Methods and compositions for biosynthesis of tryptamine alkaloids

Abstract

Provided herein is a vector comprising: a nucleic acid sequence encoding one or more enzymes that mediate the biosynthesis of one or more alkaloids; a promoter; and a system for regulating expression of the one or more enzymes. Additionally provided herein are systems of vectors and pharmaceutical formulations, the systems and formulations comprising a vector provided herein. Provided also herein are compositions comprising two vectors, a first vector and a second vector, wherein the first vector comprises a nucleic acid sequence encoding one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids and a promoter; and wherein the first vector and the second vector comprise a system for independently regulating the expression of the one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids.

Description

WSGR Docket No. 66180-701.601METHODS AND COMPOSITIONS FOR BIOSYNTHESIS OF TRYPTAMINE ALKALOIDSCROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 762,589, filed February 24, 2025, which application is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Tryptamine alkaloids have the potential to treat a broad array of diseases. For example, tryptamine alkaloids having psychoactive properties can be used to treat diseases ranging from depression to addiction. Tryptamine alkaloids are naturally produced in organisms, for example, some mushrooms of the genus Psilocybe. However, use of tryptamine alkaloids in their naturally occurring form (e g., through consumption of a Psilocybe mushroom) for the treatment of disease presents challenges. For example, the quantity and concentration of tryptamine alkaloids can vary between individual mushrooms. Additionally, in nature, compositions of different tryptamine alkaloids exist. For example, Psilocybe mushrooms produce not only psilocybin, but also psilocin and baeocystin, all three of which have psychoactive properties. Chemical synthesis of tryptamine alkaloids (e.g., in a laboratory) can be limited in its ability to produce compositions of tryptamine alkaloids as effective in their treatment of disease as naturally occurring compositions. Due to potential limitations with current systems and methods, both natural and artificial, for production of tryptamine alkaloids, insufficient ability to regulate production of tryptamine alkaloid compositions (e g., composition comprising two or more tryptamine alkaloid) may not yield clinical benefits or such clinical benefits may be hard to achieve.BRIEF SUMMARY

[0003] Provided herein are systems and methods for synthesis of tryptamine alkaloids (e.g., psilocybin and bufotenine e.g., bufotenin). Systems and methods provided herein for synthesizing tryptamine alkaloids can regulate the synthesis of the tryptamine alkaloids. Provided also herein are formulations of tryptamine alkaloids.

[0004] Provided herein is a vector comprising: a nucleic acid sequence encoding one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids; a promoter; and a system for regulating expression of the one or more enzymes. In some embodiments, the system comprises a first enzyme and a second enzyme. In some embodiments, the expression of the first enzyme and the second enzyme are regulated independently.WSGR Docket No. 66180-701.601promoter comprises a benzoic acid inducible promoter. In some embodiments, the promoter comprises a benzoate-para-hydroxylase (bphA) promoter. In some embodiments, the system for regulating expression comprises a benzoic acid-induced promoter system.

[0010] In some embodiments, the promoter comprises a sucrose inducible promoter. In some embodiments, the promoter comprises a beta-fructofuranosidase (sucA) promoter. In some embodiments, the system for regulating expression comprises a sucrose-induced promoter system.

[0011] In some embodiments, the system for regulating expression comprises a promoter that is repressed in the presence of thiamine. In some embodiments, the promoter comprises a thiamine thiazole synthase (thiA) promoter. In some embodiments, the system for regulating expression comprises a thiamine-repressed promoter system.

[0012] In some embodiments, the system for regulating expression comprises a constitutive promoter. In some embodiments, the promoter comprises a glyceraldehyde-3-phosphate dehydrogenase (gpdA) promoter.

[0013] In some embodiments, provided herein is a system of vectors, the system comprising a vector provided herein.

[0014] Provided herein is a composition comprising two vectors, a first vector and a second vector, wherein the first vector comprises: a nucleic acid sequence encoding one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids, and a promoter, wherein the first vector and the second vector comprise a system for independently regulating the expression of the one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids. In some embodiments, the first vector and the second vector comprise a system for independently regulating the expression of the one or more enzymes that mediate the biosynthesis of the one or more tryptamine alkaloids.

[0015] In some embodiments, the promoter comprises an inducible promoter. In some embodiments, the promoter comprises a repressible promoter. In some embodiments, the promoter comprises a constitutive promoter.

[0016] In some embodiments, the one or more enzymes encoded by the nucleic acid sequence of the first vector comprise a member selected from the group consisting of tryptamine 4-monooxygenase (PsiH), 4-hydroxytryptamine kinase (PsiK), Rhinella marina indolethylamine N-methyltransferase (RmINMT), psilocybin synthase (PsiM), tryptamine 5-hydroxylase (T5H), acetylserotonin methyltransferase (ASMT), and 5-hydroxy-indolethylamine-N-methyltransferase (5OH-INMT).

[0017] In some embodiments, the one or more enzymes encoded by the nucleic acid sequence of the first vector comprise a member selected from the group consisting of tryptamine 4-monooxygenase (PsiH), 4-hydroxytryptamine kinase (PsiK), and psilocybin synthase (PsiM). In some embodiments, the one or more enzymes encoded by the nucleic acid sequence of the first vector comprise tryptamineWSGR Docket No. 66180-701.6014-monooxygenase (PsiH). In some embodiments, wherein the one or more enzymes encoded by the nucleic acid sequence of the first vector comprise a member selected from the group consisting of 4-hydroxytryptamine kinase (PsiK) and psilocybin synthase (PsiM).

[0018] In some embodiments, wherein the one or more enzymes encoded by the nucleic acid sequence of the first vector comprise a member selected from the group consisting of tryptamine 4-monooxygenase (PsiH), 4-hydroxytryptamine kinase (PsiK) and Rhinella marina indolethylamine N-methyltransferase (RmINMT). In some embodiments, the one or more enzymes encoded by the nucleic acid sequence of the first vector comprise a member selected from the group consisting 4-hydroxytryptamine kinase (PsiK) and Rhinella marina indolethylamine A^-methyltransferase (RmINMT).

[0019] In some embodiments the one or more enzymes encoded by the nucleic acid sequence of the first vector comprise a member selected from the group consisting of acetyl serotonin methyltransferase (ASMT) and 5-hydroxy-indolethylamine-A-methyltransferase (5OH-INMT). In some embodiments, the one or more enzymes encoded by the nucleic acid sequence of the first vector comprise a member selected from the group consisting of Rhinella marina indolethylamine N-methyltransferase (RmINMT), psilocybin synthase (PsiM), tryptamine 5-hydroxylase (T5H), and acetylserotonin methyltransferase (ASMT).

[0020] In some embodiments, the tryptamine alkaloids comprise a member selected from the group consisting of tryptamine (1), N-methyltryptamine (NMT) (2), N,N-dimethyltryptamine (DMT) (3), N,N,N-trimethyltryptamine (TMT) (4), 4-hydroxy-tryptamine (5), 4-hydroxy-N-methyltryptamine (norpsilocin) (6), 4-hydroxy-N,N-dimethyltryptamine (psilocin) (7), 4-phosphoryloxy-tryptamine (norbaeocystin) (8), 4-phosphoryloxy-N-methyltryptamine (baeocystin) (9), 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) (10), 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin) (11), N,N-dimethyl-5-hydroxytryptamine (bufotenine) (12), 5-hydroxytryptamine (serotonin, 5-HT) (13), N-methylserotonin (14), N,N,N-trimethylserotonin (15), 5-methoxyserotonin (5-MeO-serotonin) (16), 5-methoxy-N-methyltryptamine (5-MeO-NMT) (17), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) (18), 5-methoxy-N,N,N-methyltryptamine (5-MeO-TMT) (19).

[0021] In some embodiments, the tryptamine alkaloids comprise DMT (3) and a member selected from the group consisting of tryptamine (1), NMT (2), and TMT (4). In some embodiments, the tryptamine alkaloids comprise psilocybin (10) and a member selected from the group consisting of tryptamine (1), 4-hydroxy-tryptamine (5), norpsilocin (6), psilocin (7), norbaeocystin (8), baeocystin (9), and aeruginascin (11). In some embodiments, the tryptamine alkaloids comprise bufotenine (12) and a member selected from the group consisting of tryptamine (1), serotonin (13), N-methyl serotonin (14), and N,N,N-trimethylserotonin (15). In some embodiments, the tryptamine alkaloids comprise 5-MeO-WSGR Docket No. 66180-701.601DMT (18) and a member selected from the group consisting of tryptamine (1), serotonin (13), 5-MeO-serotonin (16), 5-MeO-NMT (17), 5-MeO-DMT (18), and 5-MeO-TMT (19).

[0022] In some embodiments, the promoter of the first vector comprises a tetracycline response element (TRE). In some embodiments, the promoter comprises a tetracycline-responsive element promoter (TRE promoter). In some embodiments, the system for regulating expression comprises a tetracycline-controlled transcriptional activation system. In some embodiments, the system for regulating expression comprises a tetracycline-controlled transcriptional silencing system.

[0023] In some embodiments, the promoter of the first vector encoded by the nucleic acid of the first vector comprises a benzoic acid inducible promoter. In some embodiments, the promoter of the first vector comprises a benzoate-para-hydroxylase bphA) promoter. In some embodiments, the system for regulating expression comprises a benzoate-activated promoter system.

[0024] In some embodiments, the system for regulating expression comprises a promoter that is repressed in the presence of thiamine. In some embodiments, the promoter comprises a thiamine thiazole synthase (thiA') promoter. In some embodiments, the system for regulating expression comprises a thiamine-repressed promoter system.

[0025] In some embodiments, the system for regulating expression comprises a promoter that is induced in the presence of sucrose. In some embodiments, the promoter comprises a beta-fructofuranosidase (sucA) promoter. In some embodiments, the system for regulating expression comprises a sucrose-induced promoter system.

[0026] In some embodiments, the system for regulating expression comprises a constitutive promoter. In some embodiments, the promoter comprises a glyceraldehyde-3-phosphate dehydrogenase (gpdA) promoter.

[0027] In some embodiments, the second vector comprises a transcription factor. In some embodiments, the second vector comprises a transcription factor whose activity is dependent on an antibiotic. In some embodiments, the second vector comprises a transcription factor whose activity is dependent on tetracycline or on a tetracycline derivative. In some embodiments, the second vector comprises a tetracycline-controlled transcriptional silencer (tTS) transcription factor. In some embodiments, the second vector comprises a reverse tetracycline responsive transcriptional activator (rtTA) transcription factor.

[0028] In some embodiments, the second vector comprises a promoter. In some embodiments, the second vector comprises a putative ribosomal subunit (An16g04690) promoter (PfraA).

[0029] In some embodiments, the composition further comprises a third vector. In some embodiments, the third vector comprises: a second nucleic acid sequence encoding the one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids, and a second promoter, wherein the firstWSGR Docket No. 66180-701.601vector, the second vector, the third vector, or a combination thereof comprise the system for regulating the expression of the one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids.

[0030] In some embodiments, the second promoter comprises an inducible promoter. In some embodiments, the second promoter comprises a repressible promoter. In some embodiments, the second promoter comprises a constitutive promoter.

[0031] In some embodiments, the one or more enzymes encoded by the second nucleic acid sequence comprise a member of the group consisting of tryptamine 4-monooxygenase (PsiH), 4-hydroxytryptamine kinase (PsiK), Rhinella marina indolethylamine N-methyltransferase (RmINMT), psilocybin synthase (PsiM), tryptamine 5-hydroxylase (T5H), acetylserotonin methyltransferase (ASMT), and 5-hydroxy-indolethylamine-N-methyltransferase (5OH-INMT).

[0032] In some embodiments, the one or more enzymes encoded by the second nucleic acid sequence comprise a member selected from the group consisting of tryptamine 4-monooxygenase (PsiH), 4- hydroxy tryptamine kinase (PsiK), and psilocybin synthase (PsiM). In some embodiments, wherein the one or more enzymes encoded by the second nucleic acid sequence comprise tryptamine 4-monooxygenase (PsiH). In some embodiments, wherein the one or more enzymes encoded by the second nucleic acid sequence comprise a member selected from the group consisting of 4-hydroxytryptamine kinase (PsiK) and psilocybin synthase (PsiM).

[0033] In some embodiments, wherein the one or more enzymes encoded by the second nucleic acid sequence comprise a member selected from the group consisting of tryptamine 4-monooxygenase (PsiH), 4-hydroxy tryptamine kinase (PsiK) and Rhinella marina indolethylamine N-methyltransferase (RmINMT). In some embodiments, wherein the one or more enzymes encoded by the second nucleic acid sequence comprise a member selected from the group consisting 4-hydroxytryptamine kinase (PsiK) and Rhinella marina indolethylamine N-methyltransferase (RmINMT).

[0034] In some embodiments, wherein the one or more enzymes encoded by the second nucleic acid sequence comprise a member selected from the group consisting of acetyl serotonin methyl transferase (ASMT) and 5-hydroxy-indolethylamine-A-methyltransferase (5OH-INMT). In some embodiments, wherein the one or more enzymes encoded by the second nucleic acid sequence comprise a member selected from the group consisting of Rhinella marina indolethylamine N-methyltransferase (RmINMT), psilocybin synthase (PsiM), tryptamine 5-hydroxylase (T5H), and acetylserotonin methyltransferase (ASMT).

[0035] In some embodiments, the tryptamine alkaloids comprise a member selected from the group consisting of tryptamine (1), A’-m ethyltryptamine (NMT) (2), A, A-dimethyltryptamine (DMT) (3), AfAA'-triniethyltryptanune (TMT) (4), 4-hydroxy-tryptamine (5), 4-hydroxy-A-m ethyltryptamineWSGR Docket No. 66180-701.601(norpsilocin) (6), 4-hydroxy- ( / V-dimethyltryptamine (psilocin) (7), 4-phosphoryloxy-tryptamine (norbaeocystin) (8), 4-phosphoryloxy-A-methyltryptamine (baeocystin) (9), 4-phosphoryloxy-A(A’-dimethyl tryptamine (psilocybin) (10), 4-phosphoryloxy-AfAvV-trimethyltryptamine (aeruginascin) (11), A(AMimethyl-5-hydroxytryptamine (bufotenine) (12), 5-hydroxytryptamine (serotonin, 5-HT) (13), A-methylserotonin (14), Af ^A'-trimethylserotonin (15), 5 -methoxy serotonin (5-MeO-serotonin) (16), 5-methoxy-A^-niethyltryptaniine (5-MeO-NMT) (17), 5 -methoxy -AAV-dimetliylttyptamine (5-MeO-DMT) (18), 5-methoxy-AriV, A methyltryptamine (5-MeO-TMT) (19).

[0036] In some embodiments, the tryptamine alkaloids comprise DMT (3) and a member selected from the group consisting of tryptamine (1), NMT (2), and TMT (4). In some embodiments, the tryptamine alkaloids comprise psilocybin (10) and a member selected from the group consisting of tryptamine (1), 4-hydroxy-tryptamine (5), norpsilocin (6), psilocin (7), norbaeocystin (8), baeocystin (9), and aeruginascin (11), In some embodiments, the tryptamine alkaloids comprise bufotenine (12) and a member selected from the group consisting of tryptamine (1), serotonin (13), A-methyl serotonin (14), and N,N,N-trimethylserotonin (15). In some embodiments, the tryptamine alkaloids comprise 5-MeO-DMT (18) and a member selected from the group consisting of tryptamine (1), serotonin (13), 5-MeO-serotonin (16), 5-MeO-NMT (17), 5-MeO-DMT (18), and 5-MeO-TMT (19).

[0037] In some embodiments, the second promoter comprises a tetracycline response element (TRE). In some embodiments, the second promoter comprises a tetracycline-responsive element promoter (TRE promoter). In some embodiments, the system for regulating expression comprises a tetracycline-controlled transcriptional activation system. In some embodiments, the system for regulating expression comprises a tetracycline-controlled transcriptional silencing system.

[0038] In some embodiments, the second promoter comprises a benzoic acid inducible promoter. In some embodiments, the second promoter comprises a hphA promoter. In some embodiments, the system for regulating expression comprises a benzoate-activated promoter system.

[0039] In some embodiments, the system for regulating expression comprises a promoter that is repressed in the presence of thiamine. In some embodiments, the second promoter comprises a thiamine thiazole synthase (thiA') promoter. In some embodiments, the system for regulating expression comprises a thiamine-repressed promoter system.

[0040] In some embodiments, the system for regulating expression comprises a promoter that is induced in the presence of sucrose. In some embodiments, the second promoter comprises a beta-fructofuranosidase (sucA) promoter. In some embodiments, the system for regulating expression comprises a sucrose-induced promoter system.WSGR Docket No. 66180-701.601

[0041] In some embodiments, the system for regulating expression comprises a constitutive promoter. In some embodiments, the second promoter comprises a glyceraldehyde-3-phosphate dehydrogenase (gpdA) promoter.

[0042] In some embodiments, the composition further comprises an antibiotic. In some embodiments, the antibiotic is tetracycline. In some embodiments, the antibiotic is a tetracycline derivative. In some embodiments, the tetracycline derivative is doxycycline.

[0043] In some embodiments, the composition further comprises benzoic acid.

[0044] In some embodiments, the composition further comprises thiamine.

[0045] In some embodiments, the composition further comprises tryptamine.

[0046] Provided herein is a system of vectors, the system comprising a first vector provided herein and a second vector provided herein.

[0047] Provided herein is a system of vectors, the system comprising a first vector provided herein, a second vector provided herein, and a third vector provided herein.

[0048] Provided herein is a pharmaceutical formulation, the pharmaceutical formulation comprising at least one tryptamine alkaloid produced by a vector provided herein.

[0049] In some embodiments, the at least one tryptamine alkaloid produced by a vector provided herein is substantially purified.

[0050] In some embodiments, the pharmaceutical formulation comprises two or more tryptamine alkaloids produced by a vector provided herein. In some embodiments, the two or more tryptamine alkaloids produced by a vector provided herein are substantially purified. In some embodiments, the pharmaceutical formulation comprises at least one substantially purified tryptamine alkaloid produced by a vector provided herein and a pharmaceutical excipient. In some embodiments, the pharmaceutical excipient is selected from the group consisting of a disintegrant, a binder, a lubricant, a colorant, a preservative, a diluent, a glidant, a flavoring, a humectant, and a suspending agent.INCORPORATION BY REFERENCE

[0051] All publications, patents, and patent applications mentioned in this specification are herein 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. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.WSGR Docket No. 66180-701.601BRIEF DESCRIPTION OF THE DRAWINGS

[0052] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0053] FIG. 1A, FIG. 1B, FIG. 1C, FIG. 1D, FIG. 1E, and FIG. 1F provide vectors for use in a system or method of synthesizing tryptamine alkaloids, the tryptamine alkaloids including but not limited to, dimethyltryptamine (DMT), 4-hydroxytryptamine, and psilocybin.

[0054] FIG. 2A and FIG. 2B provide example synthesis schemes for production of tryptamine alkaloids, the tryptamine alkaloids including but not limited to 4-hydroxy-tryptamine and psilocybin.

[0055] FIG. 3 provides a vector for use in a system or method of synthesizing tryptamine alkaloids, the tryptamine alkaloids including but not limited to, serotonin, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and bufotenine.

[0056] FIG. 4A and FIG. 4B provide example synthesis schemes for production of tryptamine alkaloids, the tryptamine alkaloids including but not limited to, serotonin and bufotenine.

