protein (ICE2) with type-III transmembrane domains and promotes ER membrane expansion;139.r) a gene encoding a NADP-cytochrome P450 reductase assisting in electron transfer of associated P450 enzymes;140.s) a gene encoding a nuclear RNA-binding protein (GRP7); t) a gene encoding a UDP-glucose pyrophosphorylase (UGPase); catalyses the reversible formation of UDP-GIc from glucose 1-phosphate and UTP (UGP1);141.u) a gene encoding a Glucose-6-phosphate dehydrogenase (G6PD) catalyzing the first step of the pentose phosphate pathway;142.v) a gene encoding a protein involved in homologous recombination (RAD52);143.w) a gene encoding a Phospholipid hydroperoxide glutathione peroxidase involved in the antioxidant system that decreases mitochondrial ROS production and preserves electron transport chain (ETC) function (GPX2);144.x) a gene encoding a 3'-5' exonuclease specific for poly-A RNAs (NGL3);145.y) a gene encoding an L119A mutant of a component of the cleavage and polyadenylation factor I (INO2);146.z) a gene encoding a Component of the cleavage and polyadenylation factor I (RNA15);147.aa) a gene encoding a yeast RNA annealing protein (YRA2);148.bb) a gene encoding a phospholipase A2, membrane associated precursor (PA2GA);149.cc) a gene encoding a transcription factor in oxidative stress response (STB5);150.dd) a gene encoding a mutant (R206) heat shock transcription factor (HSF1);151.ee) a gene encoding an alcohol dehydrogenase (ADH1) converting acetaldehyde to ethanol; ff) a gene encoding a Mitochondrial NADH kinase (POS5);152.gg) a gene encoding a Bifunctional alcohol dehydrogenase and formaldehyde dehydrogenase (SFA1) involved in formaldehyde detoxification and long chain alcohols;153.hh) a gene encoding a Transcription factor involved in phospholipid synthesis (INO4);154.ii) a gene encoding a Plasma membrane protein involved in maintaining membrane organization (HSP12);155.jj) a gene encoding a Membrane-bound peptidyl-prolyl cis-trans isomerase (PPIase);156.kk) a gene encoding a Cytosolic copper-zinc superoxide dismutase / sulfide oxidase (sodl) acting to detoxify superoxide and hydrogen sulfide;157.II) a gene encoding an Aminolevulinate dehydratase (HEM2) converting 5-aminolevulinate to porphobilinogen;158.mm) a gene encoding a Lanosterol 14-alpha-demethylase (ERG11) catalyzes C-14 demethylation of lanosterol to form 4,4"-dimethyl cholesta-8,14,24-triene-3-beta-ol;159.nn) a gene encoding a Damage resistance protein (DAP1) Heme-binding protein involved in regulation of cytochrome P450 protein Ergllp and damage response protein; and160.oo) a gene encoding a membrane steroid binding protein (MSBP).

58. The host cell of any of the preceding claims, wherein the host cell has been genetically modified to express one or more heterologous genes and / or overexpress one or more endogenous genes each independently selected from the group consisting of:161.a) a gene encoding a MmPGD, wherein the gene encoding said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 96, and / or wherein the polypeptide encoded by said MmPGD has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 95, or any of its orthologs or paralogs; b) a gene encoding a NCB5R_MORAP_GA, wherein the gene encoding said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 98, and / or wherein the polypeptide encoded by said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 97, or any of its orthologs or paralogs;162.c) a gene encoding a CYB5_MORAP_GA, wherein the gene encoding said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 100, and / or wherein the polypeptide encoded by said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 99, or any of its orthologs or paralogs;163.d) a gene encoding a McELO, wherein the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs; e) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs; f) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs;164.g) a gene encoding a MaD12D_2, wherein the gene encoding said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 108, and / or wherein the polypeptide encoded by said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 107, or any of its orthologs or paralogs;165.h) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109, or any of its orthologs or paralogs;166.i) a gene encoding a MaD6Elo_2, wherein the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111, or any of its orthologs or paralogs;167.j) a gene encoding a MaD5D_2, wherein the gene encoding said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 114, and / or wherein the polypeptide encoded by said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 113, or any of its orthologs or paralogs;168.k) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115, or any of its orthologs or paralogs;169.l) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs; m) a gene encoding a ScOLE1, wherein the gene encoding said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 120, and / or wherein the polypeptide encoded by said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 119, or any of its orthologs or paralogs;170.n) a gene encoding an RnCOX2_GS_YALI, wherein the gene encoding said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 121, or any of its orthologs or paralogs;171.o) a gene encoding a PGF2_12_GS_YALI, wherein the gene encoding said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 123, or any of its orthologs or paralogs;172.p) a gene encoding a HsPGES-1_GS_YALI, wherein the gene encoding said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 126, and / or wherein the polypeptide encoded by said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 125, or any of its orthologs or paralogs;173.q) a gene encoding a D6D_YALI, wherein the gene encoding said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 128, and / or wherein the polypeptide encoded by said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 127, or any of its orthologs or paralogs;174.r) a gene encoding a D6Elo_YALI, wherein the gene encoding said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 130, and / or wherein the polypeptide encoded by said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 129, or any of its orthologs or paralogs;175.s) a gene encoding a D5D_YALI, wherein the gene encoding said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 132, and / or wherein the polypeptide encoded by said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 131, or any of its orthologs or paralogs;176.t) a gene encoding a KAR2, wherein the gene encoding said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 134, and / or wherein the polypeptide encoded by said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, or any of its orthologs or paralogs;177.u) a gene encoding a PDI1, wherein the gene encoding said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 136, and / or wherein the polypeptide encoded by said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, SEQ ID NO: 314, or any of its orthologs or paralogs;178.v) a gene encoding a CTT1_prepro, wherein the gene encoding said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 138, and / or wherein the polypeptide encoded by said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 137, SEQ ID NO: 319, SEQ ID NO: 320, SEQ ID NO: 321, or any of its orthologs or paralogs;179.w) a gene encoding a CTA1_prepro, wherein the gene encoding said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 140, and / or wherein the polypeptide encoded by said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 139, or any of its orthologs or paralogs;180.x) a gene encoding a CPR5, wherein the gene encoding said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 142, and / or wherein the polypeptide encoded by said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 141, or any of its orthologs or paralogs; y) a gene encoding an ICE2, wherein the gene encoding said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 144, and / or wherein the polypeptide encoded by said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 143, or any of its orthologs or paralogs; z) a gene encoding an NCP1, wherein the gene encoding said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 146, and / or wherein the polypeptide encoded by said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 145, or any of its orthologs or paralogs; aa) a gene encoding an AtMSBP1, wherein the gene encoding said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 148, and / or wherein the polypeptide encoded by said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 147, or any of its orthologs or paralogs;181.bb) a gene encoding an AtGRP7, wherein the gene encoding said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 150, and / or wherein the polypeptide encoded by said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 149, or any of its orthologs or paralogs;182.cc) a gene encoding an UGP1, wherein the gene encoding said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 152, and / or wherein the polypeptide encoded by said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 151, or any of its orthologs or paralogs; dd) a gene encoding a ZWF1, wherein the gene encoding said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 154, and / or wherein the polypeptide encoded by said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 153, SEQ ID NO: 326, SEQ ID NO: 327, SEQ ID NO: 328, SEQ ID NO: 329, or any of its orthologs or paralogs;183.ee) a gene encoding a HaCPR5hom_7, wherein the gene encoding said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 156, and / or wherein the polypeptide encoded by said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 155, or any of its orthologs or paralogs;184.ff) a gene encoding a RAD52, wherein the gene encoding said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 158, and / or wherein the polypeptide encoded by said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 157, or any of its orthologs or paralogs; gg) a gene encoding a GPX2, wherein the gene encoding said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 160, and / or wherein the polypeptide encoded by said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 159, or any of its orthologs or paralogs; hh) a gene encoding an NGL3, wherein the gene encoding said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 162, and / or wherein the polypeptide encoded by said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 161, or any of its orthologs or paralogs; ii) a gene encoding an INO2_L119A, wherein the gene encoding said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 164, and / or wherein the polypeptide encoded by said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 163, or any of its orthologs or paralogs;185.jj) a gene encoding an RNA15, wherein the gene encoding said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 166, and / or wherein the polypeptide encoded by said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 165, or any of its orthologs or paralogs; kk) a gene encoding a YRA2, wherein the gene encoding said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 168, and / or wherein the polypeptide encoded by said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 167, SEQ ID NO: 315, SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, or any of its orthologs or paralogs;186.II) a gene encoding an RnPA2GA, wherein the gene encoding said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 170, and / or wherein the polypeptide encoded by said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 169, SEQ ID NO: 322, SEQ ID NO: 323, or any of its orthologs or paralogs;187.mm) a gene encoding a STB5, wherein the gene encoding said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 172, and / or wherein the polypeptide encoded by said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 171, or any of its orthologs or paralogs; nn) a gene encoding a HSF1_R206S, wherein the gene encoding said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 174, and / or wherein the polypeptide encoded by said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 173, or any of its orthologs or paralogs;188.oo) a gene encoding an ADH1, wherein the gene encoding said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 176, and / or wherein the polypeptide encoded by said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 175, or any of its orthologs or paralogs; pp) a gene encoding a HvCPR5hom_6, wherein the gene encoding said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 178, and / or wherein the polypeptide encoded by said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 177, or any of its orthologs or paralogs;189.qq) a gene encoding a POS5, wherein the gene encoding said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 180, and / or wherein the polypeptide encoded by said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 179, SEQ ID NO: 324, SEQ ID NO: 325, or any of its orthologs or paralogs;190.rr) a gene encoding a SFA1, wherein the gene encoding said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 182, and / or wherein the polypeptide encoded by said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 181, or any of its orthologs or paralogs; ss) a gene encoding an INO4, wherein the gene encoding said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 184, and / or wherein the polypeptide encoded by said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 183, or any of its orthologs or paralogs; tt) a gene encoding an HSP12, wherein the gene encoding said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 186, and / or wherein the polypeptide encoded by said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 185, or any of its orthologs or paralogs; uu) a gene encoding an FPR2, wherein the gene encoding said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 188, and / or wherein the polypeptide encoded by said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 187, or any of its orthologs or paralogs; vv) a gene encoding an MSBP_40, wherein the gene encoding said MSBP_40 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 190, and / or wherein the polypeptide encoded by said MSBP_40 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 189, or any of its orthologs or paralogs;191.ww) a gene encoding an MSBP_56, wherein the gene encoding said MSBP_56 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 192, and / or wherein the polypeptide encoded by said MSBP_56 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 191, or any of its orthologs or paralogs;192.xx) a gene encoding an MSBP_22, wherein the gene encoding said MSBP_22 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 194, and / or wherein the polypeptide encoded by said MSBP_22 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 193, or any of its orthologs or paralogs;193.yy) a gene encoding a DAP1_9, wherein the gene encoding said DAP1_9 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 196, and / or wherein the polypeptide encoded by said DAP1_9 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 195, or any of its orthologs or paralogs;194.zz) a gene encoding an MSBP_21, wherein the gene encoding said MSBP_21 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 198, and / or wherein the polypeptide encoded by said MSBP_21 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 197, or any of its orthologs or paralogs;195.aaa) a gene encoding an MSBP_62, wherein the gene encoding said MSBP_62 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 200, and / or wherein the polypeptide encoded by said MSBP_62 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 199, or any of its orthologs or paralogs;196.bbb) a gene encoding an MSBP_26, wherein the gene encoding said MSBP_26 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 202, and / or wherein the polypeptide encoded by said MSBP_26 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 201, or any of its orthologs or paralogs;197.ccc) a gene encoding an MSBP_35, wherein the gene encoding said MSBP_35 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 204, and / or wherein the polypeptide encoded by said MSBP_35 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 203, or any of its orthologs or paralogs;198.ddd) a gene encoding an MSBP_17, wherein the gene encoding said MSBP_17 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 206, and / or wherein the polypeptide encoded by said MSBP_17 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 205, or any of its orthologs or paralogs; and199.eee) a gene encoding an MSBP_79, wherein the gene encoding said MSBP_79 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 208, and / or wherein the polypeptide encoded by said MSBP_79 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 207, or any of its orthologs or paralogs.

59. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes selected from the group consisting of:201.a) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs; b) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs;202.c) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 107, or any of its orthologs or paralogs;203.d) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115, or any of its orthologs or paralogs; and204.e) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs.

60. The host cell of any of the preceding claims, wherein the host cell has been genetically modified to express one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:206.a) a gene encoding an RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22 or SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21 or SEQ ID NO: 121, or any of its orthologs or paralogs;207.b) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 69 or SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54 or SEQ ID NO: 123, or any of its orthologs or paralogs;208.c) a gene encoding an ACC1 mutant, wherein the gene encoding said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71, and / or wherein the polypeptide encoded by said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 56, or any of its orthologs or paralogs;209.d) a gene encoding an McELO, wherein the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs; and210.e) optionally a gene encoding an ScOLE1, wherein the gene encoding said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 120, and / or wherein the polypeptide encoded by said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 119, or any of its orthologs or paralogs.

61. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:212.a) a gene encoding a MaD12D_2, wherein the gene encoding said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 108, and / or wherein the polypeptide encoded by said MaD12D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 107;213.b) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109;214.c) a gene encoding a MaD6Elo_2, wherein the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111; and215.d) a gene encoding a MaD5D_2, wherein the gene encoding said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 114, and / or wherein the polypeptide encoded by said MaD5D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 113.

62. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:217.a) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103;218.b) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105;219.c) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109;220.d) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115; and221.e) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117.

63. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:223.a) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs; b) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs;224.c) a gene encoding a MaD6D_2, wherein the gene encoding said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 110, and / or wherein the polypeptide encoded by said MaD6D_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 109, or any of its orthologs or paralogs;225.d) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115, or any of its orthologs or paralogs; e) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs; f) a gene encoding an RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21, or any of its orthologs or paralogs; g) a gene encoding an McELO, wherein the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs;226.h) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 69 or SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54 or SEQ ID NO: 123, or any of its orthologs or paralogs; and227.i) a gene encoding an ACC1 mutant, wherein the gene encoding said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71; and / or wherein the polypeptide encoded by said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 56, or any of its orthologs or paralogs.

64. The host cell of any of the preceding claims, wherein the host cell comprises one or more metabolic pathways for producing said prostaglandins, characterised in that the host cell is further modified to express a gene encoding a mutant acetyl-CoA carboxylase (ACC1) having enhanced catalytic activity compared to its wild-type counterpart, thereby increasing the supply of prostaglandin precursors.

65. The host cell of claim 64, wherein the gene encoding the ACC1 mutant has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polynucleotide of SEQ ID NO: 71, such as wherein the gene comprises or consists of SEQ ID NO: 71; and / or wherein the ACC1 mutant has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polypeptide of SEQ ID NO: 56.

66. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing an optionally heterologous gene encoding an ACC1 mutant, wherein the gene encoding said ACC1 mutant has at least 70% identity to SEQ ID NO: 71 and / or wherein the polypeptide encoded by said ACC1 mutant has at least 70% identity to SEQ ID NO: 56.

67. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes encoding one or more copies of RnCOX2, such as two copies of RnCOX2, wherein the one or more genes encoding said one or more copies of RnCOX2 has at least 60% identity to SEQ ID NO: 22 or SEQ ID NO: 122, and / or wherein the polypeptide(s) encoded by said one or more RnCOX2 has at least 60% identity to SEQ ID NO: 21 or SEQ ID NO: 121.

68. The host cell of claim 67, wherein the host cell is genetically modified to express genes encoding two copies of RnCOX2, such as encoding a copy of RnCOX2 having at least 60% identity to SEQ ID NO: 21 and a copy of RnCOX2_GS_YALI having at least 60% identity to SEQ ID NO: 121.

69. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes encoding one or more copies of PGF2_12, such as two copies of PGF2_12, wherein the one or more genes encoding said one or more copies of PGF2_12 has at least 60% identity to SEQ ID NO: 69 or SEQ ID NO: 124, and / or wherein the polypeptide(s) encoded by said one or more PGF2_12 has at least 60% identity to SEQ ID NO: 54 or SEQ ID NO: 123.

70. The host cell of claim 69, wherein the host cell is genetically modified to express genes encoding two copies of PGF2_12, such as encoding a copy of PGF2_12 having at least 60% identity to SEQ ID NO: 54 and a copy of PGF2_12_GS_YALI having at least 60% identity to SEQ ID NO: 123.

71. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:234.a) a gene encoding a RnCOX2_GS_YALI, wherein the gene encoding said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 121; and b) a gene encoding a HsPGES-1_GS_YALI, wherein the gene encoding said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 126, and / or wherein the polypeptide encoded by said HsPGES-1_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 125.

72. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:236.a) a gene encoding a RnCOX2_GS_YALI, wherein the gene encoding said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 121; and b) a gene encoding a PGF2_12_GS_YALI, wherein the gene encoding said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 124, and / or wherein the polypeptide encoded by said PGF2_12_GS_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 123.

73. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:238.a) a gene encoding a D6D_YALI, wherein the gene encoding said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 128, and / or wherein the polypeptide encoded by said D6D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 127;239.b) a gene encoding a D6Elo_YALI, wherein the gene encoding said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 130, and / or wherein the polypeptide encoded by said D6Elo_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 129; and240.c) a gene encoding a D5D_YALI, wherein the gene encoding said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 132, and / or wherein the polypeptide encoded by said D5D_YALI has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 131.

74. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:242.a) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103;243.b) a gene encoding an RmD12D, wherein the gene encoding said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said RmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105;244.c) a gene encoding a PaD6Elo, wherein the gene encoding said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 116, and / or wherein the polypeptide encoded by said PaD6Elo has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 115; d) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117;245.e) a gene encoding a RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21;246.f) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 69, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54;247.g) a gene encoding an ACC1_S659A_S1157A, wherein the gene encoding said ACC1_S659A_S1157A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71, and / or wherein the polypeptide encoded by said ACC1_S659A_S1157A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71; and248.h) a gene encoding a ScOLE1, wherein the gene encoding said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 120, and / or wherein the polypeptide encoded by said ScOLE1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 119.

75. The host cell of any of the preceding claims, wherein the host cell has been genetically modified to produce one or more prostaglandins from a carbon source, such as wherein the carbon source is glucose.

76. The host cell of any of the preceding claims, wherein the host cell has been genetically modified to produce arachidonic acid (ARA) and / or dihomo-gamma-linolenic acid (DGLA).

77. The host cell of claim 76, wherein the host cell has been genetically modified to produce prostaglandin Hl (PGH1) from dihomo-gamma-linolenic acid (DGLA), optionally by expressing COXI and / or COX2.

78. The host cell of any of the preceding claims, wherein the host cell has been genetically modified to express one or more extra copies of one or more genes as defined in any one of the preceding claims, and / or overexpress one or more of said genes.

79. The host cell of any of the preceding claims, wherein the host cell has been genetically modified to express a heterologous membrane-associated progesterone receptor (MAPR) family polypeptide, said polypeptide comprising a cytochrome bS-like heme / steroid-binding domain.

80. The host cell of claim 79, wherein the expressed MAPR family polypeptide further comprises:254.(i) a single-pass transmembrane segment;255.(ii) a cytosolic MAPR / PGRMC-like cytochrome b5-fold structured for heme and / or steroid binding; and256.(iii) a polypeptide sequence selected from the group consisting of:257.(a) a polypeptide having at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to any one of SEQ ID NO: 189 (MSBP_40), SEQ ID NO: 191 (MSBP_56), SEQ ID NO: 193 (MSBP_22), SEQ ID NO: 197 (MSBP_21), SEQ ID NO: 199 (MSBP_62), SEQ ID NO: 201 (MSBP_26), SEQ ID NO: 203 (MSBP_35), SEQ ID NO: 205 (MSBP_17), or SEQ ID NO: 207 (MSBP_79), and exhibiting membrane-associated progesterone receptor (MAPR) activity; (b) a polypeptide having at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to SEQ ID NO: 195 (DAP1_9), and exhibiting membrane-associated progesterone receptor (MAPR) activity; and258.(c) a variant polypeptide of any of (a) or (b) having at least 50%, such as at least 60%, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to the respective SEQ ID NO and exhibiting membrane-associated progesterone receptor (MAPR) activity.

81. The host cell of any of the preceding claims, wherein the host cell has been genetically modified to introduce one or more heterologous genes encoding a polypeptide having enzymatic activity in aprostaglandin biosynthesis pathway, and / or to increase the expression of one or more endogenous genes encoding a polypeptide having enzymatic activity in a prostaglandin biosynthesis pathway.

82. The host cell of claim 81, wherein the gene encodes a protein disulfide isomerase (PDI) polypeptide selected from the group consisting of:261.(i) a polypeptide comprising the amino acid sequence of any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, and SEQ ID NO: 314; and262.(ii) a variant polypeptide, such as a paralog or ortholog thereof, having at least 50%, such as at least 60%, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, and SEQ ID NO: 314 and retaining protein disulfide isomerase activity.

83. The host cell of any of the preceding claims, wherein the host cell has been genetically modified to express and / or overexpress one or more auxiliary genes, such as auxiliary genes capable of increasing production of one or more prostaglandins and / or intermediates in a biosynthetic prostaglandin pathway.

84. The host cell of any of the preceding claims, wherein the host cell has been genetically modified by one or more modifications independently selected from the group consisting of:265.a) expressing one or more heterologous auxiliary genes; and266.b) overexpressing one or more endogenous auxiliary genes;267.wherein said auxiliary genes are capable of increasing production of one or more prostaglandins or intermediates in a prostaglandin biosynthetic pathway.

85. The host cell of claim 84, wherein the one or more genes encodes a protein disulfide isomerase, such as an ER-luminal protein disulfide isomerase (PDI), for example encoding a PDI1 or PDIA1, a paralog or ortholog thereof.

86. The host cell of any of the preceding claims, wherein the host cell has been genetically modifiedto express a gene encoding an endoplasmic reticulum (ER) chaperone of the HSP70 family comprising an ATP-binding domain.

87. The host cell of claim 86, wherein the ER chaperone is selected from the group consisting of: (i) a polypeptide comprising the amino acid sequence of any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299; and271.(ii) a variant polypeptide, such as a paralog or ortholog thereof, having at least 50%, such as at least 60%, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% sequence identity to any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, and retaining endoplasmic reticulum chaperone activity.

88. The host cell of any of claims 86-87, wherein the gene encodes a KAR2 having at least 60% identity to SEQ ID NO: 134, or any of its orthologs or paralogs.

89. The host cell of any of the preceding claims, wherein the host cell is genetically modified by a) expressing one or more heterologous auxiliary genes, and / or b) overexpressing one or more endogenous auxiliary genes, wherein said gene(s) is / are independently selected from the group consisting of:274.a) a gene encoding an ATPase involved in protein import into the ER and acting as a chaperone to mediate protein folding (KAR2), or any of its orthologs or paralogs;275.b) a gene encoding a Membrane steroid-binding protein (MSBP);276.c) a gene encoding a NADP-cytochrome P450 reductase associated with Ergllp (NCP1), or any of its orthologs or paralogs;277.d) a gene encoding a protein disulfide isomerase (PDI) of the ER lumen with multifunctional oxidoreductase activity;278.e) a gene encoding a cytosolic or peroxisomal catalase (CT) which acts on hydrogen peroxide to degrade it;279.g) a gene encoding a a nuclear RNA-binding protein from Arabidopsis thaliana (AtGRP7), or any of its orthologs or paralogs; h) a gene encoding Peptidyl-prolyl cis-trans isomerase located in the ER (CPR5), or any of its orthologs or paralogs;280.i) a gene encoding Integral ER membrane protein with type-III transmembrane domain (ICE2),, or any of its orthologs or paralogs;281.j) a gene encoding a UDP-glucose pyrophosphorylase (UGPase); catalysing the reversible formation of UDP-GIc from glucose 1-phosphate and UTP;282.k) a gene encoding Glucose-6-phosphate dehydrogenase (G6PD) (ZWF1), or any of its orthologs or paralogs;283.l) a gene encoding a cytochrome P450 reductase (CPR) acting with P450 enzymes to transfer electrons from cofactors;284.m) a gene encoding a Protein involved in homologous recombination; attenuating resection of DNA double-strand break ends (RAD52), or any of its orthologs or paralogs;285.n) a gene encoding Phospholipid hydroperoxide glutathione peroxidase (GPX2), or any of its orthologs or paralogs;286.o) a gene encoding a 3'-5' exonuclease specific for poly-A RNAs;287.p) a gene encoding a transcription factor involved in derepression of phospholipid biosynthetic genes; q) a gene encoding a Component of the cleavage and polyadenylation factor I (CF I);288.r) a gene encoding RNA and export factor binding proteins involed in export of polyA;289.s) a gene encoding Phospholipase A2, group HA type acting to hydrolyze phospholipids to free fatty acids;290.t) a gene encoding a Transcription factor involved in regulating multidrug resistance and the oxidative stress response (STB5), or any of its orthologs or paralogs;291.u) a gene encoding a modified Trimeric heat shock transcription factor (HSF1_R206S), or any of its orthologs or paralogs;292.v) a gene encoding alcohol dehydrogenase (ADH) converting acetaldehyde to ethanol;293.x) a gene encoding a Mitochondrial NADH kinase; acting to phosphorylate NADH during oxidative stress (POS5);294.y) a gene encoding a Bifunctional alcohol dehydrogenase and formaldehyde dehydrogenase involved in detoxification of formaldehyde;295.z) a gene encoding a Transcription factor involved in phospholipid synthesis (INO4), or any of its orthologs or paralogs;296.aa) a gene encoding a heat shock protein (HSP12), a plasma membrane protein involved in maintaining membrane organization, or any of its orthologs or paralogs;297.bb) a gene encoding a Membrane-bound peptidyl-prolyl cis-trans isomerase (PPIase), and cc) a gene encoding a Lanosterol 14-alpha-demethylase (ERG11) catalyzes C-14 demethylation of lanosterol to form 4,4"-dimethyl cholesta-8,14,24-triene-3-beta-ol;298.dd) a gene encoding a Cytosolic copper-zinc superoxide dismutase / sulfide oxidase (sodl) acting to detoxify superoxide and hydrogen sulfide; and299.ee) a gene encoding an Aminolevulinate dehydratase (HEM2) converting 5-aminolevulinate to porphobilinogen.