[0057] FIG. 5A, FIG. 5B, FIG. 5C, and FIG. 5D provide vectors for use in a system or method of synthesizing tryptamine alkaloids, the tryptamine alkaloids including but not limited to, dimethyltryptamine (DMT), 4-hydroxytryptamine, and psilocybin.

[0058] FIG. 6A and FIG. 6B provide example synthesis schemes for production of tryptamine alkaloids, the tryptamine alkaloids including but not limited to, psilocybin, psilocin, and DMT.

[0059] FIG. 7 provides a vector for use in a system or method of synthesizing tryptamine alkaloids, the tryptamine alkaloids including but not limited to, serotonin, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and bufotenine.

[0060] FIG. 8A, FIG. 8B, FIG.8C, and FIG. 8D provide example synthesis schemes for production of tryptamine alkaloids, the tryptamine alkaloids including but not limited to, serotonin, 5-MeO-DMT, and bufotenine.

[0061] FIG. 9 shows a schematic illustration of an exemplary enzymatic cascade performed by the engineered Aspergillus niger cell to convert tryptamine to 4-hydroxy-tryptamine through expression and activity of the enzyme PsiH, conversion of 4-hydroxy-tryptamine to norbaeocystin through expression and activity of the enzyme PsiK, conversion of norbaeocystin to baeocystin through expression and activity of the enzyme RmINMT, and conversion of baeocystin to psilocybin through expression and activity of RmINMT.WSGR Docket No. 66180-701.601

[0062] FIG. 10 shows a representative gel electrophoresis image of Aspergillus niger gDNA extracted after transformation with N0 vector (SEQ ID NO: 36). Lane A shows the molecular weight marker, Lane B shows N0 vector transformant 4, Lane C shows N0 vector transformant 5, Lane D shows N0 vector transformant 6, Lane E shows N0 vector transformant 7, and Lane F shows N0 vector transformant 8.

[0063] FIG. 11 shows a representative gel electrophoresis image of rtTA amplicons from vector N0 DNA (Lane B), transformant 5 DNA (Lane C), untransformed A. niger DNA (Lane D), no DNA (Lane E), and a molecular weight marker (Lane A), with an expected amplicon size of 2928 bp.

[0064] FIG. 12 shows a representative gel electrophoresis image of pyrG locus amplicons from no DNA (Lane A), a molecular weight marker (Lane B), from wild-type A. niger (Lane C), N0 vector Transformant 4 (Lane D), N0 vector Transformant 5 (Lane E), N0 vector Transformant 6 (Lane F), N0 vector Transformant 7 (Lane G), and N0 vector Transformant 8 (Lane H), with an expected amplicon size of 4200 bp.

[0065] FIG. 13 shows a representative gel electrophoresis image of PsiH amplicons from no DNA (Lane A), Wild-Type DNA (Lane B), a molecular weight marker (Lane C), N1-β vector DNA (Lane D), N1 / N1-β vector transformant 1 DNA (Lane E), N1 / N1-β vector transformant 2 DNA (Lane F), N1 / N1-β vector transformant 3 DNA (Lane G), N1 / N1-β vector transformant 4 DNA (Lane H), and N1 / N1-β vector transformant 5 DNA (Lane I), with an expected amplicon size of 2496 bp.

[0066] FIG. 14 shows a representative gel electrophoresis image of PsiK amplicons from no DNA (Lane A), a molecular weight marker (Lane B), N1-β vector DNA (Lane C), N1 / N1-β vector transformant 1 DNA (Lane D), N1 / N1-β vector transformant 2 DNA (Lane E), N1 / N1-β vector transformant 3 DNA (Lane F), N1 / N1-β vector transformant 4 DNA (Lane G), and N1 / N1-β vector transformant 5 DNA (Lane H), with an expected amplicon size of 1499 bp.

[0067] FIG. 15 shows a representative gel electrophoresis image of RmINMT amplicons from no DNA (Lane A), wild-type DNA (Lane B), a molecular weight marker (Lane C), N1-β vector DNA (Lane D), N1 / N1-β vector transformant 1 DNA (Lane E), N1 / N1-β vector transformant 2 DNA (Lane F), N1 / N1-β vector transformant 3 DNA (Lane G), N1 / N1-β vector transformant 4 DNA (Lane H), and N1 / N1-β vector transformant 5 DNA (Lane I) with an expected amplicon size of 3298 bp.

[0068] FIG. 16 shows a representative gel electrophoresis image of CPR amplicons from no DNA (Lane A), wild-type DNA (Lane B), a molecular weight marker (Lane C), N1-β vector DNA (Lane D), N1 / N1-β vector transformant 1 DNA (Lane E), N1 / N1-β vector transformant 2 DNA (Lane F), N1 / N1-β vector transformant 3 DNA (Lane G), a molecular marker (Lane H), N1 / N1-β vector transformant 4 DNA (Lane I), and N1 / N1-β vector transformant 5 DNA (Lane J), with an expected amplicon size of 4020 bp.WSGR Docket No. 66180-701.601

[0069] FIG. 17 shows a representative gel electrophoresis image of RNA from N1 / N1-β vector transformants from Condition A (Lane A) or Condition B (Lane B).

[0070] FIG. 18 shows a representative gel electrophoresis image of amplicons of psiK, psiH, RmINMT, and CPR from cDNA extracted from N1 / N1-β vector transformants from Condition A (Lane A) or Condition B (Lane B).

[0071] FIG. 19 shows a representative gel electrophoresis image of T5H amplicons with a molecular marker (Lane A), from wild-type DNA (Lane B), N1-γ vector DNA (Lane C), N1-γ vector transformant 1 DNA (Lane D), N1-γ vector transformant 2 DNA (Lane E), and N1-γ vector transformant 3 DNA (Lane F), with an expected amplicon size of 2163 bp.

[0072] FIG. 20 shows a representative gel electrophoresis image of RmINMT amplicons from wild¬ type DNA (Lane A), N1-γ vector DNA (Lane B), N1-γ vector transformant 1 DNA (Lane C), N1-γ vector transformant 2 DNA (Lane D), N1-γ vector transformant 3 DNA (Lane E), and a molecular marker (Lane F) with an expected amplicon size of 1761 bp.

[0073] FIG. 21 shows a representative gel electrophoresis image of ASMT amplicons with a molecular weight marker (Lane A), wild-type DNA (Lane B), N1-γ vector DNA (Lane C), N1-γ vector transformant 1 DNA (Lane D), N1-γ vector transformant 2 DNA (Lane E), and N1-γ vector transformant 2 DNA (Lane F) with an expected amplicon size of 3567 bp.

[0074] FIG. 22 shows a representative gel electrophoresis image of RNA extracted from N1-γ Vector Transformants in condition A (Lane A) and N1-γ Vector Transformants in condition B (Lane B).

[0075] FIG. 23 shows a representative gel electrophoresis image of actin, RmINMT, or T5H cDNA from N1-γ Vector Transformants in condition A (Lane A) and N1-γ Vector Transformants in condition B (Lane B).

[0076] FIG. 24 shows an enzymatic cascade of converting tryptamine to serotonin via T5H, serotonin to N-methyl-serotonin via RmINMT, and N-methyl-serotonin to bufotenine via RmINMT.DETAILED DESCRIPTION OF THE INVENTIONOverview

[0077] Tryptamine alkaloids, for example, psilocybin and serotonin, can treat diseases ranging from anxiety and depression to substance abuse disorder. Many tryptamine alkaloids are naturally occurring and can exist in their natural form in compositions with other tryptamine alkaloids. For example, some mushrooms of the genus Psilocybe produce the psychoactive tryptamine alkaloid psilocybin from tryptamine. Also present in these mushrooms are other intermediaries in the biosynthesis of psilocybin that are themselves psychoactive, for example, baeocystine. It can be challenging to control the amount (e.g., concentration) of specific tryptamine alkaloids in naturally occurring compositions. WhenWSGR Docket No. 66180-701.601tryptamine alkaloids are artificially produced, it can be difficult to replicate the compositions and medicinal properties of naturally occurring compositions of tryptamine alkaloids.

[0078] Provided herein are systems and methods for regulating the biosynthesis of tryptamine alkaloids (e.g., psilocybin and serotonin). Tryptamine alkaloids provided herein can be synthesized in a biological reservoir, e.g., Aspergillus niger. In some embodiments, the biological reservoir (e.g., a host cell) that synthesizes the tryptamine alkaloids is engineered to express exogenous enzymes. Systems and methods provided herein can regulate the expression of the exogenous enzymes (e.g., increase or decrease the production level of an enzyme). The composition of the tryptamine alkaloids in the biological reservoir can thereby be regulated, as the biosynthesis of tryptamine alkaloids can be dependent on the presence of an enzyme.Vectors

[0079] A vector (e.g., a vector comprising a sequence of nucleic acids) provided herein can comprise a nucleic acid sequence encoding one or more enzymes (e.g., an enzyme provided herein) that mediate the biosynthesis of one or more tryptamine alkaloids (e.g,, a tryptamine alkaloid provided herein). In some embodiments, a vector provided herein can comprise one or more promoters, one or more nucleic acid sequences each encoding one or more enzymes (e.g., one or more enzymes that regulate the biosynthesis of one or more tryptamine alkaloids), and a system for regulation of the expression of the one or more enzymes. A vector provided herein can comprise a plasmid. For example, a vector provided herein can comprise a standard bacterial self-replicating plasmid (e.g., pUC19). A vector provided herein can comprise a pUC19 plasmid.

[0080] A vector provided herein can comprise a promoter (e g., a promoter provided herein). In some embodiments, a promoter provided herein can be endogenous to a host cell. In some embodiments, a promoter provided herein can be exogenous to a host cell. A vector provided herein can comprise a constitutive promoter. In some embodiments, a constitutive promoter comprises a promoter that is active in all circumstances in a host cell. For example, a constitutive promoter provided herein can comprise a putative ribosomal subunit (Anl6g04690) promoter (PfraA) or a glyceraldehyde-3-phosphate dehydrogenase (gpdA) gene promoter (PgpdA). In some embodiments, a vector provided herein can comprise a regulated promoter, e.g., a promoter whose activity is regulated in response to specific stimuli (e.g., an inducible promoter or a repressible promoter). A vector provided herein can comprise an inducible promoter. In some embodiments, an inducible promoter is a promoter that is activated by the presence of a specific stimulus. For example, an inducible promoter can be a promoter that is activated in the presence of benzoic acid or of an aromatic compound similar to benzoic acid, e.g., a benzoate para-hydroxylase (bphA) promoter or a cytochrome P450 reductase (cprA) promoter. In certain embodiments, an inducible promoter is a response element (e.g,, a response element in aWSGR Docket No. 66180-701.601tetracycline-responsive system). For example, an inducible promoter can be a promoter that is activated in the presence of tetracycline or a tetracycline derivative, e.g., a tetracycline response element (TRE) in a tetracycline-induced system (Tet-ON). In some embodiments, an inducible promoter can be a promoter that is inducible by sucrose, e.g., a beta-fructofuranosidase (sucA) promoter (PsucA). A vector provided herein can comprise a repressible promoter. In some embodiments, a repressible promoter is a promoter that is repressed by the presence of a specific stimulus. For example, a repressible promoter can be a promoter whose activity is repressed in the presence of thiamine, e.g., a thiamine thiazole synthase (thiA) promoter. In certain embodiments, a repressible promoter is a response element (e.g., a response element in a tetracycline-responsive system). For example, a repressible promoter can be a promoter whose activity is repressed in the presence of tetracycline or a tetracycline derivative, e.g., a TRE in a tetracycline-repressed system (Tet-OFF). A vector provided herein can comprise a minimal promoter. A minimal promoter can be constitutive, inducible, or repressible.

[0081] Examples of promoters described herein include, but are not limited to, promoters provided in Table 1.