90. The host cell of any of the preceding claims, wherein the host cell is genetically modified by a) expressing one or more heterologous auxiliary genes, and / or b) overexpressing one or more endogenous auxiliary genes, wherein said gene(s) is / are independently selected from the group consisting of:301.a) a gene encoding KAR2, wherein the gene encoding said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 134, and / or wherein the polypeptide encoded by said KAR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, SEQ ID NO: 299, or any of its orthologs or paralogs;302.b) a gene encoding AtMSBP1, wherein the gene encoding said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 148, and / or wherein the polypeptide encoded by said AtMSBP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 147, or any of its orthologs or paralogs;303.c) a gene encoding NCP1, wherein the gene encoding said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 146, and / or wherein the polypeptide encoded by said NCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 145, or any of its orthologs or paralogs; d) a gene encoding PDI1, wherein the gene encoding said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 136, and / or wherein the polypeptide encoded by said PDI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, SEQ ID NO: 314, or any of its orthologs or paralogs;304.e) a gene encoding CTT1_prepro, wherein the gene encoding said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 138, and / or wherein the polypeptide encoded by said CTT1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 137, SEQ ID NO: 319, SEQ ID NO: 320, SEQ ID NO: 321, or any of its orthologs or paralogs;305.f) a gene encoding CTA1_prepro, wherein the gene encoding said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 140, and / or wherein the polypeptide encoded by said CTA1_prepro has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 139, or any of its orthologs or paralogs;306.g) a gene encoding AtGRP7, wherein the gene encoding said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 150, and / or wherein the polypeptide encoded by said AtGRP7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 149, or any of its orthologs or paralogs; h) a gene encoding CPR5, wherein the gene encoding said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 142, and / or wherein the polypeptide encoded by said CPR5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 141, or any of its orthologs or paralogs; i) a gene encoding ICE2, wherein the gene encoding said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 144, and / or wherein the polypeptide encoded by said ICE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 143, or any of its orthologs or paralogs; j) a gene encoding UGP1, wherein the gene encoding said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 152, and / or wherein the polypeptide encoded by said UGP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 151, or any of its orthologs or paralogs; k) a gene encoding ZWF1, wherein the gene encoding said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 154, and / or wherein the polypeptide encoded by said ZWF1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 153, SEQ ID NO: 326, SEQ ID NO: 327, SEQ ID NO: 328, SEQ ID NO: 329, or any of its orthologs or paralogs;307.l) a gene encoding HaCPR5hom_7, wherein the gene encoding said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 156, and / or wherein the polypeptide encoded by said HaCPR5hom_7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 155, or any of its orthologs or paralogs;308.m) a gene encoding RAD52, wherein the gene encoding said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 158, and / or wherein the polypeptide encoded by said RAD52 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 157, or any of its orthologs or paralogs; n) a gene encoding GPX2, wherein the gene encoding said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 160, and / or wherein the polypeptide encoded by said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 159, or any of its orthologs or paralogs; o) a gene encoding NGL3, wherein the gene encoding said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 162, and / or wherein the polypeptide encoded by said NGL3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 161, or any of its orthologs or paralogs; p) a gene encoding INO2_L119A, wherein the gene encoding said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 164, and / or wherein the polypeptide encoded by said INO2_L119A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 163, or any of its orthologs or paralogs;309.q) a gene encoding RNA15, wherein the gene encoding said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 166, and / or wherein the polypeptide encoded by said RNA15 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 165, or any of its orthologs or paralogs; r) a gene encoding YRA2, wherein the gene encoding said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 168, and / or wherein the polypeptide encoded by said YRA2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 167, SEQ ID NO: 315, SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318, or any of its orthologs or paralogs;310.s) a gene encoding RnPA2GA, wherein the gene encoding said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 170, and / or wherein the polypeptide encoded by said RnPA2GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 169, SEQ ID NO: 322, SEQ ID NO: 323, or any of its orthologs or paralogs;311.t) a gene encoding STB5, wherein the gene encoding said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 172, and / or wherein the polypeptide encoded by said STB5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 171, or any of its orthologs or paralogs; u) a gene encoding HSF1_R206S, wherein the gene encoding said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 174, and / or wherein the polypeptide encoded by said HSF1_R206S has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 173, or any of its orthologs or paralogs;312.v) a gene encoding ADH1, wherein the gene encoding said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 176, and / or wherein the polypeptide encoded by said ADH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 175, or any of its orthologs or paralogs; w) a gene encoding HvCPR5hom_6, wherein the gene encoding said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 178, and / or wherein the polypeptide encoded by said HvCPR5hom_6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 177, or any of its orthologs or paralogs;313.x) a gene encoding POS5, wherein the gene encoding said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 180, and / or wherein the polypeptide encoded by said POS5 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any of SEQ ID NO: 179, SEQ ID NO: 324, SEQ ID NO: 325, or any of its orthologs or paralogs;314.y) a gene encoding SFA1, wherein the gene encoding said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 182, and / or wherein the polypeptide encoded by said SFA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 181, or any of its orthologs or paralogs; z) a gene encoding INO4, wherein the gene encoding said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 184, and / or wherein the polypeptide encoded by said INO4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 183, or any of its orthologs or paralogs; aa) a gene encoding HSP12, wherein the gene encoding said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 186, and / or wherein the polypeptide encoded by said HSP12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 185, or any of its orthologs or paralogs; bb) a gene encoding FPR2, wherein the gene encoding said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 188, and / or wherein the polypeptide encoded by said FPR2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 187, or any of its orthologs or paralogs; cc) a gene encoding ERG11, wherein the gene encoding said ERG11 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 262, and / or wherein the polypeptide encoded by said ERG11 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 261, or any of its orthologs or paralogs; dd) a gene encoding SOD1, wherein the gene encoding said SOD1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 264, and / or wherein the polypeptide encoded by said SOD1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 263, or any of its orthologs or paralogs; and315.ee) a gene encoding HEM2, wherein the gene encoding said HEM2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 266, and / or wherein the polypeptide encoded by said HEM2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 265, or any of its orthologs or paralogs.

91. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding KAR2, wherein the gene encoding said KAR2 has at least 70% identity to SEQ ID NO: 134 and / or wherein the polypeptide encoded by said KAR2 has at least 70% identity to any of SEQ ID NO: 133, SEQ ID NO: 283, SEQ ID NO: 284, SEQ ID NO: 285, SEQ ID NO: 286, SEQ ID NO: 287, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, SEQ ID NO: 292, SEQ ID NO: 293, SEQ ID NO: 294, SEQ ID NO: 295, SEQ ID NO: 296, SEQ ID NO: 297, SEQ ID NO: 298, and SEQ ID NO: 299.

92. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding AtMSBP1, wherein the gene encoding said AtMSBP1 has at least 70% identity to SEQ ID NO: 148 and / or wherein the polypeptide encoded by said AtMSBP1 has at least 70% identity to SEQ ID NO: 147.

93. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding NCP1, wherein the gene encoding said NCP1 has at least 70% identity to SEQ ID NO: 146 and / or wherein the polypeptide encoded by said NCP1 has at least 70% identity to SEQ ID NO: 145.

94. The host cell of any of the preceding claims, wherein the host cell is genetically modified byexpressing a heterologous gene or overexpressing an endogenous gene encoding PDI1, wherein the gene encoding said PDI1 has at least 70% identity to SEQ ID NO: 136 and / or wherein the polypeptide encoded by said PDI1 has at least 70% identity to any of SEQ ID NO: 135, SEQ ID NO: 300, SEQ ID NO: 301, SEQ ID NO: 302, SEQ ID NO: 303, SEQ ID NO: 304, SEQ ID NO: 305, SEQ ID NO: 306, SEQ ID NO: 307, SEQ ID NO: 308, SEQ ID NO: 309, SEQ ID NO: 310, SEQ ID NO: 311, SEQ ID NO: 312, SEQ ID NO: 313, and SEQ ID NO: 314.

95. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding CTT1_prepro, wherein the gene encoding said CTT1_prepro has at least 70% identity to SEQ ID NO: 138 and / or wherein the polypeptide encoded by said CTT1_prepro has at least 70% identity to any of SEQ ID NO: 137, SEQ ID NO: 319, SEQ ID NO: 320, SEQ ID NO: 321.

96. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding CTA1_prepro, wherein the gene encoding said CTA1_prepro has at least 70% identity to SEQ ID NO: 140 and / or wherein the polypeptide encoded by said CTA1_prepro has at least 70% identity to SEQ ID NO: 139.

97. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene encoding AtGRP7, wherein the gene encoding said AtGRP7 has at least 70% identity to SEQ ID NO: 150 and / or wherein the polypeptide encoded by said AtGRP7 has at least 70% identity to SEQ ID NO: 149.

98. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding CPR5, wherein the gene encoding said CPR5 has at least 70% identity to SEQ ID NO: 142 and / or wherein the polypeptide encoded by said CPR5 has at least 70% identity to SEQ ID NO: 141.

99. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding ICE2, wherein the gene encoding said ICE2 has at least 70% identity to SEQ ID NO: 144 and / or wherein the polypeptide encoded by said ICE2 has at least 70% identity to SEQ ID NO: 143.

100. The host cell of any of the preceding claims, wherein the host cell is genetically modified byexpressing a heterologous gene or overexpressing an endogenous gene encoding UGP1, wherein the gene encoding said UGP1 has at least 70% identity to SEQ ID NO: 152 and / or wherein the polypeptide encoded by said UGP1 has at least 70% identity to SEQ ID NO: 151.

101. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding ZWF1, wherein the gene encoding said ZWF1 has at least 70% identity to SEQ ID NO: 154 and / or wherein the polypeptide encoded by said ZWF1 has at least 70% identity to any of SEQ ID NO: 153, SEQ ID NO: 326, SEQ ID NO: 327, SEQ ID NO: 328, and SEQ ID NO: 329.

102. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding HaCPR5hom_7, wherein the gene encoding said HaCPR5hom_7 has at least 70% identity to SEQ ID NO: 156 and / or wherein the polypeptide encoded by said HaCPR5hom_7 has at least 70% identity to SEQ ID NO: 155.

103. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding RAD52, wherein the gene encoding said RAD52 has at least 70% identity to SEQ ID NO: 158 and / or wherein the polypeptide encoded by said RAD52 has at least 70% identity to SEQ ID NO: 157.

104. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding GPX2, wherein the gene encoding said GPX2 has at least 70% identity to SEQ ID NO: 160 and / or wherein the polypeptide encoded by said GPX2 has at least 70% identity to SEQ ID NO: 159.

105. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding NGL3, wherein the gene encoding said NGL3 has at least 70% identity to SEQ ID NO: 162 and / or wherein the polypeptide encoded by said NGL3 has at least 70% identity to SEQ ID NO: 161.

106. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding INO2_L119A, wherein the gene encoding said INO2_L119A has at least 70% identity to SEQ ID NO: 164 and / or wherein the polypeptide encoded by said INO2_L119A has at least 70% identity to SEQ ID NO: 163.

107. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding RNA15, wherein the gene encoding said RNA15 has at least 70% identity to SEQ ID NO: 166 and / or wherein the polypeptide encoded by said RNA15 has at least 70% identity to SEQ ID NO: 165.

108. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding YRA2, wherein the gene encoding said YRA2 has at least 70% identity to SEQ ID NO: 168 and / or wherein the polypeptide encoded by said YRA2 has at least 70% identity to any of SEQ ID NO: 167, SEQ ID NO: 315, SEQ ID NO: 316, SEQ ID NO: 317, SEQ ID NO: 318.

109. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding RnPA2GA, wherein the gene encoding said RnPA2GA has at least 70% identity to SEQ ID NO: 170 and / or wherein the polypeptide encoded by said RnPA2GA has at least 70% identity to any of SEQ ID NO: 169, SEQ ID NO: 322, and SEQ ID NO: 323.

110. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding STB5, wherein the gene encoding said STB5 has at least 70% identity to SEQ ID NO: 172 and / or wherein the polypeptide encoded by said STB5 has at least 70% identity to SEQ ID NO: 171.

111. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding HSF1_R206S, wherein the gene encoding said HSF1_R206S has at least 70% identity to SEQ ID NO: 174 and / or wherein the polypeptide encoded by said HSF1_R206S has at least 70% identity to SEQ ID NO: 173.

112. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding ADH1, wherein the gene encoding said ADH1 has at least 70% identity to SEQ ID NO: 176 and / or wherein the polypeptide encoded by said ADH1 has at least 70% identity to SEQ ID NO: 175.

113. The host cell of any of the preceding claims, wherein the host cell is genetically modified byexpressing a heterologous gene or overexpressing an endogenous gene encoding HvCPR5hom_6, wherein the gene encoding said HvCPR5hom_6 has at least 70% identity to SEQ ID NO: 178 and / or wherein the polypeptide encoded by said HvCPR5hom_6 has at least 70% identity to SEQ ID NO: 177.

114. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding POS5, wherein the gene encoding said POS5 has at least 70% identity to SEQ ID NO: 180 and / or wherein the polypeptide encoded by said POS5 has at least 70% identity to any of SEQ ID NO: 179, SEQ ID NO: 324, and SEQ ID NO: 325.

115. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding SFA1, wherein the gene encoding said SFA1 has at least 70% identity to SEQ ID NO: 182 and / or wherein the polypeptide encoded by said SFA1 has at least 70% identity to SEQ ID NO: 181.

116. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding INO4, wherein the gene encoding said INO4 has at least 70% identity to SEQ ID NO: 184 and / or wherein the polypeptide encoded by said INO4 has at least 70% identity to SEQ ID NO: 183.

117. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding HSP12, wherein the gene encoding said HSP12 has at least 70% identity to SEQ ID NO: 186 and / or wherein the polypeptide encoded by said HSP12 has at least 70% identity to SEQ ID NO: 185.

118. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding FPR2, wherein the gene encoding said FPR2 has at least 70% identity to SEQ ID NO: 188 and / or wherein the polypeptide encoded by said FPR2 has at least 70% identity to SEQ ID NO: 187.

119. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing a heterologous gene or overexpressing an endogenous gene encoding ScOLE1, wherein the gene encoding said ScOLE1 has at least 70% identity to SEQ ID NO: 120 and / or wherein the polypeptide encoded by said ScOLE1 has at least 70% identity to SEQ ID NO: 119.

120. The host cell of any of the preceding claims, wherein the host cell has been genetically modified to comprise a gene encoding a cytochrome b5 (CYB5) enzyme and / or a cytochrome b5 reductase.

121. The host cell of claim 120, wherein the gene encoding the cytochrome b5 enzyme and the gene encoding the cytochrome b5 reductase are heterologous to the host cell.

122. The host cell of any of claims 120-121, wherein the gene encoding the cytochrome b5 (CYB5) enzyme has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polynucleotide of SEQ ID NO: 100; and / or wherein the cytochrome b5 (CYB5) enzyme has at least 60%, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polypeptide of SEQ ID NO: 99.

123. The host cell of any of claims 120-122, wherein the gene encoding the cytochrome b5 reductase has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polynucleotide of SEQ ID NO: 98, such as wherein the gene comprises or consists of SEQ ID NO: 98; and / or wherein the cytochrome b5 reductase has at least 60% sequence identity, such as at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to the polypeptide of SEQ ID NO: 97.

124. The host cell of any of the preceding claims, wherein the host cell is genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:348.a) a gene encoding a RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21;349.b) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 69, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54;350.c) a gene encoding an ACC1_S659A_S1157A, wherein the gene encoding said ACC1_S659A_S1157A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71, and / or wherein the polypeptide encoded by said ACC1_S659A_S1157A has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71;351.d) a gene encoding a NCB5R_MORAP_GA, wherein the gene encoding said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 98, and / or wherein the polypeptide encoded by said NCB5R_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 97; and352.e) a gene encoding a CYB5_MORAP_GA, wherein the gene encoding said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 100, and / or wherein the polypeptide encoded by said CYB5_MORAP_GA has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 99.

125. The host cell of any of the preceding claims, wherein the host cell is further genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:354.a) a gene encoding an RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21, or any of its orthologs or paralogs; b) a gene encoding an McELO, wherein the gene encoding said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 102, and / or wherein the polypeptide encoded by said McELO has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 101, or any of its orthologs or paralogs;355.- 277 - c) a gene encoding an HsPGES1, wherein the gene encoding said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 126 or SEQ ID NO: 40, and / or wherein the polypeptide encoded by said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 125 or SEQ ID NO: 39, or any of its orthologs or paralogs;126. The host cell of any of the preceding claims, wherein the host cell is further genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:357.a) a gene encoding a PGF2_12, wherein the gene encoding said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 69, and / or wherein the polypeptide encoded by said PGF2_12 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 54, or any of its orthologs or paralogs; and358.b) a gene encoding an ACC1 mutant, wherein the gene encoding said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 71, and / or wherein the polypeptide encoded by said ACC1 mutant has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 56, or any of its orthologs or paralogs.

127. The host cell of any of the preceding claims, for producing prostaglandin El, wherein the host cell has been genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:360.a) a gene encoding a RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22 or SEQID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21 or SEQ ID NO: 121, or any of its orthologs or paralogs;361.b) a gene encoding a HsPGES1, wherein the gene encoding said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 40, and / or wherein the polypeptide encoded by said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 39, or any of its orthologs or paralogs; c) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs; d) a gene encoding an RmD12D, wherein the gene encoding said aRmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said aRmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs; and362.e) a gene encoding a MaD6Elo_2, wherein the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111, or any of its orthologs or paralogs.

128. The host cell of any of the preceding claims, for producing prostaglandin E2, wherein the host cell has been genetically modified by expressing one or more heterologous genes, wherein said heterologous gene(s) is / are selected from the group consisting of:364.a) a gene encoding a RnCOX2, wherein the gene encoding said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 22 or SEQ ID NO: 122, and / or wherein the polypeptide encoded by said RnCOX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 21 or SEQ ID NO: 121, or any of its orthologs or paralogs;365.b) a gene encoding a HsPGES1, wherein the gene encoding said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 40, and / or wherein the polypeptide encoded by said HsPGES1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 39, or any of its orthologs or paralogs; c) a gene encoding an EpD6D, wherein the gene encoding said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 104, and / or wherein the polypeptide encoded by said EpD6D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 103, or any of its orthologs or paralogs; d) a gene encoding an RmD12D, wherein the gene encoding said aRmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 106, and / or wherein the polypeptide encoded by said aRmD12D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 105, or any of its orthologs or paralogs; and366.e) a gene encoding a MaD6Elo_2, wherein the gene encoding said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 112, and / or wherein the polypeptide encoded by said MaD6Elo_2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 111, or any of its orthologs or paralogs, and367.f) a gene encoding an EgD5D, wherein the gene encoding said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 118, and / or wherein the polypeptide encoded by said EgD5D has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 117, or any of its orthologs or paralogs129. A genetically modified host cell comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, wherein the host cell has been genetically modified by attenuating, disrupting and / or deleting, for example deleting, one or more endogenous genes of the host cell.

130. The host cell of claim 129, wherein the host cell is as defined in any one of claims 1-128.

131. The host cell of claim 129, wherein the attenuating, disrupting and / or deleting one or more endogenous genes of the host cell provides for reduced formation of byproducts and / or increased production of one or more prostaglandins.

132. The host cell of any of claims 129-131, wherein the one or more endogenous genes are selected from the group consisting of:371.a) gtt2;372.b) yprl;373.c) gre3;374.d) gcyl;375.e) gre2;376.f) ydr541c;377.g) gtt1;378.h) ecm4;379.i) adh6;380.j) aril;381.k) ycrl07w;382.l) adh7;383.m) aral;384.n) gpxl;385.o) gpx2;386.p) gpx3;387.q) ithl;388.r) ydll24w;389.s) yjl068c;390.t) prxl;391.u) tsa1;392.v) oye2;393.w) oye3;394.x) bdhl;395.y) bdh2;396.z) ccpl; and397.any paralogs, and any orthologs thereof.

133. The host cell of claim 132, wherein the one or more endogenous genes are selected from the group consisting of:399.a) a gene encoding a GTT2, wherein the gene encoding said GTT2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 210, and / or wherein the polypeptide encoded by said GTT2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 209, or any of its orthologs or paralogs;400.b) a gene encoding a YPR1, wherein the gene encoding said YPR1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 212, and / or wherein the polypeptide encoded by said YPR1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 211, or any of its orthologs or paralogs;401.c) a gene encoding a GRE3, wherein the gene encoding said GRE3 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 214, and / or wherein the polypeptide encoded by said GRE3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 213, or any of its orthologs or paralogs;402.d) a gene encoding a GCY1, wherein the gene encoding said GCY1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 216, and / or wherein the polypeptide encoded by said GCY1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 215, or any of its orthologs or paralogs;403.e) a gene encoding a GRE2, wherein the gene encoding said GRE2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 218, and / or wherein the polypeptide encoded by said GRE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 217, or any of its orthologs or paralogs;404.f) a gene encoding a YDR541C, wherein the gene encoding said YDR541C has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 220, and / or wherein the polypeptide encoded by said YDR541C has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 219, or any of its orthologs or paralogs;405.g) a gene encoding a GTT1, wherein the gene encoding said GTT1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 222, and / or wherein the polypeptide encoded by said GTT1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 221, or any of its orthologs or paralogs; h) a gene encoding an ECM4, wherein the gene encoding said ECM4 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 224, and / or wherein the polypeptide encoded by said ECM4 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 223, or any of its orthologs or paralogs;406.i) a gene encoding an ADH6, wherein the gene encoding said ADH6 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 226, and / or wherein the polypeptide encoded by said ADH6 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 225, or any of its orthologs or paralogs;407.j) a gene encoding an ARI1, wherein the gene encoding said ARI1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 228, and / or wherein the polypeptide encoded by said ARI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 227, or any of its orthologs or paralogs;408.k) a gene encoding a YCR107W, wherein the gene encoding said YCR107W has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 230, and / or wherein the polypeptide encoded by said YCR107W has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 229, or any of its orthologs or paralogs;409.l) a gene encoding an ADH7, wherein the gene encoding said ADH7 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 232, and / or wherein the polypeptide encoded by said ADH7 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 231, or any of its orthologs or paralogs;410.m) a gene encoding an ARA1, wherein the gene encoding said ARA1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 234, and / or wherein the polypeptide encoded by said ARA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 233, or any of its orthologs or paralogs;411.n) a gene encoding a GPX1, wherein the gene encoding said GPX1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 236, and / or wherein the polypeptide encoded by said GPX1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 235, or any of its orthologs or paralogs;412.o) a gene encoding a GPX2, wherein the gene encoding said GPX2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 238, and / or wherein the polypeptide encoded by said GPX2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 237, or any of its orthologs or paralogs;413.r) a gene encoding a YDL124W, wherein the gene encoding said YDL124W has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 244, and / or wherein the polypeptide encoded by said YDL124W has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 243, or any of its orthologs or paralogs;414.s) a gene encoding a YJL068C, wherein the gene encoding said YJL068C has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 246, and / or wherein the polypeptide encoded by said YJL068C has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 245, or any of its orthologs or paralogs;415.t) a gene encoding a PRX1, wherein the gene encoding said PRX1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 248, and / or wherein the polypeptide encoded by said PRX1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 247, or any of its orthologs or paralogs;416.u) a gene encoding a TSA1, wherein the gene encoding said TSA1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 250, and / or wherein the polypeptide encoded by said TSA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 249, or any of its orthologs or paralogs;417.v) a gene encoding an OYE2, wherein the gene encoding said OYE2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 252, and / or wherein the polypeptide encoded by said OYE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 251, or any of its orthologs or paralogs;418.w) a gene encoding an OYE3, wherein the gene encoding said OYE3 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 254, and / or wherein the polypeptide encoded by said OYE3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 253, or any of its orthologs or paralogs;419.x) a gene encoding a BDH1, wherein the gene encoding said BDH1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 256, and / or wherein the polypeptide encoded by said BDH1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 255, or any of its orthologs or paralogs;420.y) a gene encoding a BDH2, wherein the gene encoding said BDH2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 258, and / or wherein the polypeptide encoded by said BDH2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 257, or any of its orthologs or paralogs; and421.z) a gene encoding a CCP1, wherein the gene encoding said CCP1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 260, and / or wherein the polypeptide encoded by said CCP1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 259, or any of its orthologs or paralogs.

134. The host cell of any of claims 129-133, wherein the one or more endogenous genes are selected from the group consisting of:423.a) GTT1;424.b) YJL068C;425.c) GRE2;426.d) ARI1;427.e) YDL124W;428.f) TSA1;429.g) OYE3; and430.any paralogs, and any orthologs thereof.

135. The host cell of claim 134, wherein the one or more endogenous genes are selected from the group consisting of:432.a) a gene encoding a GTT1, wherein the gene encoding said GTT1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 222, and / or wherein the polypeptide encoded by said GTT1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 221, or any of its orthologs or paralogs;433.b) a gene encoding a YJL068C, wherein the gene encoding said YJL068C has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 246, and / or wherein the polypeptide encoded by said YJL068C has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 245, or any of its orthologs or paralogs;434.c) a gene encoding a GRE2, wherein the gene encoding said GRE2 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 218, and / or wherein the polypeptide encoded by said GRE2 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 217, or any of its orthologs or paralogs;435.d) a gene encoding an ARI1, wherein the gene encoding said ARI1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 228, and / or wherein the polypeptide encoded by said ARI1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 227, or any of its orthologs or paralogs;436.e) a gene encoding a YDL124W, wherein the gene encoding said YDL124W has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 244, and / or wherein the polypeptide encoded by said YDL124W has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 243, or any of its orthologs or paralogs;437.f) a gene encoding a TSA1, wherein the gene encoding said TSA1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 250, and / or wherein the polypeptide encoded by said TSA1 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 249, or any of its orthologs or paralogs;438.g) a gene encoding an OYE3, wherein the gene encoding said OYE3 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 254, and / or wherein the polypeptide encoded by said OYE3 has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 253, or any of its orthologs or paralogs.