[0082] Table 1. PromotersSEQ ID NO. Promoter Sequence7 PsucA (A. niger) AGTAGTGATATGTCGGCTCTAGTTCCTTGCTGTAAGTAA GGAGACGGGTATATGTCAACGTAGTATAAAGTGAAGCA GGCGAATITrAAAGAATnGCAAIGGCCCATCTGTGITC C ATCTTCGC AC AACATTTAATTA 1111 ATATGATTTGTC A TAGACCCACCAACTTCAACTCGAACTACATCACTTGGAC CAACATCACGCGTTCAACATGGACAAGGGTTGATAACCC GGGATGCATTCATTGTCTGCCTCAAGTGTCGCTACTAGT TCCATCTITIGTAAATITGGATA rGTCCGITITCTTCTAT CGCAACAAGCCATCCAACAAGAGAATACCGACCTGGAT CATGTAATTCTGGCAATGGTCAACAGCCCCGTCCCGCAG AGC ATACG GATTCTTG 1 11 1 GCGACCCCCCTGG A ACGAT ATAATAATTTCGCAGTCTCCACTATATTCCGGCCCGGGA AACACCCTTGGGTCCTCTCTAGGCACGACTGATTGATAA TGATATCGTAAGAAGTAC AACCI TGGGC TGAGGGCCI GC CACCCATCTTCCATGATAAGACATCTTTCTGGACGATCA GCGCTGTCACAGGTGACGGGCCAGTGTGAACAAATCAC ATCGAAGGCACACATTGCGCGATGAAGACTCTGCACTCT ATTGCGTCAAACACGCAAACCATTATACCTGAAGCATCA CCTCGTGTCCTATACGAGTCGTTAAACTTTTCTTCCTCTA rTCTGCCCACTlTrCATTTCrTrTATACTCCCGTTCTrGCT CGATCTCCACCGCTTCATACCGACAAACCTCCGGCTTTC AGTTTCTTCTTACGGTAAAACCAAAGCACCCCACGAGCA AGCTAGATTCCACACCAGGTAACTTCAGTCAAGCCAACA GAACCTCGGTGGGTCTCAAGTTGAAGATCGGCAGCATCA I AACCTCGTTGCGAGAACTCGGGGGAAATCTCGGGGAA TCCGCGCTGAATCTGCCCCCGCGAACCCTAAGCGGACTT CCTCCGCAATCCTCAATTTCCCCGAGGATACGGACTATT CATCCAGCATTCCAACCATTCTAGTTCTAGTGATCGGAAATTCCCCGGCACCCCTGCATCAACAGAAGCATACCATATWSGR Docket No. 66180-701.601SEQ ID NO. Promoter Sequence ATAATGTCACAATTTCCCCTCTGCCAAGGGAGGGGAAGT GAGTGTCCCCTCCI CTGCTATT8 VgpdA _mim TCGGAGAATATGGAGCTTCATCGAATCACCGGCAGTAA {Aspergillus GCGAAGGAGAATGTGAAGCCAGGGGTGTATAGCCGTCG nidulans) GCGAAATAGCATGCCATTAACCTAGGTACAGAAGTCCA ATTGCTTCCGATCTGGTAAAAGATTCACGAGATAGTACC TTCTCCGAAGTAGGTAGAGCGAGTACCCGGCGCGTAAG CTCCCTAATTGGCCCATCCGGCATCTGTAGGGCGTCCAA ATATCGTGCCTCTCCTGCTTTGCCCGGTGTATGAAACCG GAAAGGCCGCTCAGGAGCTGGCCAGCGGCGCAGACCGG GAACACAAGCTGGCAGTCGACCCATCCGGTGCTCTGCAC TCGACCTGCTGAGGTCCCTCAGTCCCTGGTAGGCAGCTT TGCCCCGTCTGTCCGCCCGGTGTGTCGGCGGGGTTGACA AGGTCGTTGCGTCAGTCCAACATTTGTTGCCATATTTTCC TGCTCTCCCCACCAGCTGCTCTTTTCTTTTCTCTTTCTTTT CCCA TCTTCAGTA TATTCATCT TCCCATCCAAGAACC IT T ATTTCCCCTAAGTAAGTACTTTGCTACATCCATACTCCAT CCTTCCCATCCCTTATTCCTTTGAACCTTTCAGTTCGAGC TTTCCCACTTCATCGCAGCTTGACTAACAGCTACCCCGCT TGAGCAGACATCAC9 Vmm_gpdA (Pmin) CCCATCTTCAGTATATTCATCTTCCCATCCAAGAACCTTT {A. nidulans) ATTTCCCCTAAGTAAGTACTTTGCTACATCCATACTCCAT CCTTCCCATCCCTTATTCCTTTGAACCTTTCAGTTCGAGC TITCCCACTTCATCGCAGCTTGACTAACAGCTACCCCGCT TGAGCAGACATCAC10 VbphA (A. niger) CGTGTCCGTTCTACAAGATCATCCCTGGATTCTCCCTCTG TGTGGATGCATTTCGATACGGAGCCGTAGAGGGATGTAA I GCGTACTTCCT TAGTCACTTCCACAGCGACCAITACAI C GGCCTGACGGGGTCGTGGCGCCATGGACCAATCTACTGC AGCAGACCTACGGCCAACTTGGTGTGCCAGCAACTGAA GGTCGACCGGAAGTGGCTTGTACCACTTGAGTTCGAGCG GAAGACGGAAATCCCGGATACAGGAGGAGCGCAGGTGA CTTTGATCGAGGCTAAI CATIGTCCTGGGAGCGCCATCT TICTCT rCGAGAAATCAATGGGATCGGGTCCCTCGCAGA GAACACATCGTGTCCTCCACTGTGGTGACTTTCGCGCCT CGCCGCTTCATGTGCAACATGCCCTTCTCCGCCCGGAGA TTGCTGACCCCGCAACCGGCAAGGCTCGCCAGCAACGA ATCGATGCCTGCTATCTGGACACTACATATTTGAGCCCC AAGTATGCATTCCCTGGCCAAGAAGATGTCATACAAGCC I GCGCAGAACTTTGCGTTGAGCTCGAI GGGGACGCCAAC GACACCAATGGACGAGCGTTTGGACGACCAGTCAATGG AAAAAGCGGAATGCTGAGCAAGTTTGTTACGGCTGTGA CTGGATCCCGCCCGTCTCCGACGCAAGACAGCCGCCCCC CTGGCCGGCTATTGGTAGTAATAGGGACGTACAGCATCG GCAAAGAACGCATCTGTCI GGGGA PCGCACGGGCATTG AAGAGCAAGATCTACGCGACGCCAGCTAAGCAGCGCGT CTGTGCGTGCCTCGAGGATGCTGAGCTGTCATCGCTGCT GACAGACGATCCCACGGAGGCGCAGGTGCATATGCAAA CGCTATTCGAGATCCGGGCGGAAACGCTGGCGGATTACC TGGACTCGATGAAGCCGCACTTCACGCGGGTGGTGGGAT TICGACCAACCGGGTGGACGTATCGCCCGCCAGCTGGCC GAATGCTGGACAACCCACCGGTGTCGGTGGTGCTCAATT CGGCACATTGGAAGACGCCCTTTTCTGCGAAAGACCTGG TGCCACAGCGAGGGAGTACGCGGGAAAGCGCATGCTTTGGAGTGCCGTACAGTGAGCACAGCTCATTTCGGGAGTTGWSGR Docket No. 66180-701.601SEQ ID NO. Promoter Sequence AGCATGTTCTGCTGCGCACTCCGGATCGGACGGGTGATC CCGAC AGTGAACGTAGGTAGCCGGAAAAGTCGGGAGCG CATGAAGGCGTGGATTGAGCGATGGGAGGCGGAGAAGC GGAAGAATGGGTTGTACCGCGTGGAGGGGAATAGCTGG TAGGGGATAGATAGACGGCTCTACCAACGTCCAAAGTA CTGCTGGAACACAAGGATCAGCAGGATCAGAAGGATTG CGAAAGACGGGTCGGAACATGTTGCCTAATAGAGTAAG I AAGGAGTTGGTGCI GTAACTAGI CAC AAGTIACGAITT GTGTACATAACATCATTAGTCATGGAGATCAATTGCCTT TATGCTTCCGTAACTCTCGCCTCCCCGGAGTCACGAGAT CAATAGAAACCACCGCCGTTGACCATTCGCGATGCTCTC ACTGGCTGTATGCTGTCGATAGCCATGGAGCCGTTCAAA G TATGGACCCTTTGGGI GAGGA TCTCCCTCCAACCCC AC GGGACGTACACGAACAACCGAGCAGAGGCGGGGGAGG GCAAAGAGGCCGGCGCTGCAAATCGGCTGGCAGATCAG TCGCGGCTCAGCAGAGACTCCCGA 11 11 CCCTTCCGTTG CCTGGCTTTGCCTCGGGGTTCGAGAGGAGCCCGTCTGCC ATAAATAAGCCTGCACTTCAACTCAAAAAAAAGGGAGA TGACAGATCAACCACTITCTCGACAAGAAACACTCTTCA CCCATGGCGATACTTGAGTGAAGTAAGTGTGACTG TGAC TGATATTA 1111 C 11 C 11 CAGCCA 1 CC 1111 TCGATATATT ACCTTATAGTTGCTTATTTCATTTCGGAGGTAAGATGGTC TCCTTGGCACCCACATTCCCGGCTGCACTTGGCGGCTGC GGAATTGCTTCTCCTGGCTGCATTTGCCGGTGTTAACTTC CGAACTCACCAGCTTCCTCCCCTCCCCCCACAAAAACAA TC25 PfraA (.4. niger) CCCTCGGCTGGTCTGTCTTACACAAGATCACACGCTTTG ATCTACAATCACCCCAAGTATGGACCTCAGGCCCACCAA C GC C C AG IGGAGGC AC GT A TC TTGC GC C C C AG AGGAC G GA AGGGC A AGA A CAC GA AGGCC ATT GC AGGT GTGGC TG GTATTGCCGTGGAAGACTTGAATACTGTCACCTTTACCG AGCAGGACTCTCCGGCCGGCCTTGCCTACTTTGACGCCT CTATCCCCGGTGGTGCTAAGTACTGGGCCACCCCTATCC GGGCCTITG TCGACTCGGAAGGCAAGA ITGGCCI GGCT T CTTACCGCGCTAGCGCTACTGCTAAAGCCCCTTACGGAA TCGATAGCCAGAAGAAGCCCGGATCGTACAGCATCTCTG ACGTGGCTCGCGGCGACCAGCGCGTGGTCCCGAGACTG GATAGACAGCGGAACGCCGCAGCGGAGACTGAGGAGGT TGCGCGTAACCTCATGAAGAGCCTTGGCTCCTAGAATAC AGGTGTTTCAGTCCCAAGCAA ITTTTGTCI C ATG TGTCAG ACATGTTCTATCTTCCACTTAGAGAGCTTTGCTGTATGAT TAGGTTTTTGGATGGTA AATGTATAGTTA 1 T 1 1 CGCACTT GTTCTCATTTGTTTGTGATATAAGCCGGCTACATCTCATT CTAAGTATAAATTAAATTGCAATTTCAAAGACGTCTCAGlAAnACTGATCACTATAAACCTGGTrnGCCATACCGI AAGGCAACAGCCAI CTTC ATAACTAACTAGTCCGTIACA TATGAAATACATAAATGGCGCTTAATAATCCAGCGCAAC GCCCGACCGCTTTGACAGGTAAGCGCACGTGACATTAAA TAGGGCATCCACATCAGGGTAGATACGCATCACATGACC CGCACATCCTAAGCGAGGGACGGGTAAGTTGAAGGAGC GAAAGAC ATCAGAACA rCTTGGACGGTTTTTCGAACATC CATCCAGCCAGCAACAAACCGCCAAA26 Pte fl (A. nidulans) CGAGACAGCAGAATCACCGCCCAAGTTAAGCCTTTGTGC TGATCATGC rCTCGAACGGGCCAAGTICGGGAAAAGCAAAGGAGCGTTTAGTGAGGGGCAATTTGACTCACCTCCCAWSGR Docket No. 66180-701.601SEQ ID NO. Promoter Sequence GGCAACAGATGAGGGGGGCAAAAAGAAAGAAATTTTCG TGAGTCAAI ATGGATICCGAGCATCATTITCTTGCGGI CT ATCTTGCTACGTATGTTGATCTTGACGCTGTGGATCAAG CAACGCCACTCGCTCGCTCCATCGCAGGCTGGTCGCAGA CAAATTAAAAGGCGGCAAACTCGTACAGCCGCGGGGTT GTCCGCTGCAAAGTACAGAGTGATAAAAGCCGCCATGC GACCATCAACGCGTTGATGCCCAGCTTTTTCGATCCGAG AATCCACCGTAGAGGCGATAGCAAGTAAAGAAAAGCTA AACAAAAAAAAATTTCTGCCCCTAAGCCATGAAAACGA GATGGGGTGGAGCAGAACCAAGGAAAGAGTCGCGCTGG GCTGCCGTTCCGGAAGGTGTTGTAAAGGCTCGACGCCCA AGGTGGGAGTCTAGGAGAAGAATTTGCATCGGGAGTGG GGCGGGTTACCCCTCCA TATCCAA TGACAGA TATC TACC AGCCAAGGG ITTGAGCCCGCCCGCTTAGTCGTCG TCCTC GCTTGCCCCTCCATAAAAGGATTTCCCCTCCCCCTCCCAC A AAA 11 11 CTTTCCCTTCCTCTCCTTGTCCG CTTCAGTAC GTATATCTTCCCTTCCCTCGCTTCTCTCCTCCATCCTTCTT TCATCCATCTCCTGCTAACTTCTCTGCTCAGCACCTCTAC GCAT TACTAGCCG lAGTATCTGAGCAClTCTCCCTTITAT ATTCCACAAAACATAACACAACCTTCACC12 TRE GGTACCGAGCTCGACTTTCACTTTTCTCTATCACTGATAG GGAGI GGTAAACTCGACTTICACTTTTCT CTATCACTGAT AGGGAGTGGTAAACTCGACTTTC AC 1111 CTCTATC ACT GATAGGGAGTGGTAAACTCGACTTTCACTTTTCTCTATC ACTGATAGGGAGTGGTAA ACTCGACTTTCAC 1 11 1 CTCT ATC A CTGATA GGG AGTGGTAAACTCG A CTTTC AC 1 1 1 1 C TCTATCACTGATAGGGAGTGGTAAACTCGACT T1 CACI T I TCTC TATCACI GATAGGGAG TGGTAAACTCGACCTATA TAAGC AGAGCTCGTTTAGTGAACCGTCAGA TCGCCTGGA GACGCCATCCACGCTG T T T TGACCTCCATAGAAGACACC GGGACCGATCCAGCCTCCGCGGCCCCGAATTG75 PthiA (Aspergillus TTCGGTAAATACACTATCACACACCGAACGTGCCCTGAT oryzae) TGCCTTGATACTCTGTGAGCGCTGGGCAGGGGACCTTGC ACCCACCGATGAAGAATTTCACCGGCAATTGAGCCGGTG TGTCTCTAAGCAGGAGGCATGGTGGTGTCAGTACTTGGG TCGGGTAGCGACCCTAATTGGAGACGTGCATCCATCCGG CCGCGTGTCGGACATGCA ITGGAGGATCCGATTGGAAAC TGAATGGGAATCCATTGTGAAGAAGAAAGACGAGTGCG ATATGCTGCGTCTCAAAGTGAAATGCAACAACGATGTGG CTGTCGCCGCGTTCTCTCTTGACAGCTTACAGGAAAGGG CGGAGAAAGTCGAGAAAGTCGGAAAGAAAAAGAACTG GATC AAGGATTATGGAGTGCGAGTGGGGGTAACGATTA TTTGCTAA PACT TAGG IT TCACTAI TGAAAAGGI TCCAGT CGTGGAGA 1111 C 1 G T H T 1 GGATAAATGTTA ACTAAC C GTGGACAGAGTACTATGTTATATAGTGGATCAGATGATC CACCATTCCTCGATCTGACAGACGGGCAATTGATTACGG GATCCCATTGGTAACGAAATGTAAAAGCTAGGAGATCGrCCGCCGArGTCAGGATGATFTCACTrGTTTCITGTCCGG CTCACCGGTCAAAGCTAAAGAGGAGCAAAAGGAACGGA TAGAATCGGGTGCCGCTGATCTATACGGTATAGTGCCCT TATCACGTTGACTCAACCCATGCTATTTAACTCAACCCCT CCTTCTGAACCCCACCATCTTCTTCCTTTTCCTCTCATCC CACACAATTCTCTATCTCAGATTTGAATTCCAAAAGTCC TCGGACGAAACTGAACAAGTCTTCCTCCCTTCGATAAACCTTrGGTGATTGGAATAACTGACCAICTTC TATAGT TCCCWSGR Docket No. 66180-701.601SEQ ID NO. Promoter Sequence AAACCAACCGACAATGTAAATACACTCCTCGATTAGCCC TCTAGAGGGCArACGATGGAAGICATGGAATACTTTTGG CTGGACTCTCACAATGATCAAGGTATCTTAGGTAACGTC TTTGGCGTGGGCCGGTGTTCGTTCCCAGTCATCGATGCA TTCACATGCCCTCCCTAAGCTGGGCCCTAGACTCTAGGA TCCTAGTCTAGAAGGACATGGCATCGATGGACTGGGTTC GTTCTGAGATTATACGGCTAAAACTTGATCTGGATAATA CCAGCGAAAAGGATC ATGCCT TCTCTCG ITCTTCCTGTTG ATGGAATGGCTAACAGATGATAGTCATTGCAACTTGAAAC

[0083] A vector provided herein can comprise one promoter. For example, a vector provided herein can comprise an inducible promoter (e.g., a TRE or a bphA promoter) or a constitutive promoter (e.g., a gpdA promoter). A vector provided herein can comprise two promoters. For example, a vector provided herein can comprise an inducible promoter (e.g., a TRE promoter or an fraA promoter) and a constitutive promoter. A vector provided herein can comprise three promoters. For example, a vector provided herein can comprise an inducible promoter (e.g., a TRE), a repressible promoter (e.g., a thiA promoter), and a constitutive promoter (e.g., gpdA promoter). A vector provided herein can comprise four or more promoters.

[0084] Provided herein are vectors comprising a promoter (e.g., a constitutive, inducible, or repressible promoter) and a system to regulate the expression of an enzyme. In some embodiments, a vector provided herein comprises a nucleic acid sequence encoding an enzyme (e.g., an enzyme associated with the biosynthesis of a tryptamine alkaloid). In a system or method provided herein, a promoter can be upstream of a nucleic acid sequence encoding an enzyme and the promoter can regulate (e.g., induce or repress) the expression (e.g., production) of the enzyme. In some embodiments, a nucleic acid sequence encoding an enzyme can comprise a nucleic acid sequence encoding tryptamine 4-monooxygenase (PsiH), hydroxytryptamine kinase (PsiK), Rhinella marina indolethylamine N-methyltransferase (2?mlNMT), psilocybin synthase (PsiM), tryptamine 5-hydroxylase (T5H), acetyl serotonin methyltransferase (ASMT), or 5-hydroxy-indolethylamine-N-methyltransferase (5OH-INMT).

[0085] Vectors provided herein can comprise components that are associated with the transcription of a nucleic acid sequence. For example, a vector provided herein can comprise nucleic acid sequences encoding promoters, transcription factors, terminating sequence, separating sequences, or combinations thereof. A vector provided herein can comprise a nucleic acid sequence encoding a promoter, e.g., a constitutive, repressible, or inducible promoter provided herein. In certain embodiments, a vector comprises a nucleic acid sequence encoding a transcription factor (e.g., a transcription factor provided herein). For example, a vector provided herein can comprise a nucleic acid sequence encoding a reverse tetracycline transactivator (rtTA) protein or a tetracyclineWSGR Docket No. 66180-701.601transactivator (rtTA) protein. In certain embodiments, a vector can comprise a nucleic acid sequence encoding a transcriptional terminating sequence (e.g., a terminator). For example, a vector can comprise a nucleic acid sequence encoding the transcriptional terminator TtrpC, the transcriptional terminator TcgrA, or the transcriptional terminator TamyB. In certain embodiments, a terminator sequence is downstream of a sequence encoding an enzyme. In certain embodiments, a vector can comprise a nucleic acid sequence encoding a separating sequence. For example, a vector can comprise a nucleic acid sequence encoding a P2a separator. A separator sequence can be downstream of a first nucleic acid sequence encoding a first enzyme and upstream of a second nucleic acid sequence encoding a second enzyme.

[0086] In some embodiments, a vector provided herein can comprise a selection marker (e g., a positive or negative selection marker). Examples of selection markers include, but are not limited to, a selection marker that confers antibiotic resistance to a host cell (e.g., beta-lactamase or the neo gene from Tn5), a selection marker that confers antibacterial or antifungal properties to a host cell (e.g., a mutant Fabl gene (mFabl) from E. coli), an enzyme provides negative and positive selection (e.g., a URA3 gene). In some embodiments, a selection marker comprises ergA, amdS, pyrG, ble, hph, sdh2, uprT, and hisB.

[0087] In some embodiments, a vector can comprise a standard bacterial self-replicating plasmid without lacZ (e.g., pUC19). A vector provided herein can further comprise a nucleic acid molecule encoding an enzyme, e.g., tryptamine 4-monooxygenase (PsiH). i vector provided herein can further comprise a system for regulating the production of the enzyme (e.g., PsiH). For example, a system for regulating the production of the enzyme (e.g., PsiH) can comprise an inducible promoter of the second generation Tet-ON system, e.g., the tetracycline-responsive element (TRE), upstream of the nucleic acid molecule encoding PsiH. In certain embodiments, TRE is induced by the presence of tetracycline. In certain embodiments, a vector can comprise a minimal promoter (e.g., PgpdA inin) downstream of the inducible promoter. In certain embodiments, an inducible promoter can comprise a minimal promoter (Pmin). In certain embodiments, a vector can further comprise a nucleic acid sequence encoding a terminator (e.g., TArpC) downstream of the nucleic acid molecule encoding the enzyme (e.g., PsiH). A vector provided herein can additionally comprise nucleic acid sequences to recover a uridine auxotrophy, e.g., a system to recover a uridine auxotrophy. A system to recover a uridine auxotrophy can comprise a nucleic acid sequence that encodes the enzyme CTP synthetase, pyrG wt, a gene that controls the synthesis of ribonucleotides of pyrimidine. In some embodiments, a vector provided here in can comprise pUC19; TRE:psiH:TtrpC:pyrG_wt (FIG. 1B). In some embodiments, a vector provided here in can comprise pUC19; TRE-Pmin::psiH::TtrpC::pyrG_wt (FIG. 1D and FIG.5B)WSGR Docket No. 66180-701.601

[0088] In some embodiments, a vector can comprise a standard bacterial self-replicating plasmid without lacZ (e.g., pUC19), and can further comprise nucleic acid molecules encoding a first enzyme, e.g., psilocybin kinase (PsiK), and a second enzyme, e.g., psilocybin methylase (PsiM). The vector can comprise a system for regulating the expression of the first enzyme (e.g., PsiK) and the second enzyme (e.g., PsiM). For example, a vector can comprise an inducible promoter (e.g., bphA). In certain embodiments, an inducible promoter can be induced by the presence of benzoic acid (e.g., a bphA promoter). The bphA promoter can be upstream of the nucleic acid sequences encoding the first enzyme (e.g., PsiK) and the second enzyme (e.g., PsiM). In certain embodiments, the vector comprises a P2a separator between the nucleic acid sequences encoding the first enzyme (e.g., PsiK) and the second enzyme (e.g., Psi ). A vector provided herein can comprise a nucleic acid sequence encoding a terminator (e.g., TtrpC) downstream of the nucleic acid molecule encoding the second enzyme (e.g., PsiM), In certain embodiments, a vector provided herein can comprise pUC19: PbphA:psiK:P2a:psiM:TtrpC (FIG. 1C).

[0089] In some embodiments, a vector provided herein can comprise: (i) a standard bacterial selfreplicating plasmid without lacZ (e.g., pUC19); (ii) nucleic acid molecules encoding a first enzyme, e.g., psilocybin kinase (PsiK), and a second enzyme, e.g., psilocybin methylase (PsiM); and (iii) a system for regulating the expression of the first enzyme (e.g., PsiK) and the second enzyme (e.g., PsiM). The system for regulating the expression of the first enzyme (e.g., PsiK) and the second enzyme (e.g., PsiM) can comprise an inducible promoter and a repressible promoter. The inducible promoter can be a promoter induced in the presence of benzoic acid, e.g., bphA. The repressible promoter can be a promoter inhibited in the presence of thiamine, e.g., thiA. The inducible promoter (e.g., bphA)' can be upstream of the first enzyme (PsiK). The repressible promoter can be upstream of the first enzyme (e.g., PsiM). The vector can further comprise a nucleic acid sequence encoding a transcriptional terminator (e.g. TtrpC downstream of the nucleic acid sequence encoding the first enzyme (e.g., PsiK) and a different transcriptional terminator sequence (e.g. TcgrA) downstream of the nucleic acid sequence encoding the second enzyme (e.g., PsiM). In certain embodiments, a vector provided herein comprises a system to direct a nucleic acid molecule to integrate into a specific locus in the host cell (e.g., the uprT locus). A system to direct integration of a nucleic acid molecule into a specific locus can comprise flanking sequences (e.g., 5'-UTR and 3'-UTR flanking sequences). In some embodiments, a flanking sequence can comprise a fragment of a gene into which a nucleic acid molecule can integrate (e.g., uprT). In certain embodiments, a first flanking sequence can comprise w?r7-5’UTR and a second flanking sequence can comprise « / ?rZ-3’UTR. In certain embodiments, a homologous recombination in the wpr TTocus can be associated with a loss of pyrimidine biosynthesisWSGR Docket No. 66180-701.601and a reduction in cell growth. In certain embodiments, a vector provided herein can comprise pUC19; uprT-5'UTR:PbphA:psiK:TtrpC:PthiA:PsiM:TcgrA:uprT-3'UTR (FIG. IE).In some embodiments, a vector provided herein can comprise: (i) a standard bacterial self-replicating plasmid without lacZ (e.g., pUC19); (ii) nucleic acid molecules encoding a first enzyme, e.g., psilocybin kinase (RmINMT), a second enzyme, e.g., psilocybin methylase (psiK), a third enzyme, e.g., cytochrome p450 reductase (CPR); and (iii) a system for regulating the expression of the first enzyme (e.g., A / MINMT), the second enzyme (e.g., psiK), and the third enzyme (e.g., CPR). The system for regulating the expression of the first enzyme (e.g., RmINMT), the second enzyme (e.g., psiK), and the third enzyme (e.g., CPR) can comprise a first and second inducible promoter and a repressible promoter. The first inducible promoter can be a promoter induced in the presence of benzoic acid, e.g., bphA. The second inducible promoter can be a promoter induced in the presence of sucrose, e.g., sucA. The repressible promoter can be a promoter inhibited in the presence of thiamine, e.g., thiA. The first inducible promoter (e.g., bphA) can be upstream of the first enzyme (RmINMT). The second inducible promoter (e.g., sucA) can be upstream of the second enzyme (e.g., psiK). The repressible promoter can be upstream of the third enzyme (e.g., CPR). The vector can further comprise a nucleic acid sequence encoding a transcriptional terminator (e.g. TtrpC) downstream of the nucleic acid sequence encoding the first enzyme (e.g., 7? / «INMT) and a different transcriptional terminator sequence (e.g. TcgrA) downstream of the nucleic acid sequence encoding the second enzyme (e.g., psiK). In certain embodiments, a vector provided herein can comprise pUC19; PbphA::RmINMT::TtrpC::PsucA::psiK::TcgrA::PthiA::CPR::Ttefl::pyrG_wt (FIG. IF).

[0090] In some embodiments, a vector can comprise a standard bacterial self-replicating plasmid without lacZ (e.g., pUC19), and can further comprise nucleic acid molecules encoding a first enzyme, e.g,, Rhinella marina indolethylamine A’-methyltransferase (RmINMT), and a second enzyme, e.g., psilocybin kinase (PsiK). The vector can comprise a system for regulating the expression of the first enzyme (e.g., RmINMT) and the second enzyme (e.g., PsiK). The system for regulating the expression of the first enzyme (e.g., RmINMT) can be the same system as the system for regulating the second enzyme (e.g., PsiK). For example, a vector can comprise an inducible promoter (e.g., bphA). In certain embodiments, an inducible promoter can be induced by the presence of benzoic acid (e.g., a bphA promoter). The bphA promoter can be upstream of the nucleic acid sequences encoding the first enzyme (e.g., RmINMT) and the second enzyme (e.g., PsiK), In certain embodiments, the vector comprises a P2a separator between the nucleic acid sequences encoding the first enzyme (e.g., PsiK) and the second enzyme (e.g., ArnlNMT), A vector provided herein can comprise a nucleic acid sequence encoding a transcriptional terminator (e.g., TtrpC) downstream of the nucleic acid sequence encoding the second enzyme (e.g., PsiK), In some embodiments, the system for regulating theWSGR Docket No. 66180-701.601expression of the expression of the first enzyme and the system for regulating the expression of the second enzyme are different. For example, a vector can comprise a first inducible promoter (e.g., a bphA promoter) upstream of the nucleic acid sequences encoding the first enzyme (e.g., RmINMT) and a second inducible promoter (e.g., a sucA promoter) upstream of the second enzyme (e.g., PsiK). A vector provided herein can comprise a nucleic acid sequence encoding a transcriptional terminator (e.g., PtrpC) downstream of the nucleic acid sequence encoding the first enzyme (e.g., 7?mINMT) and a transcriptional terminator sequence (e.g., TcgrA) downstream of the nucleic acid sequence encoding the second enzyme (e.g., PsiK). In certain embodiments, a vector provided herein comprises a system to direct a nucleic acid molecule to integrate into a specific locus in the host cell (e.g., the w / vTlocus). In certain embodiments, a vector provided herein can comprise pUC19; 5'UTR __uprP:: PbphA:: RmINMT:: TtrpC:: Psi / cA::psiK:: TcgrA:: 3'UTR (FIG. 5C). In certain embodiments, a vector provided herein can encode a protein (e g., a NADPH-ferrihemoprotein reductase de Psilocybe cubensis, CPR) to rescue the loss of pyrimidine biosynthesis and reduction in cell growth associated with a homologous recombination in a gene locus (e.g., the wprTlocus). In some embodiments, the expression of the rescue protein can be regulated by a promoter, e.g., a PthA promoter, a promoter inhibited in the presence of thiamine. In certain embodiments, a vector provided herein can comprise pUC19; 5 'UTR uprT'. PbphA:: RmINMT:: T trpC'.: PsucA: psiK'.. TcgrA: PthiA::cpr:: TamyB:: 3 TR uprT (FIG. 5D)

[0091] In some embodiments, a vector provided herein can comprise: (i) a standard bacterial self¬ replicating plasmid without lacZ (e.g., pUC19); (ii) nucleic acid molecules encoding a first enzyme, e.g., acetylserotonin methyltransferase (ASMT), a second enzyme, e.g., tryptamine 5-hydroxylase (T5H), and a third enzyme, e.g., 5-hydroxy-indolmethylamine- / V-methyltransferase (5OH-INMT); and (iii) a system for regulating the expression of the first enzyme (e.g., ASMT), the second enzyme (e.g., T5H), and the third enzyme (e g., 50H-INMT). A vector can further comprise an inducible promoter and a constitutive promoter. An inducible promoter can comprise a tetracycline-responsive element (TRE). In certain embodiments, an inducible promoter is a promoter inducible by benzoic acid, e.g., bphA. A vector can comprise a first inducible promoter (e.g., TRE) and a second inducible promoter (e.g., bphA). In certain embodiments, constitutive promoter can comprise a gpdA promoter. The first inducible promoter (e.g., TRE) can be upstream of the first enzyme (e.g., ASMT). The constitutive promoter (e.g., gpdA) can be upstream of the second enzyme (e.g., T5H). In certain embodiments, the second inducible promoter can be upstream of the third enzyme (e.g., 5OH-INMT). In certain embodiments, a transcriptional terminator (e.g., PtrpC) can be present after the stop codon for the second enzyme (e.g., T5H). In certain embodiments, a transcriptional terminator (e.g., TcgrA) isWSGR Docket No. 66180-701.601present after the stop codon for the third enzyme (e.g., 50H-INMT). In certain embodiments, a vector provided herein can further comprise a system to recover a uridine auxotrophy, the system comprising a nucleic acid sequence that encode the enzyme C TP synthetase, pyrG wt, a gene that controls the synthesis of ribonucleotides of pyrimidine. To recover the uridine auxotrophy induced by the transformation of the second vector, the first vector can also comprise a wildtype gene that encodes the enzyme CTP synthetase, pyrG wt, the gene that controls the synthesis of ribonucleotides of pyrimidine. In some embodiments, a vector provided herein comprises pUC19-ME0D; TRE: ASMT: TfrpC: P^ 4: T5H: T777? C: P ’ / ? / l:5-OH-INMT: Tcg7 / 4:j?jrG pwt (FIG. 3).

[0092] In some embodiments, a vector provided herein can comprise: (i) a standard bacterial selfreplicating plasmid without lacZ (e.g., pUC19); (ii) nucleic acid molecules encoding a first enzyme, e.g., 7?» / INMT, a second enzyme, e.g., tryptamine 5-hydroxylase (T5H), and a third enzyme, e.g., acetylserotonin methyltransf erase (ASMT); and (iii) a system for regulating the expression of the first enzyme (e.g., ASMT), the second enzyme (e.g., T5H), and the third enzyme (e.g., 50H-INMT). The system for regulating the expression of the first, second, and third enzymes can be the same for each enzyme, different for each enzyme, or a combination thereof. A vector can further comprise an inducible promoter and a constitutive promoter. An inducible promoter can comprise a tetracycline¬ responsive element (TRE). In some embodiments, an inducible promoter is a promoter inducible by benzoic acid, e.g., bphA. A vector can comprise a first inducible promoter (e.g., TRE) and a second inducible promoter (e.g., bphA). In certain embodiments, constitutive promoter can comprise a gpdA promoter. The first inducible promoter (e.g., TRE) can be upstream of the first enzyme (e g., 7?mINMT), The constitutive promoter (e.g,, Pgpt 4) can be upstream of the second enzyme (e.g., T5H). In certain embodiments, the second inducible promoter can be upstream of the third enzyme (e.g., ASMT). In certain embodiments, a transcriptional terminator (e.g., TtrpC) can be present after the stop codon for the first enzyme (e.g., RW / INMT). In certain embodiments, a transcriptional terminator (e.g., TamyB) is present after the stop codon for the second enzyme (e.g., ASMT) In certain embodiments, a transcriptional terminator (e.g., TcgrA) is present after the stop codon for the third enzyme (e.g., ASMT). In certain embodiments, a vector provided herein can further comprise a system to recover a uridine auxotrophy, the system comprising a nucleic acid sequence that encode the enzyme CTP synthetase, pyrG wt, a gene that controls the synthesis of ribonucleotides of pyrimidine. To recover the uridine auxotrophy induced by the second vector, the first vector can also comprise a wildtype gene that encodes the enzyme CTP synthetase, pyrG wt, the gene that controls the synthesis of ribonucleotides of pyrimidine. In some embodiments, a vector provided herein comprises pUC19; TRE:: RmINMT:. TtrpC, PgpdA::5HT:: TamyB: PbphA'.: ASMT:. TcgrA: pyrGpvt (FIG. 7).WSGR Docket No. 66180-701.601

[0093] In some embodiments, provided herein are systems and methods comprising a first vector and a second vector. The first vector and the second vector can comprise a system for regulating the expression of an enzyme. In some embodiments, the first vector comprises: (i) a nucleic acid sequence encoding one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids; and (ii) a promoter.

[0094] In some embodiments, a vector provided herein (e.g., a second vector) can comprise a standard bacterial self-replicating plasmid without lacZ (e.g., pUC19) and a promoter. In certain embodiments, a second vector can comprise a constitutive promoter (e.g., a constitutive promoter for A. niger). A constitutive promoter can comprise putative ribosomal subunit (Anl6g04690) promoter (PfraA The constitutive promoter (e.g., VfraA') can be upstream of a system to regulate the expression of an enzyme (e.g., an enzyme disclosed herein). A system to regulate the expression of an enzyme can comprise a transcription factor. In certain embodiments, a system to regulate the expression of an enzyme is a tetracycline-controlled transcriptional activation system. In certain embodiments, a second vector can comprise a nucleic acid sequence encoding a first transcription factor, e.g., tetracycline-controlled transcription silencer (tTS). In certain embodiments, a second vector can comprise a nucleic acid sequence encoding a second transcription factor, e.g., a reverse tetracycline responsive transcriptional activator (rtTA). In certain embodiments, the constitutive promoter (e.g., PfraA) is upstream of an open reading frame (ORF) comprising a first nucleic acid sequence encoding a first transcription factor (e.g., tTS) and a second nucleic acid sequence encoding a second transcription factor (e.g., rtTA). In certain embodiments, the ORF can be finished with a transcriptional, e.g., the transcriptional terminator from Aspergillus fumigatus, TcgrA. In certain embodiments, a second vector provided herein comprises a system to direct a nucleic acid molecule to integrate into a specific locus in the host cell (e.g., the pyrG locus). A system to direct integration of a nucleic acid molecule into a specific locus can comprise flanking sequences (e.g., 5'-UTR and 3'-UTR flanking sequences). In some embodiments, a flanking sequence can comprise a fragment of a gene into which a nucleic acid molecule can integrate (e.g., pyrCAy In certain embodiments, a first flanking sequence can comprise pyrG* (5' UTR) and a second flanking sequence can comprise pyrG** (3' UTR). In certain embodiments, a homologous recombination in the pyrG locus can be associated with a uridine auxotrophy. In some embodiments, the second vector can comprise pCUl; 5'UTR ^jrG:: P) <x4::tTS:: T2A::rtTA:: Tcgr4:: 3'UTR _pyrG (FIG. 1A and FIG. 5A).

[0095] Examples of vector components described herein include, but are not limited to, promoters provided in Table 2. In Table 2, bold and italicized contiguous nucleotide sequences (e.g., ATG and 714 / 1) represent start and stop codons, respectively, which are 5’ and 3’ to, respectively, the protein coding sequence of PyrG.WSGR Docket No. 66180-701.601