136. The host cell of any of claims 129-135, wherein the host cell is Saccharomyces cerevisiae,Yarrowia lipolytica, or Komagataella phaffii, for example Saccharomyces cerevisiae.

137. The host cell of any of claims 129-136, wherein the host cell is configured for producing prostaglandin E2 (PGE2)138. The host cell of any of claims 129-136, wherein the host cell is configured for producing prostaglandin E2 (PGE2), characterized in that i) the endogenous gene GTT1, a paralog or ortholog thereof, is attenuated or deleted; and / or ii) the endogenous gene YJL068C, a paralog or ortholog thereof, is attenuated or deleted, optionally wherein the host cell is S. cerevisiae.

139. The host cell of any of claims 129-136, wherein the host cell is configured for producing prostaglandin D2 (PGD2), characterized in that i) the endogenous gene GTT1, a paralog or ortholog thereof, is attenuated or deleted; and / or ii) the endogenous gene YJL068C, a paralog or ortholog thereof, is attenuated or deleted, optionally wherein the host cell is S. cerevisiae.

140. The host cell of any of claims 129-136, wherein the host cell is a Komagataella phaffii host cell, and the endogenous gene GTT1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 268, and / or wherein the polypeptide encoded by said gene has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 267; or444.the host cell is a Yarrowia lipolytica host cell, and the endogenous gene GTT1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to any one of SEQ ID NOs: 270, 272, 274, 276, or 278, and / or wherein the polypeptide encoded by said gene has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to any one of SEQ ID NOs: 269, 271, 273, 275, or 277.

141. The host cell of any of claims 129-136, wherein the host cell is configured for producing prostaglandin F2a, characterized in that the endogenous gene TSA1, a paralog or ortholog thereof, is attenuated or deleted.

142. The host cell of any of claims 129-136, wherein the host cell is a Komagataella phaffii host cell, and the endogenous gene TSA1 has at least 60%, such as at least 70%, such as at least 80%, such as atleast 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 282, and / or wherein the polypeptide encoded by said gene has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 281; or447.the host cell is a Yarrowia lipolytica host cell, and the endogenous gene TSA1 has at least 60%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as 100% identity to SEQ ID NO: 280, and / or wherein the polypeptide encoded by said gene has at least 70%, such as at least 75%, such as at least 80%, such as at least 90%, such as at least 95%, such as at least 99%, such as at least 100% identity to SEQ ID NO: 279.

143. A genetically modified host cell for the production of prostaglandin E2 (PGE2), wherein the host cell comprises one or more metabolic pathways capable of producing PGE2 from a prostaglandin precursor, characterised in that an endogenous gene encoding a glutathione S-transferase (GTT1), or a paralog or ortholog thereof, is attenuated or deleted, thereby increasing the production specificity for PGE2.

144. A genetically modified host cell for the production of prostaglandin F2a (PGF2a), wherein the host cell comprises one or more metabolic pathways capable of producing PGF2a from a prostaglandin precursor, characterised in that an endogenous gene encoding a thioredoxin peroxidase (TSA1), or a paralog or ortholog thereof, is attenuated or deleted, thereby increasing the production of PGF2a.

145. A genetically modified host cell for the de novo production of one or more prostaglandins from a carbon source, wherein the host cell comprises one or more metabolic pathways for producing said prostaglandins, characterised in that the host cell is further modified to express a gene encoding a mutant acetyl-CoA carboxylase (ACC1) having enhanced catalytic activity compared to its wild-type counterpart, thereby increasing the supply of prostaglandin precursors.

146. A genetically modified host cell comprising a heterologous metabolic pathway for producing one or more prostaglandins, characterised in that the host cell is further modified to express or overexpress one or more auxiliary genes selected from the group consisting of:452.a) a gene encoding an endoplasmic reticulum (ER) chaperone, such as a polypeptide encoded by a KAR2 gene; and453.b) a gene encoding a protein disulfide isomerase, such as a polypeptide encoded by a PDI1 gene; thereby enhancing the folding or function of one or more polypeptides of the metabolic pathway.

147. A genetically modified host cell for the production of prostaglandin D2 (PGD2), wherein the host cell comprises one or more metabolic pathways capable of producing PGD2 from a prostaglandin precursor, said pathway comprising a prostaglandin D synthase (PGDS), characterised in that an endogenous gene encoding a glutathione S-transferase (GTT1), or a paralog or ortholog thereof, is attenuated or deleted, thereby reducing the formation of prostaglandin F2a as a byproduct.

148. A genetically modified host cell for the production of prostaglandin El (PGE1), wherein the host cell comprises one or more metabolic pathways capable of producing PGE1 from dihomo-gamma-linolenic acid (DGLA), characterised in that the one or more metabolic pathways do not comprise a functional delta-5 desaturase (D5D) enzyme, thereby directing metabolic flux towards DGLA and preventing its conversion to arachidonic acid.

149. The host cell of any of the preceding claims, wherein the host cell is capable of producing DGLA de novo from a carbon source and expresses one or more heterologous genes selected from the group consisting of a delta-9 desaturase, a delta-12 desaturase, a delta-6 desaturase, and a delta-6 elongase.

150. A polynucleotide construct comprising a polynucleotide sequence encoding a heterologous polypeptide of any of the preceding claim operably linked to one or more control sequences.

151. A cell culture, comprising a genetically modified host cell comprising one or more metabolic pathways capable of producing one or more prostaglandins, from a precursor, and a growth medium.

152. The cell culture of claim 151, wherein the host cell is defined according to any of claims 1-149.

153. A method for producing a prostaglandin comprising:460.a) culturing the host cell culture of any of claims 151-152 at conditions allowing the host cell to produce the prostaglandin; and / or461.b) optionally recovering and / or isolating the prostaglandin.

154. The method of claim 153, wherein the prostaglandin is selected from the group consisting of: Prostaglandin E2 (PGE2), Prostaglandin F2a, and Prostaglandin El (PGE1).

155. The method of any of claims 153-154, wherein the prostaglandin is selected from the group consisting of Prostaglandin E2 (PGE2) and Prostaglandin D2 (PGD2).

156. The method of any of claims 153-155, wherein the host cell is genetically modified by attenuating, disrupting or deleting an endogenous gene encoding a glutathione S-transferase (GTT1), or a paralog or ortholog thereof.

157. The method of any of claims 153-156, wherein the host cell is genetically modified by attenuating, disrupting, or deleting one or more endogenous genes selected from the group consisting of an aldoketo reductase (OYE3), an aldose reductase (GRE2), and an aldehyde reductase (ARI1).

158. The method of claim 154, wherein the prostaglandin is Prostaglandin F2a (PGF2a).

159. The method of claim 158, wherein the host cell is genetically modified by attenuating, disrupting or deleting an endogenous gene encoding a thioredoxin peroxidase (TSA1), or a paralog or ortholog thereof.

160. The method of any of claims 154-159, wherein the host cell is further modified to express or overexpress one or more auxiliary genes selected from the group consisting of a gene encoding an ER chaperone (KAR2), a gene encoding a protein disulfide isomerase (PDI1), and a gene encoding a phospholipase A2 (RnPA2GA).

161. The method of any of claims 158-160, wherein the host cell is further modified to express a gene encoding a cytochrome b5 (CYB5) and a gene encoding a cytochrome b5 reductase (NCB5R).

162. The method of claim 154, wherein the prostaglandin is Prostaglandin El (PGE1).

163. The method of claim 162, wherein the host cell comprises one or more metabolic pathways that do not comprise a delta-5 desaturase (D5D) polypeptide and / or a gene encoding a delta-5 desaturase (D5D), thereby directing metabolic flux towards dihomo-gamma-linolenic acid (DGLA) and preventing and / or reducing its conversion to arachidonic acid.

164. The method of claim 163, wherein the host cell is capable of producing DGLA de novo from a carbon source and expresses one or more heterologous genes selected from the group consisting ofa delta-9 desaturase, a delta-12 desaturase, a delta-6 desaturase, and a delta-6 elongase.

165. The method of any of claims 153-164, wherein the recovering and / or isolation step comprises one or more steps selected from:473.a) Solid:liquid separation (eg centrifugation or microfiltration)474.b) Adsorption475.c) Ultrafiltration or nanofiltration476.d) Precipitation477.e) Crystallization478.f) Drying479.g) Chromatography480.h) Extraction, and481.i) Distillation166. The method of claim 165, wherein the recovering and / or isolating step comprises:483.a) performing a solid:liquid separation to provide a cell-containing solid phase and a cell-free liquid phase; and484.b) extracting the prostaglandin from the solid phase and / or the liquid phase using a solvent.

167. The method of claim 166, wherein the prostaglandin is extracted from the cell-containing solid phase using an alcohol, such as ethanol.