[0096] Table 2. Vector componentsSEQ ID NO. Vector component Sequence11 pyrG wt CCTCGGTCGCTCACTGTTCCTTTACGGATATGTGTACTCC GGCAAGCCGCGGGGTCGCGGTCGTTTGTACGGCAGCTTC TACTTGCTTGCACAGGGAGCTCTCTGGGGCTTGACGTCT TTTGGAGTTGCGAGGGAGTTGATTT TCCTACTTCTAAG1TT GGACTGAATCCGTGGTGTGAI TGAGGTGATTGGCGATGTTTGGCTATACCAGCTATATGTAATAATCTCTACTGTATACTACTATTCAACGCATTTTACTATGCGTGCTGCTAGGGTC GGCAATGACAATGGCAATCTGACTGACGTGGTCTATTTC TCCATGTGCAGCAGGGAATACGAGCTCCAATGGACCTCG GGAGTGGCACAGTCAATGGCAAGGAAACTCCGCCTTTG CAGGTGTGGCTGAACCCCACGGGTCGGAGGCGGAGCAA TCCACCCCCGATGTGGCTGGTGCGTGGAGGGGCTCGCGA TGATTTTACTGAGCTTGCTTTTCTTGTCGACATTGAACAT TGTCCTTGGTCTTCCTTCAGATTTAAGGGTCAGTCACTGC TACATTTTTCAGTAGTATCCGCGCACGTCTCTGGATTTAC GAATCAGGGTCCACCAGTCGAAACTTCGAACTACTCTCATTATACAATCCTCTTTCCATTCCCGCATTAACCCCTCCATCAACACCTTGTCCTCCAAGTCGCGATTGACCTACACTGC CCGTGCCAGCAAGCATCCCAATGCTCTGGCGAAGAGGCT GTTCGAGATTGCCGAGGCCAAGAAGACCAATGTGACTG TCTCGGCTGACGTTACCACCACTAAGGAGCTACTAGATCTTGCTGACCGTAGGCCGACCCGCTACTCTGCCTGATTATGCTGCATGCAAACTTATTAACGGTGATACCGGACTGCAG GTCTCGGTCCCTACATTGCCGTGATCAAAACCCACATCG ATATCCTCTCTGATTTCAGCAACGAGACCATTGAGGGAC TTAAGGCTCTCGCGCAGAAGCACAACTTTCTCATCTTCG AGGACCGCAAGTTCATTGACATCGGCAACACGGTCCAG AAGCAATACCACGGCGG TACCC TCCGTA ICTCGGAATGG GCCCACATCATCAACTGCAGCATTCTCCCTGGTGAGGGT ATCGTCGAGGCTCTCGCTCAGACGGCGTCTGCACCGGAC TTCGCCTACGGCCCCGAACGCGGTCTGTTGATCTTGGCA GAGATGACCTCTAAGGGCTCCTTGGCTACCGGCCAGTAC ACI ACTTCCI CGGTCGATTATGCCCGGAAA TACAAGAAC TI CGTTATGGGATI CGTGTCGACGCGCGCGT I’GGGI GAG GTGCAGTCGGAAGTCAGCTCTCCTTCGGATGAGGAGGAC TTTGTGGTCTTCACGACTGGTGTGAACATTTCITCCAAGG GAGATAAGCTTGGTCAGCAGTACCAGACGCCCGGATCG GCTATCGGCCGGGGTGCTGACTTCATTATCGCGGGTCGC GGTATCTACGCCGCGCCGGAI CCGGTGCAGGCTGCGCAA C AG IATC AGAAGGAGGGGTGGGA AGCCTACCTGGC CCG TGTCGGCGGAAAACTAATACTA2X4AAGGAGGATCGAA GTTCTGATGGTTATGAATGATATAGAAATGCAACTTGCC GCAACGGATACGGAAGCGGAAACGGACCAATGTCGAGC ACGGGTAGTCAGACTGCGGCATCGGATGTCCAAACGGT A ITGATCCTGCAGGC IACTATGGI GTGGC ACAAGGATCA ATGCGGTACGACGATTTGATGCAGATAAGCAGGCTGCG AAGTAGTAACTCTTGCGTAGAGAAAATGGCGACGGGTG GCTGATAAGGGCGGTGATAAGCTTAATTGTCATCGCAGA TAAGCACTGCTGTCTTGCATCCAAGTCAGCGTCAGCAGA AATACGGGACITCCGAAAGTAIATGGCAAAATTAAAGA ACTI GACTCTCCAGCAATGITITGCCCTGACCG I’CGCTA AAACGTTACTACCCCTATACCCGTCTGTTTGTCCCAGCCCGAGGCATTAGGTCTGACTGACAGCACGGCGCCATGCGGWSGR Docket No. 66180-701.601SEQ ID NO. Vector component Sequence GCTTGGGACGCCATGTCCGTCGCGTGATAAGGGTTGATC CAI GCAGCTACI ATCCTTCCATCGITCCATTCCC ATCCTT GTCCTATCTCCATCCTTGAAACTTTACTAGTTTAGTTGGA TGCTCGAGCTTGCTCTCGGCTACTCCGTC12 IKE GGTACCGAGCTCGACTTTCACTTTTTCTCTA TCACTGATAG GGAGTGGTAAACTCGACTTTCACTTTTCTCTATCACTGAT AG G GAGTGGTA AACTCG ACTTTC A C 11 11 CTCT ATC A CT GATAGGGAGTGGTAAACTCGACTTTCACTTTTCTCTATC ACTGATAGGGAGTGGTAAACTCGACTTTCACTTTTCTCT A TCACTGA TAGGGAGTGGTAAACI CGACTTTCACTTTTTCTCTATCACTGATAGGGAGTGGTAAACTCGACTTTCACTTTTTCTCTATCACTGATAGGGAGTGGTAAACTCGACCTATA TAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGCCTGGA GACGCCATCCACGCTGTTTTGACCTCCATAGAAGACACC GGGACCGATCCAGCCTCCGCGGCCCCGAATTG13 Aspergillus nidulans GGATCCACTTAACGTTACTGAAATCATCAAACAGCTTGA trpC gene terminator CGAATCTGGATATAAGATCGTTGGTGTCGATGTCAGCTC (XtrpC) CGGAGTTGAGACAAATGGTGTTCAGGATCTCGATAAGAT ACGT TC ATTTG ICC AAGCAGCAAAGAGTGCCTTCTAGTG ATTTAATAGCTCCATGTCAACAAGAATAAAACGCGTTTC GGGTTTACCTCTTCCAGATACAGCTCATCTGCAATGCAT TAATGCATTGGACCTCGCAACCCTAGTACGCCCTTCAGG CTCCGGCGAAGCAGAAGAATAGCTTAGCAGAGTCTATTT TCATTTTTCGGGAGACGAGATCAAGCAGATCAACGGTCGTCAAGAGACCTACGAGACTGAGGAATCCGCTCTTGGCTCC ACGCG14 Aspergillus oryzae AGGGTGGAGAGTATATGATGGTACTGCTATTCAATCTGG amyB gene C Al TGGAC AGTGAGTTTGAGTTTGAI GTAACTTGTCTATT terminator (TamyB) CTATGATGTATGGTCTTTTTGTTCTATAGTTGGAAATCGG AATGATCTCAAATCTTGAATAAATATAAAAAGGATAATA CTCACATCCATCACAACCTTACAAGGTTAATTCCGAGCT ATATTCCACCGACACAAATAGGCAGTATCTTCTCTCGCC AGAGAATCGCGATATTATTGGCATGCAAATAACGATAA CTGTCTCC AGAAGG TAAA TATATGCAG rCTTGAAACCTA AACAAGGCTTCTCAATCCATTGATTCTCAGTGATATCCT CTTACGAGAATAGGGAAGGTATATACCGTTGCTGGGGTT GCGTTTAGGCTAAATTCGTATGATAGTTGAATCTGTTTG GATGGGTATGCTGTGGTTTTATTTGGCATATCATTAGGG1TTGACCTGGTGG1TGCTCGCGACTATAGAATGAAGTGG AATGGGGGAAAGAAAGCAGGAAAAACAGCTTGGAGAG GAGCTATATCATAAAATATTATACGATTGTGGGCATAAT GTCAAATGTATTAGGTCTAGGTTTAAGTTTATGTTAGTAT ATCATGGAGATATAGTAAAAGGGAACTCTTTCCACTGAT GTATGTTCTCTTCTCACAAAGCCAGAAGGGTATAGTGAT A I’CCCGAGCC rGATAGCGTATTAGGATTCAGTTTTGG IG AGATACCATAAGTTTTTCATACACAAACCGATGTCTAGA GAGAGGGGAAGAGGGGTAGGAGGGGAAGGGCGAGTGT TGCCGCCTTGCCTAACACAAGACAGGTATACGTACTACT GACCAGCTACATGTATCAATACAGTAATGGTCCTCAAGA AIT15 Aspergillus CTAGTACAGCAGAAGAATCTCTCTCCGCTGTTGCTTCAG fumigatus cgrA gene TGTCTGCCATGCATTAACTTCATCCTACTGTCCTACCCGC terminator (TcgrA) AGTACCCATTCACATTTGCGGCAGATACCAGGTTGTTTTCTATTCCCTCGGTTCTTCAGTTCTTCAGATATTACATTACTCGAGAAATTGGCGGCGATGCAGGAGTTTGGTTGGTTTTWSGR Docket No. 66180-701.601SEQ ID NO. Vector component Sequence AATTGTTTCAGTCTCCTTGACCTGATTTGTATGACATGCA ATGTTTCGACGGAAGACTATCTCGGTGA ATATACGI C AT GAATCATGC16 uprT_ 5'UTR TCTCGTCTCCTGTTATAGAGTCAGAAGTTGCGGGAGGGC CGTCTGCCGCAGTTCI ATGTAI TA TCAACAAGG TTAAAC AATAGGCGACGATTAATTCCTTAGCTGCTTCGACTCTGA GCATTCCTATTGCTAGTTATCAGACACAATCCAAAATTA AGTATACTGCAATGGAGTTACCCATGTCAGAGGCTAGAG AGGGCGAACTTCAGCGATTATGTCATATCGGCGGAAGG GT TATGTAI TAGCCTCTTGTTATGGATGCAI T ITTGCATG G ITATACGCGTTCTCCTAC CG TGTTGGI AAAGGAAGCTT TATAGTCAAGGCTAAGTGGTTTAGTGTGGGAAATGGCAC TTATAAAATCCTGTACACGGAGAATAGAAAGTACTATCA CCTAAGAGCAAAGTGCATGACCTGGAAGGAAAAAGGCC TTGTGTCAAACTTTCGCTCTTGATAGATATGCAATCCGTT GACGAACTTTAGGCI T TGCTTGCAAATTAAAC CTTTTC AT TITCCT TGACGATC AAT TGCC AGTACCAGATTTTAGCTAC CCAGTATACAGCTACGTCGCAGGATCAGCCGGACTGATT ATGACAAATACACTCGGATGCTTATTTAGGAACTTATCA ATTGGGGTTTATTTTCACAAGGCGAAGTGATCCACAAGA CACATGCATGAAAGAACATTCATGAGCAATCCAGTCATT GGCT ITT CCAAAAGGI GGCCGGGGAACAGCAC TGTTCC A CCAGTCGGTACCCCGTAATGAGGGGAGAGGGTATTATTA TTAGCAATTATTTCCAGATGTATCAACTTAGGCAGAGAC CC AGGG A AATACTGGCCCTGAACTTG A AAGGC 1 I 1 I GTT GAATGCTAGCTTGGGTCTTCTCTGCAGAAGATAGTrGAC GGTTCTAGATIAATTGCATGTGGTTGAACCCAC TCCTAC GAATAG IT TACCGC ACTACTCCGI ACTACCCGTGATACT GTATTACGCAGTCGACTACGGAGCACTCCGTACAGAATA GTCATTGTAATAGCCAACTACTTAAGTAGTCCCACTAAC CGTCCCAATGAGGAAAATGTTCAACCCTCGCATATTAAT TCCTTAGCTTTAAATGCCTGCGTTACTTCCTACACTTCAA CTCAACCCCACTACCTTTGGAACGGTTTACAGTTCGCTG C AGATATCCTIC ATTTCTTGTTTC TIC ACCTCI TAGTCGT ACTTTGCATCCGTGGAAGAAGGAGGGGGAAAGCTACCA TAGCCAAGACGAACGAG18 CPR ATGACCGACCCTAATCGTACCACCTTCTCTTCAGCACTA CATCCTCTAGCTGTGGTCTCAATGGCCTCCTCTTCCTCAG ACGTTTTCGTCTTGGGCTTGGGTGTCGTCCTCGCTGCCCTTTATATATATTCCGCGACCAGCTTTTCGCTGCGTCCAAACCAAAG AAAGGTCGCCCCAGTATCCACCACCAAACCCGCCAATG GCTCTGCCAACCCTCGCGAC ITCAI CGCAAAGAI GAAGC AGGGTAAAAAGCGCAnUTCATn’nTACGGTICTCAGA CGGGTACTGCAGAAGAGTATGCCATTCGTCTCGCAAAGG AGGCTAAGCAGAAGTTTGGTTTGGCGTCCCTTGTGTGCG ATCCAGAGGAATACGACTTTGAGAAACTTGACCAACTGC CAGAGGACTCCATCGCTTTCTTCGTCGTTGCCACCTATG G TGAGGGAGAACCTACCGACAACGCCGTCCAGCTTTGCAGAACTTGCAAGACGAGTCTTTCGAGTTCAGCAGTGGAG AGCGCAAATTGAGTGGCCTCAAATATGTCGTCTTTGGTC TTGGGAACAAAACTTACGAGCACTACAATCTTATTGGAC GCACTGTTGACGCTCAACTCGCCAAGATGGGAGCTATCC GTATCGGCGAACGCGGTGAAGGTGACGATGATAAGAGC ATGGAGGAGGATTAC C ITGAATGGAAGGACGG IATGTGGGAGGCTTTCGCTACTGCCATGGGTGTCGAAGAGGGACWSGR Docket No. 66180-701.601SEQ ID NO. Vector component Sequence AGGGCGGCGACTCTGCCGACTTCGTTGTTTCGGAACTCG AGTC TC ATCCTCCCGAGAAGGTTTACCAAGGTGAATTCT CGGCTCGCGCTCTTACAAAGACCAAAGGAATCCATGAC GCCAAGAACCCCTTCGCTGCACCTATCACTGTCGCCCGT GAACTTTTCCAGTCTGTTGTCGACAGGAACTGTGTCCAT GTCGAATTCAACATTGAAGGCTCTGGCATTACGTACCAA CATGGTGACCACGTCGGTCTTTGGCCCTTGAACCCGGAT GTCGAAGTGGAGCGTCTCCTGTGCGTTCTGGGATTGACC GAAAAGCGCGACGCTGTTATCAGCATCGAATCTCTCGAT CCCGCTCTGGCCAAGGTACCATTCCCTGTCCCTACTACCT ACGGTGCTGTCCTTCGCCACTACATCGACATCAGCGCTG TTGCTGGTCGTCAAATTCTTGGGACATTGTCGAAGTTCG CTCCI ACTCCGGAGGCCGAGGC IT TCCTCAGGAATCTCA ATACCAACAAGGAAGAATACCACAACGTTGTCGCTAAT GGATGCCTCAAGTTGGGCGAAATTCTCCAAATCGCTACT GGTAACGATATCACTGTCCCACCTACTACTGCCAATACC ACCAAGTGGCCTATACCCTTTGATATCATCGTCTCTGCC ATTCCCCGTCTTCAACCCCGGTACTACTCCATTTCCTCGA GCCCCAAAATCCACCCCAACACTATCCACGCTACCGTTG TTGTCCTCAAGTACGAGAACGTTCCCACCGAGCCAATTCCTCGTAAATGGGTATACGGTGTTGGATCCAACTTCTTACTTAACCTCAAGTATGCCGTCAACAAGGAGCCCGTACCTT ACATCACTCAGAACGGTGAACAACGTGTTGGCGTTCCGG AATACCTTATTGCAGGACCTCGTGGCTCGTACAAGACTG AGACTTrCTACAAGGCCCCCATCCAI GT TAGGCGCTCGA CC I’TCAGAC TTCCCACTAACCCCAAGAGCCCTGTTATCA TGATCGGTCCTGGAACTGGAGTTGCTCCTTTCCGTGGATTTGTGCAAGAACGTGTTGCCCTTGCCCGCCGCTCCATTGAGAAGAACGGACCTGATTCACTTGCTGACTGGGGTCGCATCTCTCTGTTCTACGGTTGCCGCCGATCGGATGAAGATTTCTTGTACAAGGACGAATGGCCACAATACGAGGCTGAACTCAAGGGCAAATTCAAACTTCACTGCGCCTTCTCTCGAC AGAACTACAAGCCTGATGGAAGCAAGATTTACGTCCAGGATCTCATTTGGGAAGACAGGGAGCACATTGCTGACGCTATTCTCAATGGCAAAGGTTACGTGTATATCTGTGGTGAGGCGAAGAGCATGAGCAAGCAGGTCGAGGAGGTGTTAGCCAAAATCTTGGGAGAGGCCAAGGGTGGATCTGGCCCTGTTGAGGGTGTCGCTGAAGTTAAGCTATTGAAGGAGAGATCAAGGCTCATGTTGGATGTCTGGAGTTAA27 Aspergillus niger ATGCGACCGTAGAGCAGTGCAAGACCAACGTAAGCCAA pyrG 5 ’ UTR CCTCACACAAACAGGATTCCTCGAGCTAACATACATTCC {pyrG*} GAACCGTGCAGCCCAAGGCCGAGCAGTTCAACTGCGCT CAGCGCGCTCATGCCAACTTCCTTGAGAACTCCAGCCAA ACTATGCTCTTCCTCCTGGTAGCTGGACTGAAGTACCCC CAG ITGGCGACTGGCCTCGGAAGCATCTGGGTCCI CGGT CGCTCACTG ITCCTTTACGGATATGTGTACI CCGGCAAG CCGCGGGGTCGCGGTCGTTTGTACGGCAGCTTCTACTTG CTTGCACAGGGAGCTCTCTGGGGCTTGACGTCTTTTGGA GTTGCGAGGGAGTTGATTTCCTACTTCTAAGTTTGGACT GAATCCGTGGTGTGATTGAGGTGATTGGCGATGTTTGGC TA TACCAGCTA TATGTAATAAI CTCTACI GTATACTACTA TTCAACGCA U l i ACTATGCGTGCTGCTAGGGTCGGCAA TGACAATGGCAATCTGACTGACGTGGTCTATTTCTCCAT GTGCAGCAGGGAATACGAGCTCCAATGGACCTCGGGAGTGGCACAGTCAATGGCAAGGAAACTCCGCCTTTGCAGGTWSGR Docket No. 66180-701.601SEQ ID NO. Vector component Sequence GTGGCTGAACCCCACGGGTCGGAGGCGGAGCAATCCAC CCCCGATGTGGCTGGTGCGTGGAGGGGCTCGCGATGATTTTACTGAGCTTGCTTTTCTTGTCGACATTGAACATTGTCCTTGGTCTTCCTTCAGATTTAAGGGTCAGTCACTGCTACATTTTTCAGTAGTATCCGCGCACGTCTCTGGATTTACGAATCAGGGTCCACCAGTCGAAACTTCGAACTACTCTCATTATACAATCCTCTTTCCATTCCCGCATTAACCCCTCCATCAACAcc28 Tetracycline ATGTCTAGATTAGATAAAAGTAAAGTGATTAACAGCGC responsive activator AT TAGAGCI GCTTAATGAGGTCGGAATCGAAGGT TTAAC system AACCCGTAAACTCGCCCAGAAGCTAGGTGTAGAGCAGC CTACATTGTATTGGCACGTGCGCAACAAGCAGACTCTTA TGAACATGCTTTCAGAGGCAATACTGGCGAAGCATCACA CCCGTTCAGCACCGTTACCGACTGAGAGTTGGCAGCAGT TTCTCCAGGAAAATGCTCTGAGTTTCCGTAAAGCATTAC I GGTCCAI CGTGATGGAGCCCGATTGCA TATAGGGACCT CTCCTACGCCCCCCCAGTTTGAACAAGCAGAGGCGCAAC TACGCTGTCTATGCGATGCAGGGTTTTTCGGTCGAGGAGGCTCTTTTCATTCTGCAATCTATCAGCCATTTTACGTTGGG TGCAGTATTAGAGGAGCAAGCAACAAACCAGATAGAAA ATAATCATGTGATAGACGCTGCACCACCATTATTACAAGAGGCATTTAATATTCAGGCGAGAACCTCTGCTGAAATGGCCTTCCATTTCGGGCTGAAATCATTAATATTTGGATTTTCTGCACAGTTAGATGAAAAAAAGCATACACCCATTGAGGATGGTAATAAACCAAAAAAGAAGAGAAAGCTAGCAGTGTCAGTGACATTTGAAGATGTGGCTGTGCTCTTTACTCGGGACGAGTGGAAGAAGCTGGATCTGTCTCAGAGAAGCCTGTACCGTGAGGTGATGCTGGAGAATTACAGCAACCTGGCCTCCATGGCAGGATTCCTGTTTACCAAACCAAAGGTGA TCTCCCTGTTGCAGCAAGGAGAGGATCCCTGGGAGGGCAGGGGAAGTCTTCTAACATGCGGGGACGTGGAGGAAAATCCCGGCCCCATGTCTAGACTGGACAAGAGCAAAGTCATAAACGGCGCTCTGGAATTACTCAATGGAGTCGGTATCGAAGGCCTGACGACAAGGAAACTCGCTCAAAAGCTGGGAG TTGAGCAGCCTACCCTGTACTGGCACGTGAAGAACAAGCGGGCCCTGCTCGATGCCCTGCCAATCGAGATGCTGGACAGGCATCATACCCACTTCTGCCCCCTGGAAGGCGAGTCATGGCAAGACTTTCTGCGGAACAACGCCAAGTCATTCCGCTGTGCTCTCCTCTCACATCGCGACGGGGCTAAAGTGCATCTCGGCACCCGCCCAACAGAGAAACAGTACGAAACCCTGGAAAATCAGCTCGCGTTCCTGTGTCAGCAAGGCTTCTCCCTGGAGAACGCACTGTACGCTCTGTCCGCCGTGGGCCACTTTACACTGGGCTGCGTATTGGAGGAACAGGAGCATCAAGTAGCAAAAGAGGAAAGAGAGACACCTACCACCGATTTCTATGCCCCCACTTCTGAGACAAGCAATTGAGCTGTTCGACCGGCAGGGAGCCGAACCTGCCTTTCCTTTTTCGGCCTGGAACTAATCATATGTGGCCTGGAGAAACAGCTAAAGTGCGAAAGCGGCGGGCCGGCCGACGCCCTTGACGATTTTGACTTAGACATGCTCCCAGCCGATGCCCTTGACGACTTTGACCTTGATATGCTGCCTGCTGACGCTCTTGACGATTTTGACCTTGACATGCTCCCCGGGTAA29 Aspergillus CTAGTACAGCAGAAGAATCTCTCTCCGCTGTTGCTTCAG fumigants cgrA gene TGTCTGCCATGCATTAACTTCATCCTACTGTCCTACCCGC terminator AGTACCCATTCACATTTGCGGCAGATACCAGGTTGTTTTCTATICCCTCGGTTCTTCAGTTC ITCAGATATTACA ITACWSGR Docket No. 66180-701.601SEQ ID NO. Vector component Sequence TCGAGAAATTGGCGGCGATGCAGGAGTTTGGTTGGTTTT AATTGTTTCAGTCTCCTTGACCTGATTTGTATGACATGCA ATGTTTCGACGGAAGACTATCTC30 Aspergillus niger AAGGAGGATCGAAGTTCTGATGGTTATGAATGATATAG pyrG 3 ’ UTR AAATGCAACTTGCCGCAACGGATACGGAAGCGGAAACG (pyrG**) GACCAATGTCGAGCACGGGTAGTCAGACTGCGGCATCG GATGTCCAAACGGTATTGATCCTGCAGGCTACTATGGTG TGGCACAAGGATCAATGCGGTACGACGATTTGATGCAG ATAAGCAGGCTGCGAAGTAGTAACTCTTGCGTAGAGAA AATGGCGACGGGTGGCTGATAAGGGCGGTGATAAGCI T AATTGTCATCGC AGATAAGC AC TGCTGTCT TGCATCCAA GTCAGCGTCAGCAGAAATACGGGACTTCCGAAAGTATA TGGCAAAATTAAAGAACTTGACTCTCCAGCAATGTTTTG CCCTGACCGTCGCTAAAACGTTACTACCCCTATACCCGT CTGTTTGTCCCAGCCCGAGGCATTAGGTCTGACTGACAG CACGGCGCCATGCGGGCTTGGGACGCCATGTCCGTCGCG TGATAAGGGTTGATCCAI GCAGCTACTATCCTTCCATCG TTCCATTCCCATCCTTGTCCTATCTCCATCCTTGAAACTT TACTAGTTTAGTTGGATGCTCGAGCTTGCTCTCGGCTACT CCGTCCAATGGATAAGACCCCGATGCCGGTCCTCATTGG TCTCCAGCTGGTATCGCCCCAACCTTCGTGTGATCGCCTC TCTGCTTCCCCTCATCATCATTACTAACTAGTACATCCAA AAGCCATCCCAGTGCTTCCCCTCACCCTTGCCCAAGACA TTCCAAGTGGGCCTTCGGCTGGAAAACATGGACCCATTG GTTCCATCGATAAGCTAGCTCCTCGTCCGTTACCCCAGA TTGATACCAGATAACATTGACCAGCGGCTTATCACCGAG GTCIGCGGGTGAGACCCCCCCTGCGACAAGTIAGATAAA AGAAACTCGCCTCAI TGTGCT TCCGATGGGGTCGGATGA CGAGCCTTCGGAAAGAGC TGGCGCCTCT31 bacterial ori TTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGAC TATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCG TGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCT GTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCAT AGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTT CGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAG CCCGACCGCTGCGCCI TATCCGGTAAC TATCGTCT TGAG TCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCA GCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGG CGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGG CTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCT GAAGCCAGITACCTrCGGAAAAAGAGTTGG TAGCTCI TG A I’CCGGC AAACAAACCACCGCTGG rAGCGGIGGITTITT TGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGAT CTCAA32 ampicillin resistance TTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGAT gene (AmpR) CTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTC GTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGC CCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCG GCTCCAGATTTATCAGCAATAAACCAGCCAGCCGGAAG GGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCCTC CATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAG TAGTTCGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATT GCTACAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTWSGR Docket No. 66180-701.601SEQ ID NO. Vector component Sequence ACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTCTGTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCA33 A. nidulans tefl AGCGGACATTCGATTTATGCCGTTATGACTTCCTTAAAA gene terminator AAGCCTTTACGAATGAAAGAAATGGAATTAGACTTGTTA TGTAGTTGAT TCTACAATGGA ITATGAITCCTGAACTTCA AATCCGCTGTTCATTAT TAATC TCAGCTCTTCCCGTAAAG CCAATGTTGAAACTATTCGTAAATGTACCTCGTTTTGCGT GTACCTTGCTTATCACGTGATATTACATGACCTGGACAG AGTTCTGCGCGAAAGTCATAACGTAAATCCCGGGCGGTA GGTGCGTCCCGGGCGGAAGGTAGTTTTCTCGTCCACCCC AACGCGT ITATCAACCTCAACTTIC AAC AACC ATCATGC CACCAAAAGCGCGTAAAACAAAGCGAGATTTGATTGAG CAAGAGGGCAGGATCCAATGCGCGATTCAAGACATTAA AAATGGAAAATTTCAAAAAATTGCGCCCGCAGCGCGTG CATACAAAATTCATCCCAATACA34 ampicillin resistance ATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTT gene (AmpR) TTGCGGCA T IT IGCCl 1 CC 1G T 1 T 1 IGCTCACCCAGAAAC GCTGGTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTG CACGAGTGGGTTACATCGAACTGGATCTCAACAGCGGTA AGATCCTTGAGAGTTTTTCGCCCCGAAGAACGTTTTCCAATGATGAGCACTTTTAAAGTTCTGCTATGTGGCGCGGTAT TATCCCGTGTTGACGCCGGGCAAGAGCAACTCGGTCGCC GCATACACTATTCTCAGAATGACTTGGTTGAGTACTCAC CAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTA AGAGAATTATGCAGTGCTGCCATAACCATGAGTGATAAC ACTGCGGCCAACTTACTTCTGACAACGATCGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGCAGCAATGGCAACAACGTTGCGCAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAATTAATAGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGGGTCACGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAA35 Bacterial ori TTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGC TTCAGCAGAGCGCAGATACCAAATACTGTTCTTCTAGTG TAGCCGTAGTTAGGCCACCACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGWSGR Docket No. 66180-701.601SEQ ID NO. Vector component Sequence GCTGCTGCCAGTGGCGATAAGTCGTGTCTTACCGGGTTG GACTCAAGACGATAGTTACCGGATAAGGCGCAGCGGTC GGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGG AGCGAACGACCTACACCGAACTGAGATACCTACAGCGT GAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAA GGCGGACAGGTATCCGGTAAGCGGCAGGGTCGGAACAG GAGAGCGCACGAGGGAGCTTCCAGGGGGAAACGCCTGG I ATCTTTATAGTCCTGI CGGGTTTCGCCACCTCIGACTrG AGCGTCGATTTTTGTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAA

[0097] Example nucleic acid sequences comprised in vectors disclosed herein include, but are not limited to, the nucleic acid sequences provided in Table 3. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 19. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 20. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 21. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 22. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 23. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 24. In certain embodiments, a vector provide herein cancomprise a nucleic acid sequence (e g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 36. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 37. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 38. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 39. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 19. In some embodiments, a vector providedWSGR Docket No. 66180-701.601herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 20. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 21. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 22. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 23. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 24. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 36. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 37. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 38. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 39.

[0098] Table 3. Vector sequencesSEQ ID NO. Vector Sequence19 pCUl; GATATCATGCGACCGTAGAGCAGTGCAAGACCAACGTA pyrG*:PfraA:tTS:T2 AGCCAACCTCACACAAACAGGATTCCTCGAGCTAACATA A:rtTA:TcgrA.pyrG CATTCCGAACCGTGCAGCCCAAGGCCGAGCAGTTCAACT ** (e.g., FIG. 1A GCGCTCAGCGCGCTCA TGCCAACTTCC ITGAGAACTCCA and FIG. 5A) GCCAAACI ATGC TC1TCCI CC TGGTAGCTGGACTGAAGTACCCCCAGTTGGCGACTGGCCTCGGAAGCATCTGGGTCCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TCGGTCGCTCACTGTTCCTTTACGGATATGTGTACTCCGG CAAGCCGCGGGGTCGCGGTCGTTTGTACGGCAGCTTCTA CTTGCTTGCACAGGGAGCTCTCTGGGGCTTGACGTCTTTT GGAGTTGCGAGGGAGTTGATTTCCTACTTCTAAGTTTGG ACTGAATCCGTGGTGTGATTGAGGTGATTGGCGATGTTT GGCTATACCAGCTATATGTAATAATCTCTACTGTATACT ACI AT TC AACGCATTT TACTA TGCGTGC TGCTAGGGTCG GCAATGACAATGGCAATCTGACTGACGIGGTC rATTTCI CCATGTGCAGCAGGGAATACGAGCTCCAATGGACCTCG GGAGTGGCACAGTCAATGGCAAGGAAACTCCGCCTTTG CAGGTGTGGCTGAACCCCACGGGTCGGAGGCGGAGCAA TCCACCCCCGATGTGGCTGGTGCGTGGAGGGGCTCGCGA TGATTTTAC TGAGCTTGCT TITCTIGTCGACATTGAACAT I GTCCTTGGICTTCCTTCAGA IT TAAGGGTCAGTCAC TGC TACA U l i TCAGTAGTATCCGCGCACGTCTCTGGATTTAC GAATCAGGGTCCACCAGTCGAAACTTCGAACTACTCTCA TTATACAATCCTCTTTCCATTCCCGCATTAACCCCTCCAT CAACACCTCGCGCGTTTAAGCTTCCCTCGGCTGGTCTGT CTTACACAAGA TCACACGCTITGA TCTACAA TCACCCCA AGTATGGACCTCAGGCCCACCAACGCCCAGTGGAGGCA CGTATCTTGCGCCCCAGAGGACGGAAGGGCAAGAACAC GAAGGCCATTGCAGGTGTGGCTGGTATTGCCGTGGAAG ACTTGAATACTGTCACCTTTACCGAGCAGGACTCTCCGG CCGGCCTTGCCTACTTTGACGCCTCTATCCCCGGTGGTGC TAAGTACTGGGCCACCCCTATCCGGGCCTITGTCGACTC GGAAGGCAAGA ITGGCC TGGCT TCTIACCGCGC TAGCGC TACTGCTAAAGCCCCTTACGGAATCGATAGCCAGAAGA AGCCCGGATCGTACAGCATCTCTGACGTGGCTCGCGGCG ACCAGCGCGTGGTCCCGAGACTGGATAGACAGCGGAAC GCCGCAGCGGAGACTGAGGAGGTTGCGCGTAACCTCAT GAAGAGCCTIGGCTCCTAGAATACAGGTG IT TCAGTCCC AAGCAATTnTGTCTCATGTGTCAGACATGTTCTATCTTC CACTTAGAGAGCTTTGCTGTATGATTAGGTTTTTGGATG GTAAATGTATAGTTATTTTCGCACTTGTTCTCATTTGTTT GTGATATAAGCCGGCTACATCTCATTCTAAGTATAAATT AAATTGCAATTTCAAAGACGTCTCAGTAATTACTGATCA CTAIAAACCTGGTTTTGCCArACCGTAAGGCAACAGCCA TCTTCATAACTAACTAGTCCGTTACATATGAAATACATA AATGGCGCTTAATAATCCAGCGCAACGCCCGACCGCTTT GACAGGTAAGCGCACGTGACATTAAATAGGGCATCCAC ATCAGGGTAGATACGCATCACATGACCCGCACATCCTAA GCGAGGGACGGGTAAGTTGAAGGAGCGAAAGACA I CAG AAC A TCTIGGACGGITriTCGAACATCCAI CC AGCCAGC AACAAACCGCCAAAGAATTCACCATGTCTAGATTAGATA AAAGTAAAGTGATTAACAGCGCATTAGAGCTGCTTAATG AGGTCGGAATCGAAGGTTTAACAACCCGTAAACTCGCCC AGAAGCTAGGTGTAGAGCAGCCTACATTGTATTGGCACG I GCGCAAC AAGCAGACI C TTATGAAC A TGCTTTC AGAGG CAATACTGGCGAAGCATCACACCCGTTCAGCACCGTTAC CGACTGAGAGTTGGCAGCAGTTTCTCCAGGAAAATGCTC TGAGTTTCCGTAAAGCATTACTGGTCCATCGTGATGGAG CCCGATTGCATATAGGGACCTCTCCTACGCCCCCCCAGT TTGAACAAGCAGAGGCGCAACTACGCTGTCTATGCGATG C AGGGTTTTCGGTCGAGGAGGCI C 1TTTC A TTC TGCAATCTATCAGCC ATTTTACGTTGGGTGCAGIAT TAGAGGAGCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence AAGCAACAAACCAGATAGAAAATAATCATGTGATAGAC GCI GCACCACCA ITA rTACAAGAGGCATTTAATATTCAG GCGAGAACCTCTGCTGAAATGGCCTTCCATTTCGGGCTG AAATC ATTAATATTTGGA 1111 CTGCAC AGTTAGATGAA AAAAAGCATACACCCATTGAGGATGGTAATAAACCAAA AAAGAAGAGAAAGCTAGCAGTGTCAGTGACATTTGAAG A IGTGGCTGTGCTCTTTAC TCGGGACGAGTGGAAGAAGC TGGATCTGTCTCAGAGAAGCCTG TACCGTGAGGTGATGC TGGAGAATTACAGCAACCTGGCCTCCATGGCAGGATTCC TGTTTACCAAACCAAAGGTGATCTCCCTGTTGCAGCAAG GAGAGGATCCCTGGGAGGGCAGGGGAAGTCTTCTAACA TGCGGGGACGTGGAGGAAAATCCCGGCCCCATGTCTAG ACTGGACAAGAGCAAAGTCATAAACGGCGCTCTGGAAT I ACCAATGGAGTCGG TATCGAAGGCCTGACGAC AAGGA AACTCGCTCAAAAGCTGGGAGTTGAGCAGCCTACCCTGT ACTGGCACGTGAAGAACAAGCGGGCCCTGCTCGATGCC CTGCCAATCGAGATGCTGGACAGGCATCATACCCACTTC TGCCCCCTGGAAGGCGAGTCATGGCAAGACTTTCTGCGG AACAACGCCAAGTCATTCCGCTG TGCTCTCCI CTCACAT CGCGACGGGGCTAAAGTGCATCTCGGCACCCGCCCAAC AGAGAAACAGTACGAAACCCTGGAAAATCAGCTCGCGT TCCTGTGTCAGCAAGGCTTCTCCCTGGAGAACGCACTGT ACGCTCTGTCCGCCGTGGGCCACTTTACACTGGGCTGCG TATTGGAGGAACAGGAGCATCAAGTAGCAAAAGAGGAA AGAGAGACACCTACCACCGATTCTATGCCCCCACTTCTG AGACAAGCAATIGAGCTGTCGACCGGCAGGGAGCCGAA CCTGCCTTCC 11 11 CGGCCTGGA ACTA ATC ATATGTGGCC TGGAGAAACAGCTAAAGTGCGAAAGCGGCGGGCCGGCC GACGCCCTTG ACG A 1 11 1 GACTTAGAC ATGCTCCCAGCC GATGCCCTTGACGACTTTGACCTTGATATGCTGCCTGCT GACGCI CTTGACGATITTGACCT TGACATGCTCCCCGGG TAACTAGTACAGCAGAAGAATCTCTCTCCGCTGTTGCTT CAGTGTCTGCCATGCATTAACTTCATCCTACTGTCCTACC CGCAGTACCCATTCACATTTGCGGCAGATACCAGGTTGT TTTCTATTCCCTCGGTTCTTCAGTTCTTCAGATATTACAT TACTCGAGAAATTGGCGGCGATGCAGGAGTTTGGTTGGT TITAAlTOTnCAGrCTCClTGACCTGAITIGTATGACAr GCAATGTTTCGACGGAAGACTATCTCGGTGAATATACGT CATGAATCATGCGGCCAAGGAGGATCGAAGTTCTGATG GTTATGAATGATATAGAAATGCAACTTGCCGCAACGGAT ACGGAAGCGGAAACGGACCAATGTCGAGCACGGGTAGT C AGACTGCGGC ATCGGAI GTCCAAACGGTATTGA TCCTG C AGGCI ACTAI GGTGTGGC AC AAGGATC AATGCGGTAC GACGATTTGATGCAGATAAGCAGGCTGCGAAGTAGTAC TCTTGCGTAGAGAAAATGGCGACGGGTGGCTGATAAGG GCGGTGATAAGCTTAATTGTCATCGCAGATAAGCACTGC TGTCTTGCATCCAAGTCAGCGTCAGCAGAAATACGGGAC I TCCGAAAGTAI ATGGCAAAAT TAAAGAACTTGACTCTC CAGCAATGTTTTGCCCTGACCGTCGCTAAAACGTTACTA CCCCTATACCCGTCTGTTTGTCCCAGCCCGAGGCATTAG GTCTGCTGACAGCACGGCGCCATGCGGGCTTGGGACGCC ATGTCCGTCGCGTGATAAGGGTTGATCCATGCAGCTACT ATCCTTCCATCGTTCCATTCCCATCCTTGTCCTATCTCCA TCCTrGAAACnTACTAGTnAGITGGATGCTCGAGCTTGCTCrCGGCTACTCCGTCCAATGGATAAGACCCCGATGCCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GGTCCTCATTGGTCTCCAGCTGGTATCGCCCCAACCTTC G TGTGATCGCCTCI CTGCTTCCCCI CATCATC ATTACTAA CTAGTACATCCAAAAGCCATCCCAGTGCTTCCCCTCACC CTTGCCCAAGACATTCCAAGTGGGCCTTCGGCTGGAAAA CATGGACCCATTGGTTCCATCGATAAGCTAGCTCCTCGT CCGTTACCCCAGATTGATACCAGATAACATTGACCAGCG GCI TA TCACCGAGGTCI GCGGGTGAGACCCCCCCTGCGA C AAGTTAGA rAAAGAAACTCGCCTCATTGIGCTrCCGAT GGGGTCGGATGACGAGCCTTCGGAAAGAGCTGGCGCCT CTGATATCGCGGCCGCGGCGCTCTTCCGCTTCCTCGCTC ACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCG GTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACA GAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAA AGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGT TGCTGGCG T T T 1TCCATAGGCTCCGCCCCCCTGACGAGC ATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAAC CCGACAGGACTATAAAGATACCAGGGTTTCCCCCTGGAA GCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTAC CGGATACCTG TCCGCC ITTCTCTCI TCGGGAAGCGTGGC GCTTTCTCATAGCTCACGCTGTAGGTTCTCAGTTCGGTGT AGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCC CCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATC GTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCAC TGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGG TA TGTAGGCGGTGC TACAGAG TTCI TGAAGTGGTGGCCT AAC TACGGCTAC ACI AGAAGAAC AGTA IT TGTATCTGCG CTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTA GCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAA AAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGT CTGACGCTCAGTGGAACGAAAAC TCACGT IAAGGGATIT TGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCC1ITT11 AAA11 " 1 AAAAA’ 1 GAAG 111 TAAATC AATCTAAAGTA TATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAA TCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTC ATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTAC GATACGGGAGGGCI TACCAI CTGGCCCCAGTGCT GCAAT GATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATC AGAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAG TGGTCCTGCAACTrTATCCGCCTCCATCCAGTCTATTAAT TGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAAT AGTTTGCGC AACGTIGTIGCCATTGCTACAGGC A TCGTG G TGTCACGCI CGTCGTTTGGTA TGGCTTCATTCAGCTCCG GTTCCCAACGATCAAGGCGAGTTACATGATCCCCCATGT TGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCG TTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGG TTATGGCAGCACTGCATAATTCTCTTACTGTCATGCCATC CGTAAGAI GCITTTCTGTGACTGGTGAG TACTCAACCAA GTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTC TTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAG CAGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTC GGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATC CAGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTC AGCATCITITACTTIC ACCAGCGT11’CTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTC AATATTAI TGAAGC ATITA TC AGGGI TA ITGTCTCATGA GCGGATACATATTTGAATGTATTTAGAAAAATAAACAAA TAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTG ACGTCTAAGAAACCATTATTATCATGACATTAACCTATA AAAATAGGCGTATCACGAGGCCCTTTCGTCGGCGCGCCG CGGCCGC20 TRE- CAACTTTGTATAGAAAAGTTGGGTACCGAGCTCGACTTTPmin::psiH::TtrpC:: CACTTTTCTCTATCACTGATAGGGAGTGGTAAACTCGACpyrG_wt (FIG. 1D ITrCACTTTTCI CTAI C ACTGAI AGGGAGTGGI AAACTCG and FIG. 5B) ACTTTCACTIT TCTCTATCACTGATAGGGAGTGGTAAACT CGACTTTCAC 111 TCTCTATC ACTGATAGGGAGTGGTAA ACTCGACTTTCAC I 11 1 CTCTATCA CTGATAGGGAGTGGT AAACTCGACTTTCACTTTTCTCTATCACTGATAGGGAGT GGTAAACTCGACTTTCACTTTTCTCTATCACTGATAGGG AGTGGTAAACTCGACCTA rATAAGCAGAGCTCGTTTAGI GAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGTTT TGACCTCCATAGAAGACACCGGGACCGATCCAGCCTCCG CGGCCCCGAATTGCCCATCTTCAGTATATTCATCTTCCCA TCCAAGAACCTTTATTTCCCCTAAGTAAGTACTTTGCTAC ATCCATACTCCATCCTTCCCATCCCTTATTCCTTTGAACC ITrCAGTrCGAGCnTCCCACTrCATCGCAGCTTGACTAA CAGCTACCCCGCTTGAGCAGACATCACATGATCGCCGTT CTG IITI CTTTTGTC ATCG CAGGCTGC ATCTACTACATTG TGTCTCGGAGGGTGCGCCGCTCCCGATTGCCCCCGGGAC CCCCAGGTATCCCCATTCCATTTATAGGCAACATGTTTG ACATGCCGGAGGAAAGCCCATGGCTCACCTTCCTTCAGT GGGGCCGCGACTACAACACCGACATCCTGTATGTCGACG CGGGAGGTACTGAGATGGTCATTCTCAACACTCTAGAGA CCATCACTGACCTTCTGGAGAAACGTGGGTCGATCTATT CCGGCCGTCTTGAATCGACCATGGTCAACGAGTTGATGG GCTGGGAGTTCGATTTAGGGTTCATCACCTATGGCGATC GGTGGAGAGAGGAGCGGCGCATGTTCGCTAAGGAATTC I CCGAGAAGGGGATCAAGCAATTCCGACA TGCACAGGT CAAGGCAGCGCATCAGTTGGTACAGCAGCTGACGAAGA CGCCAGACAGGTGGGCTCAGCACATAAGGCACCAGATT GCGGCCATGAGTTTGGATATAGGTTACGGAATTGATCTA GCCGAAGACGACCCCTGGCTGGAGGCCACTCATCTGGC GAATGAGGGACTCGCAA ITGCI TCTGTGCCTGGGAAAI T CTGGGTCGACTCCTTCCCTTCCCTrAAAIACCTCCCCGCA TGGTTCCCCGGCGCGGTTTTCAAGCGGAAGGCCAAGGTC TGGCGTGAAGCTGCTGATCACATGGTGGATATGCCGTAC GAGACGATGCGAAAACTAGCACCACAAGGCCTGACAAG ACCAAGCTATGCCAGTGCTCGACTCCAAGCGATGGATTT GAATGGAGA TCTTGAACACC AAGAGCAI GTCA TCAAGA ACACCGCCGCAGAGGTGAATGTTGGTGGTGGGGATACC ACTGTGTCGGCTATGAGCGCTTTTATCCTCGCAATGGTT AAATATCCCGAGGTCCAACGAAAGGTTCAAGCCGAACT CGACGCTTTGACGAACAACGGTCAGATACCAGACTATG ACGAAGAAGACGATTCGCTGCCGTACCTCACGGCTTGTA I CAAAGAGCI CTTTCGCTGGAACCAGATCGCCCCTCTGG CCATTCCGCACAAGCTGATGAAGGATGATGTGTACCGTG GATATTTGATTCCCAAGAATACGCTTGTGTTTGCCAACA CATGGGCCGTGCTTAATGACCCTGAAGTGTATCCGGATCCAAGTGTCTTCAGACCTGAACGTTACCTAGGCCCTGATGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GAAAGCCTGACAACACAGTTAGGGATCCCCGCAAAGCA GCCTTTGGCTACGGTCGI CGCAATTGCCCGGGTATTCA T CTTGCCCAAAGCACAGTGTGGATCGCTGGTGCGACTCTC TTGTCAGCGTTCAACATCGAGCGCCCGGTTGATCAGAAT GGCAAGCCCATCGATATTCCTGCGGACTTCACCACCGGG TTCTTCCGGCACCCTGTCCCGTTCCAGTGTCGGTTTGTTC CCAGAACAGAACAAGTCTCTCAGTCTGTATCAGGGCCAT AAGGATCCACTTAACGTTACTGAAATCATCAAACAGCTT GACGAATCTGGATATAAGATCGTTGGTGTCGATGTCAGC TCCGGAGTTGAGACAAATGGTGTTCAGGATCTCGATAAG ATACGTTCATTTGTCCAAGCAGCAAAGAGTGCCTTCTAG TGATTTAATAGCTCCATGTCAACAAGAATAAAACGCGTT I CGGGTTTACCTCTTCCAGATACAGCTCATCTGC AATGC ATrAATGCATIGGACCTCGCAACCCTAGTACGCCCTTCA GGCTCCGGCGAAGCAGAAGAATAGCTTAGCAGAGTCTA1 11 1 CATTTTCG GGAGACGAG ATC A AGCAG ATC A ACGGT CGTCAAGAGACCTACGAGACTGAGGAATCCGCTCTTGGC TCCACGCGCCTCGGTCGCTCACTGTTCCTTTACGGATATG TG TACTCCGGCAAGCCGCGGGGTCGCGGTCGTTTGI ACG GCAGCI TCTACTTGCTTGC ACAGGGAGCTC TCTGGGGCT TGACGTCTTTTGGAGTTGCGAGGGAGTTGATTTCCTACTT CTAAGTTTGGACTGAATCCGTGGTGTGATTGAGGTGATT GGCGATGTTTGGCTATACCAGCTATATGTAATAATCTCT ACTGTATACTACTATTCAACGCATTTTACTATGCGTGCTG CTAGGGTCGGC AATGAC AATGGCAATCTGAC TGACGTG GTCI ATITCTCCA TGTGCAGCAGGGAA TACGAGCTCCAA TGGACCTCGGGAGTGGCACAGTCAATGGCAAGGAAACT CCGCCTTTGCAGGTGTGGCTGAACCCCACGGGTCGGAGG CGGAGCAATCCACCCCCGATGTGGCTGGTGCGTGGAGG GGCTCGCGATGATTTTACTGAGCTTGCTTTTCTTGTCGAC AT TGAACAI TG rCCTTGGTCTTCCTrCAGAT TTAAGGGTC AGTCACTGCI ACAT ITITCAG TAGTATCCGCGCACGTCI C TGGATTTACGAATCAGGGTCCACCAGTCGAAACTTCGAA CTACTCTCATTATACAATCCTCTTTCCATTCCCGCATTAA CCCCTCCATCAACACCATGTCCTCCAAGTCGCGATTGAC CTACACTGCCCGTGCCAGCAAGCATCCCAATGCTCTGGC GAAGAGGCTGTTCGAGATTGCCGAGGCCAAGAAGACCA ATGTGACTGTCTCGGCTGACGTTACCACCACTAAGGAGC TACTAGATCTTGCTGACCGTAGGCCGACCCGCTACTCTG