168. The method of claim 166, wherein the prostaglandin is extracted from the cell-free liquid phase or from the entire cell culture via liquid-liquid extraction.

169. The method of claim 168, wherein the liquid-liquid extraction is performed using ethanol, such as in a batch, cross-current, or counter-current mode.

170. The method of any of claims 165 to 169, wherein the recovering and / or isolating step further comprises a chromatography step.

171. The method of claim 170, wherein the chromatography is performed using a non-polar porous resin.

172. The method of claim 171, wherein the non-polar porous resin is a styrene-divinylbenzene resin.

173. The method of any of claims 170 to 172, wherein the chromatography step comprises:491.a) loading an aqueous mixture containing the prostaglandin onto a column comprising the resin; b) washing the column with water; and492.c) eluting the prostaglandin from the column using an alcohol, such as methanol or ethanol.

174. The method of claim 173, further comprising a step of reducing the concentration of an organic solvent from a prostaglandin-containing mixture by evaporation prior to loading the mixture onto the column.

175. The method of claim 165, wherein the recovering and / or isolating step comprises:495.a) performing dialysis on the cell culture or a fraction thereof at a first pH, such as about pH 8; and b) extracting the prostaglandin at a second pH, such as about pH 3, using a solvent, such as a chlorinated solvent, for example chloroform; wherein the second pH is lower than the first pH.

176. The method of any of claims 153 to 175, further comprising adding a reducing agent, such as glutathione, during the culturing, recovering, and / or isolating steps.

177. The method of any of claims 153 to 165, further comprising one or more elements selected from:498.a) culturing the host cell culture in a nutrient medium;499.b) culturing the host cell culture under aerobic500.c) culturing the host cell culture under agitation;501.d) culturing the host cell culture at a temperature of between 18 to 40 °C;502.e) culturing the host cell culture at a pH of between 3-9; and503.f) culturing the host cell culture for between 10 hours to 30 days.

178. The method of any of claims 153 to 177, wherein one or more steps of capable of producing the prostaglandin is performed in vitro.

179. The method of any of claims 153to 178, wherein the pH of the medium is from 4.5 to 8, such as from 5,0 to 6,5, such as about 6,0 during the cultivation of the cell culture.

180. The method of any of the claims 153 to 179, comprising feeding the host cell culture witharachidonic acid or one or more arachidonic acid precursors.

181. The method of any of claims 153-180, wherein the method comprises producing the prostaglandin de novo, for example from a carbon source, such as from glucose.

182. The method of any of claims 153 to 181, wherein the culturing is performed as a fed-batch process.

183. The method of claim 182, wherein the fed-batch process comprises a batch phase followed by one or more fed-batch phases.

184. The method of claim 204, wherein the batch phase comprises culturing the host cell in a minimal medium containing a carbon source, such as glucose, for example at an initial fill volume of one-third to one-half of the total final working volume.

185. The method of claim 183 or 184, wherein the one or more fed-batch phases comprise a glucose-limited exponential growth phase targeting a predefined growth rate of for example about 0.08 h-1to 0.1 h-1, followed by one or more phases with constant feed rates of a carbon source.

186. The method of any of claims 153 to 185, wherein the growth medium comprises a carbon source, a nitrogen source, a phosphate source, and optionally one or more supplements selected from the group consisting of a vitamin solution and a trace elements solution.

187. The method of claim 186, wherein the carbon source is glucose.

188. The method of claim 186, wherein the vitamin solution comprises one or more components selected from the group consisting of d-biotin, Ca-pantothenate, Nicotinic acid, Thiamine-HCI, Pyridoxine-HCI, 4-aminobenzoic acid, and Myo-inositol.

189. The method of claim 186, wherein the trace elements solution comprises one or more components selected from the group consisting of Iron (III) citrate hydrate, ZnSO4·7H2O, MnCl2·4H2O, and CuSO4·5H2O.

190. The method of any of claims 185-189, wherein the method comprises using a feed solution during the fed-batch phases comprises one or more of: glucose, (NH4)2SO4, KH2PO4, MgSO4·7H2O, K2SO4, and Na2SO4.

191. The method of any of claims 153 to 190, wherein the culturing comprises controlling one or more physical parameters selected from the group consisting of temperature, pH, aeration rate, and stirring rate.

192. The method of claim 191, wherein the one or more physical parameters are controlled such that: a) the temperature is maintained at about 30 °C;518.b) the pH is controlled to about 5.5;519.c) the aeration rate is maintained at about 1.5 vvm; and / or520.d) the stirring rate is maintained at about 1100 rpm.

193. The method of any of claims 153 to 192, further comprising a step selected from the group consisting of:522.a) limiting a nitrogen source after a biomass accumulation phase;523.b) adding an antioxidant, such as a carotenoid, to the growth medium; and524.c) adding an additional nitrogen source, such as yeast extract or one or more amino acids, to the growth medium.

194. The method of any of claims 153 to 193, further comprising a stabilizing step for stabilizing the prostaglandin and / or an arachidonic acid precursor against oxidation.

195. The method of claim 194, wherein the stabilizing step comprises adding a stabilizing agent, such as an antioxidant to the cell culture or to a solution containing the prostaglandin or arachidonic acid precursor.

196. The method of claim 195, wherein the stabilizing agent is selected from the group consisting of glutathione, nordihydroguaiaretic acid, butylated hydroxyanisole, N-acetylcysteine, citric acid, and cysteine.

197. The method of claim 196, wherein the stabilizing step comprises storing a solution containing arachidonic acid or a precursor thereof under non-oxidizing conditions prior to or during the culturingstep.

198. The method of claim 197, wherein storing under non-oxidizing conditions comprises purging the solution with an inert gas, such as argon or nitrogen.

199. The method of any of claims 153 to 198, further comprising minimizing exposure of the cell culture, a solution containing arachidonic acid, or the prostaglandin to UV light.

200. The method of any of claims 180-199, wherein the step of feeding the host cell culture with arachidonic acid or one or more arachidonic acid precursors is performed over time to prevent accumulation of arachidonic acid in the growth medium.

201. The method of any of claims 153 to 200, wherein the culturing step is controlled to minimize accumulation of arachidonic acid, wherein said control comprises regulating the dissolved oxygen set point.

202. The method of any of claims 153 to 201, wherein the recovering and / or isolating step further comprises a packaging step of packaging the prostaglandin in a protective container.

203. The method of claim 202, wherein the packaging step comprises degassing the prostaglandin and enclosing it in a non-gas permeable capsule or a hermetically-sealed container.

204. A composition comprising a prostaglandin and one or more carriers, agents, additives and / or excipients.

205. The cell culture of claim 151 or the composition of claim 204, further comprising a stabilizing agent to reduce oxidation of the prostaglandin and / or the arachidonic acid precursor.

206. The cell culture or composition of claim 205, wherein the stabilizing agent is an antioxidant.

207. The cell culture or composition of any of claims 205-206, wherein the stabilizing agent is selected from the group consisting of glutathione, nordihydroguaiaretic acid, butylated hydroxyanisole, N-acetylcysteine, citric acid, and cysteine.

208. The cell culture or composition of claim 205, wherein the antioxidant is a food-grade antioxidant.

209. The cell culture of claim 151 or the composition of claim 204, wherein the prostaglandin and / or an arachidonic acid precursor is formulated in a nanoemulsion.

210. The cell culture or composition of claim 209, wherein the nanoemulsion comprises sodium caseinate-gum Arabic complexes.

211. The composition of claim 204, wherein the composition is enclosed within a protective container configured to reduce degradation of the prostaglandin.

212. The composition of claim 211, wherein the protective container is selected from the group consisting of a non-gas permeable capsule and a hermetically-sealed container.

213. The composition of claim 211 or 212, wherein the protective container comprises a color blocking pigment or coating reducing transmission of UV light.

214. The composition of any of claims claim 204 to 213 for use as a medicament for prevention, treatment and / or relief of a disease in a mammal.

215. The composition any of the claim 204 to 214 for use in the prevention, treatment and / or relief of a non-limiting list of conditions including ocular hypertension conditions, glaucoma, postpartum bleeding, obstetric bleeding, labor induction conditions, gastric ulcers, peripheral vascular conditions, arthritis, Buergers's disease, male sexual dysfunction, and / or pulmonary hypertension in a mammal.

216. A method for enhancing the production of one or more prostaglandins in a host cell, the method comprising genetically modifying the host cell by performing at least one modification selected from the group consisting of:547.a) attenuating, disrupting, or deleting one or more endogenous genes encoding a polypeptide that catalyzes an unwanted side-reaction on a prostaglandin or a prostaglandin precursor;548.b) expressing or overexpressing one or more genes that increase the supply of one or more prostaglandin precursors; and549.c) expressing or overexpressing one or more auxiliary genes encoding a polypeptide that enhances the folding or function of a polypeptide in a prostaglandin biosynthesis pathway.