CCTGATTATGCTGCATGCAAACTTATTAACGGTGATACC GGACTGCAGGTCTCGGTCCCTACATTGCCGTGATCAAAA CCCACATCGATATCCTCTCTGATTTCAGCAACGAGACCA TIGAGGGACI TAAGGCTCTCGCGCAGAAG CACAACTTTCTCATCTTCGAGGACCGCAAGTTCATTGAC ATCGGCAACACGGTCCAGAAGCAATACCACGGCGGTAC CCTCCGTATCTCGGAATGGGCCCACATCATCAACTGCAG CATTCTCCCTGGTGAGGGTATCGTCGAGGCTCTCGCTCA GACGGCGTC IGCACCGGACTICGCC TACGGCCCCGAACG CGG I’CTGI TGA TCTIGGCAGAGATGACCTC TAAGGGC TC CTTGGCTACCGGCCAGTACACTACTTCCTCGGTCGATTA TGCCCGGAAATACAAGAACTTCGTTATGGGATTCGTGTC GACGCGCGCGTTGGGTGAGGTGCAGTCGGAAGTCAGCT CTCCTTCGGATGAGG A GG ACTTTGTGGTCTTC A CGACTG G IGTGAACAT rTCTTCCAAGGGAGATAAGCTFGGTCAGCAGTACCAGACGCCCGGA TCGGCTA TCGGCCGGGG TGCTWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GACTTCATTATCGCGGGTCGCGGTATCTACGCCGCGCCG GATCCGG TGCAGGCTGCGCAACAGTATCAGAAGGAGGG GTGGGAAGCCTACCTGGCCCGTGTCGGCGGAAAACTAA TACTATAAAAGGAGGATCGAAGTTCTGATGGTTATGAAT GATATAGAAATGCAACTTGCCGCAACGGATACGGAAGC GGAAACGGACCAATGTCGAGCACGGGTAGTCAGACTGC GGCATCGGATGTCCAAACGGTATTGATCCTGCAGGCTAC I ATGGTGI GGCACAAGGATCAATGCGGTACGACGATTTG ATGCAGATAAGCAGGCTGCGAAGTAGTAACTCTTGCGTA GAGAAAATGGCGACGGGTGGCTGATAAGGGCGGTGATA AGCTTAATTGTCATCGCAGATAAGCACTGCTGTCTTGCA TCCAAGTCAGCGTCAGCAGAAATACGGGACTTCCGAAA G TATATGGCAAAATTAAAGAAC ITGACTCTCCAGCAAI G TITIGCCCIGACCGTCGCTAAAACGITACTACCCCTATAC CCGTCTGTTTGTCCCAGCCCGAGGCATTAGGTCTGACTG ACAGCACGGCGCCATGCGGGCTTGGGACGCCATGTCCGT CGCGTGATAAGGGTTGATCCATGCAGCTACTATCCTTCC ATCGTTCCATTCCCATCCTTGTCCTATCTCCATCCTTGAA ACTITACTAGTITAGTIGGATGCTCGAGCTTGCTCrCGGC lACTCCGTCGCGGCCGCGGCGCTCITCCGCTTCCTCGCTC ACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCG GTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACA GAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAA AGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGT I GCTGGCG IT IT TCCATAGGC TCCGCCCCCCTGACGAGC ATCACAAAAATCGACGC I CAAGTCAGAGGTGGCGAAAC CCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGA AGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTA CCGGATACCTGTCCGCCTTTCTCTCTTCGGGAAGCGTGG CGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGT GTAGGTCGITCGCTCCAAGC TGGGCTGTG TGCACGAACC CCCCGTTCAGCCCGACCGCTGCGCCITA TCCGGTAAC TA TCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCC ACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGA GGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGC CTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCT GCGCTCTGCTGAAGCCAGTIACCTTCGGAAAAAGAGTrG GTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCG GTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAA A A AAAGGATCTCAAG AAG ATCCTTTGATC 1 11 1 CTACGG GGTCTG A CGCTCAGTGG A ACG A AA A CTCACGTT A AGGG ATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAG ATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAA AGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGC TTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTC GTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAA CTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTG CAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATT TATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGC AGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCT ATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCA GTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGC ATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCA GCI CCGG T1 CCCAACGA rCAAGGCGAGTTACATGA I’CCCCCATGTTGI GCAAAAAAGCGGTIAGCTCCTTCGGTCCI CWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence CGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCAC TC Al GGTIATGGCAGC ACTGCAI AATTCTCI TACI GTCAT GC CATC CGTA AGATGC 1111 CTGTGACTGGTGAGTACTC AACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGA GTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGC CACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAAC GTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGT I GAGAI CCAGTTCGATG TAACCCACTCGTGCACCCAACT GATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTG AGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGA ATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTC CTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTC ICATGAGCGGATACArATTTGAATGTATTTAGAAAAATA AAC AAAI AGGGG TTCCGCGCAC ATTTC CCCGA AAAGTGC CACCTGACGTCTAAGAAACCATTATTATCATGACATTAA CCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCGGC GCGCCGCGGCCGCCACAACTTTCTCATCTTCGAGGACCG CAAGTTCATTGACATCGGCAACACGGTCCAGAAGCAAT ACCACGGCGGTACCCTCCGTATCTCGGAATGGGCCCACA I C ATCAACTGC AGC ATICTCCCTGGIGAGGGTATCGTCG AGGCTCTCGCTCAGACGGCGTCTGCACCGGACTTCGCCT ACGGCCCCGAACGCGGTCTGTTGATCTTGGCAGAGATGA CCTCTAAGGGCTCCTTGGCTACCGGCCAGTACACTACTT CCTCGGTCGATTATGCCCGGAAATACAAGAACTTCGTTA I GGGA I TCG TGTCGACGCGCGCG I TGGGTGAGGTGCAG I CGGAAGTC AGCTCTCCTTCGGAI GAGGAGGACTITG TGG TCTTCACGACTGGTGTGAACATTTCTTCCAAGGGAGATA AGCTTGGTCAGCAGTACCAGACGCCCGGATCGGCTATCG GCCGGGGTGCTGACTTCATrATCGCGGGTCGCGGTATCT ACGCCGCGCCGGATCCGGTGCAGGCTGCGCAACAGTAT CAGAAGGAGGGGTGGGAAGCCTACCTGGCCCGTGTCGG CGGAAAACTAATACTATAAAAGGAGGA TCGAAGTTCTG ATGGTTATGAATGATATAGAAATGCAACTTGCCGCAACG GATACGGAAGCGGAAACGGACCAATGTCGAGCACGGGT AGTCAGACTGCGGCATCGGATGTCCAAACGGTATTGATC CTGCAGGCTACTATGGTGTGGCACAAGGATCAATGCGGT ACGACGATTTGA TGC AGATAAGC AGGCTGCGAAGTAGT AACTCTTGCGTAGAGAAAATGGCGACGGGTGGCTGATA AGGGCGGTGATAAGCTTAATTGTCATCGCAGATAAGCAC TGCTGTCTTGCATCCAAGTCAGCGTCAGCAGAAATACGG GACTTCCGAAAGTATATGGCAAAATTAAAGAACTTGACT CTCCAGCAATGTTTTGCCCTGACCGTCGCTAAAACGTTA CTACCCCTATACCCGICTGITIGTCCCAGCCCGAGGCATT AGGTCTGACTGACAGCACGGCGCCATGCGGGCTTGGGA CGCCATGTCCGTCGCGTGATAAGGGTTGATCCATGCAGC TACTATCCTTCCATCGTTCCATTCCCATCCTTGTCCTATC TCCATCCTTGAAACTTTACTAGTTTAGTTGGATGCTCGAG CTTGCTCTCGGCTACTCCGTCGCGGCCGCGGCGCI CTTCC GCI TCCTCGCTC AC TGACTCGCI GCGCTCGGI CGTICGGC TGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGTAATA CGGTTATCCACAGAATCAGGGGATAACGCAGGAAAGAA CATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTA AAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCC CCCCTGACGAGCA TCACAAAAA TCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCG ACCCIGCCGCTTACCGGATACCTGTCCGCCTTTCTCICTT CGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGT ATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCT GTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCT TATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGAC ACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGG A ITAGCAGAGCGAGG TATGTAGGCGGTGCTAC AGAGTT CTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAAC AGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTC GGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAAC CACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCA GAITACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTT TGATCT ITICTACGGGGTCTGACGCTCAGTGGAACGAAA ACTCACGTTAAGGGA 1111 GGTCATGAGATTATCAAAAA GGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTT TTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTG ACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAG CGATCTGTCTAITTCGI TCATCCA FAGITGCCTGACTCCC CGI CGTGI AGATAACTACGATACGGGAGGGCTIACCATC TGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTC ACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCCGG AAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGC CTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGT AAGTAG TTCGCC AGI TAATAGTTTGCGC AACGTTGT TGC C ATTGCTACAGGC ATCGTGGTGI C ACGCTCGTCGTTTGG TATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGGCG AGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAG CTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTTGGC CGCAGTGTTATCACTCATGGTTATGGCAGCACTGCATAA TJCTCT TACTG TCATGCCA TCCGTAAGATGCnTTCTGTG ACT GGTGAGTACI C AACCAAGTCA ITCTGAGAA TAGTGT ATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATACGG GATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTC ATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGG ATCTTACCGCTGTTGAGATCCAGTTCGATGTAACCCACT CGI GCACCCAAC TGATCTOAGCATCTITTACTITCACCA GCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCC GCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAAT ACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTAT CAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGT ATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTT CCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTATT ATCATGACATTAACCTATAAAAATAGGCGTATCACGAGG CCCTTTCGTCGGCGCGCCGCGGCCGC21 pUC19: TCGCGCGT T1 CGGTGATGACGGI GAAAACCTCTGACACA VbphA: psiK. VlAs.psi TGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGG A / TtrpC (e.g.. FIG. ATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCG 1C) GGTGTTGGCGGGTGTCGGGGCTGGCTTAAGCGGCCGCG ATATCTCTCGTCTCCTGTTATAGAGTCAGAAGTTGCGGG AGGGCCGTCI GCCGCAGTTCTA IGTATTATCAACAAGGT TAAACAATAGGCGACGATTAATTCCTTAGCTGCTTCGAC TCTGAGCATTCCTATTGCTAGTTATCAGACACAATCCAA AATTAAGTATACTGCAATGGAGITACCCATGTCAGAGGCTAGAGAGGGCGAACTTCAGCGATTATGTCATATCGGCGGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence AAGGGTTATGTATTAGCCTCTTGTTATGGATGCATTTTTG CATGGTTArACGCGTTCTCCTACCGTGTTGGrAAAGGAA GCTTTATAGTCAAGGCTAAGTGGTTTAGTGTGGGAAATG GCACTTATAAAATCCTGTACACGGAGAATAGAAAGTACT ATCACCTAAGAGCAAAGTGCATGACCTGGAAGGAAAAA GGCCTTGTGTCAAACTTTCGCTCTTGATAGATATGCAAT CCGTTGACGAACTTTAGGCTTTGCTTGCAAATTAAACCT ITrCATITTCCI TGACGATCAAI TGCCAGIACCAGATTTT AGCTACCCAGTATACAGCTACGTCGCAGGATCAGCCGG ACTGATTATGACAAATACACTCGGATGCTTATTTAGGAA CTTATCAATTGGGGTTTATTTTCACAAGGCGAAGTGATC CACAAGACACATGCATGAAAGAACATTCATGAGCAATC CAGrCATrGGCTITrCCAAAAGGIGGCCGGGGAACAGCA CTGITCCACCAGTCGGTACCCCG TAATGAGGGGAGAGG GTATTATTATTAGCAATTATTTCCAGATGTATCAACTTAG GCAGAGACCCAGGGAAATACTGGCCCTGAACTTGAAAG GCT 1 H GTTGAATGCTAGCTTGGGTCTTCTCTGCAGAAG ATAGTTGACGGTTCTAGATTAATTGCATGTGGTTGAACC C ACTCCTACGAATAGTTTACCGC ACTACTCCGI ACTACC CGTGATAC TGTATTACGC AGTCGACI ACGGAGCACTCCG TACAGAATAGTCATTGTAATAGCCAACTACTTAAGTAGT CCCACTAACCGTCCCAATGAGGAAAATGTTCAACCCTCG CATATTAATTCCTTAGCTTTAAATGCCTGCGTTACTTCCT ACACTTCAACTCAACCCCACTACCTTTGGAACGGTTTAC AGTTCGCI GCAGATATCCT TCAT rTCTTGITrCTTCACCT CTTAGTCGIACTTTGCArCCGTGGAAGAAGGAGGGGGA AAGCTACCATAGCCAAGACGAACGAGCGTGTCCGTTCTA CAAGATCATCCCTGGATTCTCCCTCTGTGTGGATGCATTT CGATACGGAGCCGTAGAGGGATGTAATGCGTACTTCCTT AGTCACTTCCACAGCGACCATTACATCGGCCTGACGGGG TCGIGGCGCCATGGACCAATCTACI GCAGCAGACCTACG GCCAACTTGGIGTGCCAGCAACrGAAGGTCGACCGGAA GTGGCTTGTACCACTTGAGTTCGAGCGGAAGACGGAAAT CCCGGATACAGGAGGAGCGCAGGTGACTTTGATCGAGG CTAATCATTGTCCTGGGAGCGCCATCTTTCTCTTCGAGA AATCAATGGGATCGGGTCCCTCGCAGAGAACACATCGTG rCCTCCACTGIGGTGACTITCGCGCCTCGCCGCTrCATG TGCAACATGCCCTTCTCCGCCCGGAGATTGCTGACCCCG CAACCGGCAAGGCTCGCCAGCAACGAATCGATGCCTGC TATCTGGACACTACATATTTGAGCCCCAAGTATGCATTC CCTGGCCAAGAAGATGTCATACAAGCCTGCGCAGAACTT TGCGTTGAGCTCGATGGGGACGCCAACGACACCAATGG ACGAGCGTTTGGACGACCAGTCAATGGAAAAAGCGGAA TGCTGAGCAAGTTTGTTACGGCTGTGACTGGATCCCGCC CGTCTCCGACGCAAGACAGCCGCCCCCCTGGCCGGCTAT TGGTAGTAATAGGGACGTACAGCATCGGCAAAGAACGC ATCTGTCTGGGGATCGCACGGGCATTGAAGAGCAAGAT CTACGCGACGCCAGCTAAGCAGCGCGTCTGTGCGIGCCT CGAGGATGCI GAGCTGTCATCGCI GCTGACAGACGATCC CACGGAGGCGCAGGTGCATATGCAAACGCTATTCGAGA TCCGGGCGGAAACGCTGGCGGATTACCTGGACTCGATG AAGCCGCACTTCACGCGGGTGGTGGGATTTCGACCAACC GGGTGGACGTATCGCCCGCCAGCTGGCCGAATGCTGGA CAACCCACCGGTGTCGGTGGTGCI CAAT TCGGCACATTGGAAGACGCCCT ITI CTGCGAAAGACCTGGTGCCACAGCGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence AGGGAGTACGCGGGAAAGCGCATGCTTTGGAGTGCCGT ACAGTGAGCACAGCTCATTTCGGGAGTTGAGC ATGI TCT GCTGCGCACTCCGGATCGGACGGGTGATCCCGACAGTG AACGTAGGTAGCCGGAAAAGTCGGGAGCGCATGAAGGC GTGGATTGAGCGATGGGAGGCGGAGAAGCGGAAGAATG GGTTGTACCGCGTGGAGGGGAATAGCTGGTAGGGGATA GATAGACGGCTCTACCAACGTCCAAAGTACTGCTGGAAC ACAAGGATCAGCAGGATCAGAAGGATTGCGAAAGACGG GTCGGAACATGTTGCCTAATAGAGTAAGTAAGGAGTTG GTGCTGTAACTAGTCACAAGTTACGATTTGTGTACATAA CATCATTAGTCATGGAGATCAATTGCCTTTATGCTTCCGT AACTCTCGCCTCCCCGGAGTCACGAGATCAATAGAAACC ACCGCCGT TGACCATTCGCGATGC TCTCACTGGCTGI AT GCTG TCGATAGCCA TGGAGCCGI TCAAAGTAI GGACCCT TTGGGTGAGGATCTCCCTCCAACCCCACGGGACGTACAC GAACAACCGAGCAGAGGCGGGGGAGGGCAAAGAGGCC GGCGCTGCAAATCGGCTGGCAGATCAGTCGCGGCTCAG CAGAGACTCCCGATTTTCCCTTCCGTTGCCTGGCTTTGCC TCGGGGTTCGAGAGGAGCCCGTCTGCCATAAATAAGCCT GCACTTCAACTCAAAAAAAAGGGAGATGACAGATCAAC CACTTTCTCGACAAGAAACACTCTTCACCCATGGCGATA CTTGAGTGAAGTAAGTGTG ACTGTGACTG ATATTA 1 11 1 CTTCTTCAGCCATCCTTTTTCGATATATTACCTTATAGTT GCTTATTTCATTTCGGAGGTAAGATGGTCTCCTTGGCAC CCACATTCCCGGCTGCACT TGGCGGCTGCGGAATTGCTT CTCCTGGCI GCAT I’TGCCGG IGTTAACTTCCGAACTC ACC AGCTTCCTCCCCTCCCCCCACAAAAACAATCATGGGAGA GTCTCTTTTTAAGGGCCCACGCGATTACAACCCTATTTCC TCGACTATCTGTCACCTGACTAATGAGTCCGACGGACAC ACCACGTCGCTATACGGAATTGGCTTTGGGCCGTTCATC ATTACAAACAAGCATCTCTTCCGGCGTAACAATGGCACC CTC ITGGTTCAGTCCCTCCATGGTG TCTTC AAGGTTAAGA ACACCACGACTCTCCAGCAGCATCTTATCGACGGGAGGG ACATGATCATAATTCGTATGCCCAAGGACTTCCCCCCTT TCCCGCAAAAGTTGAAGTTCCGAGAGCCGCAGCGTGAA GAACGGATTTGCTTGGTCACTACCAACTTTCAGACCAAA AGCATGTC ITCI ATGGTTTCAGA TACCTCGTGCACC ITCC CTTCTTCGGACGGCA H l TCTGGAAGC ACTGGATCC AGA CCAAGGACGGACAGTGTGGATCGCCCTTGGTCAGTACCC GCGACGGGTTTATCGTGGGTATCCACTCTGCTAGCAATT TTACTAATACAAATAATTACTTCACTTCTGTACCCAAGA ATTTTATGGAGCTGCTCACCAACCAGGAGGCCCAGCAAT GGGTTAG IGGCTGGAGACTCAATGCCGATTCTGTCT TAT GGGGTGGCCACAAGGTGTTCATGGTCAAACCTGAGGAA CCCTTCCAGCCCGTGAAAGAAGCTACGCAGTTGATGAAC CGTCGACGACGACGCATCGAAAATCTCTACTTTCAGGGT GCCATGGGGGGATCCGGTGCGACAAACTTCTCCCTTCTT AAACAAGCGGGGGATGTCGAGGAGAACCCGGG TCC TAT GGCGTTCGATCTGAAGACCGAAGACGGCCTCATAACCTA CTTGACCAAACACCTATCACTGGATGTTGACACCAGCGG AGTCAAGCGCCTCAGTGGTGGTrTCGTGAATGTCACGTG GCGCATCAAATTGAACGCTCCGTATCAGGGACATACGA GCATTATCCTGAAGCATGCACAACCACACATGTCGACAG ACGAGGACTITAAGATI GGGGI GGAGCGGAGCGTCTACGAGTATCAAGCAATCAAGCTAATGATGGCCAACCGAGAWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence AGTCTTAGGCGGTGTGGATGGTATTGTCTCTGTTCCCGA AGGTC TGAAI TATGACTTGGAGAACAATGCGC TTATCAT GCAGGATGTTGGCAAGATGAAGACGCTCCTGGACTATGT TACTGCGAAACCGCCACTCGCCACGGACATAGCAAGGC TAGTGGGCACTGAAATCGGTGGCTTCGTGGCACGGCTCC ACAACATCGGACGTGAGCGACGGGATGATCCGGAGTTC AAATTCTTCTCCGGGAATATTGTCGGGCGCACGACCAGT GACCAGCI GTACCAGAC TATTATACC AAATGCI GCAAAG TATGGCGTCGATGACCCTTTGCTCCCAACAGTTGTGAAG GATCTTGTGGATGATGTGATGCATTCTGAAGAAACACTG GTCATGGCTGACCTATGGTCAGGAAACATTCTGCTTCAA CTCGAGGAGGGAAATCCCAGCAAGCTTCAGAAGATCTA CAI CCI CGACTGGGAGCTCTGCAAGTACGGCCCGGCCAG TCTGGATCI CGGGTATTTCCTAGGTGACI GCTA TCTCATC TCCCGCTTTCAAGATGAACAGGTCGGTACCACCATGCGG CAGGCTTACTTGCAATCGTATGCGAGGACATCAAAACAT TCGATCAATTATGCGAAAGTAACAGCGGGAATCGCTGCT CATATTGTTATGTGGACTGATTTCATGCAGTGGGGCTCG GAGGAAGAGAGGATC AACT TTGTC AAAAAGGGAGI AGC CGCTTTCCAI GATGCTAGAGGC AAC AACGACAACGGGG AGATCACTAGCACATTGCTTAAAGAGAGCAGCACCGCC GAAAATTTATACTTCCAAGGCGCAATGGGCGGGAGCGG AGCTACAAACTTTTCACTGTTGAAGCAGGCAGGCGATGT AGAGGAGAATCCTGGTCCGATGCACATACGTAACCCCTA CCGCACGCC AATCGAC IACCAAGCACTITCCGAAGCG IT TCCTCCGCTGAAGCCATICGTGAGTGICAACGCCGACGG AACGTCTTCTGTAGATCTCACAATCCCCGAGGCTCAAAG GGCATTTACGGCAGCACTGCTGCACCGGGACTTTGGTCT CACCATGACTATTCCTGAGGATCGATTATGTCCCACTGT GCCCAACCGCCTGAACTACGTCCTGTGGATTGAAGATAT CTTCAAC TACACAAAI AAGACTC TAGGCCTGTCCGACGA I CGCCCAA TCAAGGG TGTGGACATCGGTACCGGTGCGA GTGCCATTTATCCCATGCTGGCCTGTGCCCGGTTCAAGG CTTGGTCCATGGTTGGAACCGAGGTGGAAAGAAAATGC ATTGATACGGCTCGTCTTAATGTTGTTGCAAACAACCTC CAAGACAGGCTGTCCATCCTGGAGACCTCAATCGATGGG CCCATCCT IGTTCCTA IATTTGAGGCC ACGGAAGAATAT GAGTACGAGTTTACAATGTGCAATCCTCCATTCTACGAC GGCGCGGCAGATATGCAAACTTCGGATGCCGCCAAGGG CTTCGGTTTTGGCGTAGGCGCCCCTCATTCAGGGACGGT CATCGAGATGTCCACTGAAGGGGGAGAATCAGCATTCG TCGCTCAGATGGTGCGTGAAAGTTTGAAACTTCGGACGA GATGCCGCI GGTACACCI CTAACCT TGGAAAGTTAAAGT CCTTGAAGGAGATTGTGGGACTCCTAAAAGAGTTGGAA ATTTCCAACTACGCCATAAACGAGTATGTGCAGGGCTCC ACCCGCAGATATGCCGTTGCCTGGAGCTTCACCGATATT CAATTGCCGGAAGAATTATCGCGACCATCCAATCCAGAG CTGI CGAGCCTA'nTTAGCT AGTAC AGC AGAAGAATCTC I CTCCGCTGI TGCI TCAGI GTCI GCC ATGCAI TAAC ITCA TCCTACTGTCCTACCCGCAGTACCCATTCACATTTGCGGC AGATACCAGGTTGTTTTCTATTCCCTCGGTTCTTCAGTTC TTCAGATATTACATTACTCGAGAAATTGGCGGCGATGCA GGAGTTTGGTTGGTTTTAATTGTTTCAGTCTCCTTGACCT GATTTGTATGAC ATGC AAI GT ITCGACGGAAGACTATCTCGGTGAATAI ACGTCA TGAAI CATGCCCATACCAATGAAWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence AATTGTGGCTTCAGAAACCACTATGGCATACATACATAT GTATGAAIAAAGTACACGTTTACAGCTTAACGATGTCGC AGCTGGTTTTCATTCACAG 1111 AGGGTATAGTATCTTCC ACTGAGGATCGTGCCGCAAGTTCAATGTTACTTCATTTG GTACGCTGCAGGATCCTCTAAGTCCAGGGTCAGTATTCA TCGGCATATGTATCGTTCCGATCCGCTTCCTCAAACCCA ACATCTCGAGCGCTGGGAGAGGTAGCAAAATCATTCGA ACG ICGGACACGAGGATCACTA rCCTCGTACTTGGTAGC AGTATCCTTGGCAACCGCGTCACAGGCATCCACCCAATC CGAGTATACATCAACAGCAGCGGAGAGATCTATGTATAT ATCATGAGCAAATGCCACTCACTTAGGAGAAATCATAA ACATGAACGCACAGTTTATGCCCGTCTGAAATCGCTGGC CACAGACITIGCAGGACAAA IT rCCTAGGCCAAGTTTCT TG TCTAG IT ITACGACGATGGAG1TCTCGTGAT TGCAGA AAAGGCAGGCAAATGTCGTAGGCAACGGTTCTCTCTAGT TGAGTATTAGCGACGGTAACCCTGAAGAATCAGAAGGT GGTCACCTTTCTGGGTTGCTGTGGTTGCCTGCTGGACTTC TTCCGCTTACCCTAAATTCAAGGAAAGCTTAGAGAAAGG TACA ITGGCGCT GTGTAGAGTGGCA TACCATGCTTCAAA G ITTCTGGGTGACGCGACCGGCAA ITATAGCTGACTITI GATACTGCAGGAAATCTGAAGCCCTTGGATTGACAGCCC AATAGCCGGTGTGAGATCAGCAGAGCAATGCACGAAAC TGCTGCAAACTCGACCGCGTATTTATGTTGTGAAGACAC AAGTCTAGTGGAACAAGGCAGTGCGAGCAAGTGACCGG ACCGATTTTA TCTGAATGI GCTTCTGAA TGCTTCAGTGG AAGACTAGAGAI CTCCGGGGGAGTTAGACAGG TATAGC CTAATAGTCCACTACATGCACTCCCGGAGACTCCAAGAA CACTATTTGGTGGCATAAAGTGATGGAAATGCAACCAGT TGGTTGACTGGCGGTAGATTAGTCATCGGATACATTAGT AACTTTTATAAGTAATTAGTTAGTTAACTAATTAGTTCCC GCCCGAATCGCTATTCCGAC TGAGA TATC TGATATCGCG GCCGCGGTGATGACGGTGAAAACCTCTGACACATGCAG CTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCC GGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGT TGGCGGGTGTCGGGGCTGGCTTAATGTGAAATTCCACAG CCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTG CGTTGCGCTCAC TGCCCGC ITTCCAGTCGGGAAACCTGT CGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGG AGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCG CTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGA GCGGTATCAGCTCACTCAAAGGCGGTAATACGGTTATCC ACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGC AAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCC GCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGAC GAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCG AAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCC TGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCC GCTrACCGGATACCTGTCCGCCTTTCTCCCTrCGGGAAG CGI GGCGCTITCTC ATAGCTCACGCT GTAGGTATCTCAG TTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCA CGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGG TAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTT ATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCA GAGCGAGGTATGI AGGCGGI GCTACAGAGTTCTTGAAGTGGTGGCC lAACTACGGCTACACTAGAAGGACAGTAITTGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAA GAGTTGG TAGCTCI TGATCCGGCAAACAAACCACCGCTG GTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGC GCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATC 1111 CTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTT AAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCA CCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAA I CTAAAGTATATATGAG rAAACTTGGI CTGAC AGTTAC C AATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTC TATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTA GATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAG TGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCC AGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCG AGCGCAGAAGTGGI CC TGCAACT TTATCCGCCTCCATCC AGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTT CGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTA CAGGCATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTT CATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACAT GATC CCCC ATG ITGTGC AAAAAAGCGGTTAGCTC CI TCG G TCCTCCGATCG TTGTCAGAAGTAAG TTGGCCGCAGTGT TATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTAC TGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGA GTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCG ACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATAC CGCGCCACATAGC AGAACT ITAAAAGTGCTCATCA ITGG AAAACGI TCTTCGGGGCGAAAACTCTC AAGGATC ITACC GCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACC CAACTGATCTTCAGCATCTTTTACTTTCACCAGCGTTTCT GGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAA AGGGAATAAGGGCGACACGGAAATGTTGAATACTCATA CTCT TCC rn’n'CAATATrATrGAAGCAITIATCAGGGTr A ITGTCTC Al GAGCGGA TAC ATATTTGA ATGTATTTAGA AAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGA AAAGTGCCACCTGACGTCTAAGAAACCATTATTATCATG ACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTT CGTC22 pUC19; uprT- TCGCGCGTTTCGGTGATGACGGTGAAAACCTCTGACACA 5 ’ UTR: P6 phA: psiK'. TGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGG TtrpC. PthiA '. PsiM'. T ATGCCGGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCG cgrA: uprT-3 ’ UTR GGTGTTGGCGGGTGI CGGGGCTGGCTTAAGCGGCCGCG (e.g.. FIG. IE) ATATCTCTCGTCTCCTGTTATAGAGTCAGAAGTTGCGGG AGGGCCGTCTGCCGCAGTTCTATGTATTATCAACAAGGT TAAACAATAGGCGACGATTAATTCCTTAGCTGCTTCGAC TCTGAGCATTCCTATTGCTAGTTATCAGACACAATCCAA AATTAAGTATACTGCAATGGAG1TACCCA IGTCAGAGGC TAGAGAGGGCGAAC ITCAGCGATTATG I’CATATCGGCGG AAGGGTTATGTATTAGCCTCTTGTTATGGATGCATTTTTG CATGGTTATACGCGTTCTCCTACCGTGTTGGTAAAGGAA GCTTTATAGTCAAGGCTAAGTGGTTTAGTGTGGGAAATG GCACTTATAAAATCCTGTACACGGAGAATAGAAAGTACT ATCACCTAAGAGCAAAGTGCATGACCTGGAAGGAAAAA GGCCTTGTGTCAAACTTTCGCTCTTGATAGATATGCAAT CCGTTGACGAACTTTAGGCTTTGCTTGCAAATTAAACCT TTTCATTTTCCTTGACGATCAATTGCCAGTACCAGATTTTAGCTACCCAGTATACAGCTACGTCGCAGGATCAGCCGGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence ACTGATTATGACAAATACACTCGGATGCTTATTTAGGAA CTTATCAArTGGGGTrTATTTTCACAAGGCGAAGTGATC CACAAGACACATGCATGAAAGAACATTCATGAGCAATC CAGTCATTGGC 111 TCCAAAAGGTGGCCGGGGAACAGCA CTGTTCCACCAGTCGGTACCCCGTAATGAGGGGAGAGG GTATTATTATTAGCAATTATTTCCAGATGTATCAACTTAG GCAGAGACCCAGGGAAATACTGGCCCTGAACTTGAAAG GCITITGI TGAATGCTAGCTIGGGTC ITCTCTGCAGAAG ATAGTTGACGGTTCTAGATTAATTGCATGTGGTTGAACC CACTCCTACGAATAGTTTACCGCACTACTCCGTACTACC CGTGATACTGTATTACGCAGTCGACTACGGAGCACTCCG TACAGAATAGTCATTGTAATAGCCAACTACTTAAGTAGT CCCACTAACCGI CCCAA IGAGGAAAATGTTCAACCCTCG CATA ITAATTCCTTAGC IT TAAAI GCCTGCGTTACTTCCT ACACTTCAACTCAACCCCACTACCTTTGGAACGGTTTAC AGTTCGCTGCAGATATCCTTCATTTCTTGTTTCTTCACCT CTTAGTCGTACTTTGCATCCGTGGAAGAAGGAGGGGGA AAGCTACCATAGCCAAGACGAACGAGCGTGTCCGTTCTA CAAGATCATCCCTGGATTCI CCCI CTGTGTGGATGCAITI CGA TACGGAGCCGTAGAGGGATGI AATGCGTACTTCCTT AGTCACTTCCACAGCGACCATTACATCGGCCTGACGGGG TCGTGGCGCCATGGACCAATCTACTGCAGCAGACCTACG GCCAACTTGGTGTGCCAGCAACTGAAGGTCGACCGGAA GTGGCTTGTACCACTTGAGTTCGAGCGGAAGACGGAAAT CCCGGATAC AGGAGGAGCGC AGGTGAC IT TGAI CGAGG CTAA rCATIGTCCTGGGAGCGCCATC ITI CTCTTCGAGA AATCAATGGGATCGGGTCCCTCGCAGAGAACACATCGT GTCCTCCACTGTGGTGACTTTCGCGCCTCGCCGCTTCATG TGCAACATGCCCTTCTCCGCCCGGAGATTGCTGACCCCG CAACCGGCAAGGCTCGCCAGCAACGAATCGATGCCTGC TA TCTGGAC ACT ACATATTTGAGCCCCAAGTATGCA ETC CCTGGCCAAGAAGAI GTCA IACAAGCCTGCGCAGAACTT TGCGTTGAGCTCGATGGGGACGCCAACGACACCAATGG ACGAGCGTTTGGACGACCAGTCAATGGAAAAAGCGGAA TGCTGAGCAAGTTTGTTACGGCTGTGACTGGATCCCGCC CGTCTCCGACGCAAGACAGCCGCCCCCCTGGCCGGCTAT I GGTAGTAATAGGGACGTACAGCAI CGGCAAAGAACGC ATCTGTCTGGGGATCGCACGGGCATTGAAGAGCAAGAT CTACGCGACGCCAGCTAAGCAGCGCGTCTGTGCGTGCCT CGAGGATGCTGAGCTGTCATCGCTGCTGACAGACGATCC CACGGAGGCGCAGGTGCATATGCAAACGCTATTCGAGA TCCGGGCGGAAACGCTGGCGGATTACCTGGACTCGATG AAGCCGCACTFCACGCGGGTGGTGGGATTTCGACCAACC GGGTGGACGTATCGCCCGCCAGCTGGCCGAATGCTGGA CAACCCACCGGTGTCGGTGGTGCTCAATTCGGCACATTG GAAGACGCCCTH rCTGCGAAAGACCTGGTGCCACAGCG AGGGAGTACGCGGGAAAGCGCATGCTTTGGAGTGCCGT ACAGTGAGCACAGCTCArnCGGGAGTTGAGC ATGTTCT GCI GCGC ACTCCGGATCGGACGGGTGATCCCGACAGTG AACGTAGGTAGCCGGAAAAGTCGGGAGCGCATGAAGGC GTGGATTGAGCGATGGGAGGCGGAGAAGCGGAAGAATG GGTTGTACCGCGTGGAGGGGAATAGCTGGTAGGGGATA GATAGACGGCTCTACCAACGTCCAAAGTACTGCTGGAAC ACAAGGATCAGCAGGATCAGAAGGATTGCGAAAGACGGGTCGGAACATGITGCCTAATAGAGTAAGTAAGGAGTTGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GTGCTGTAACTAGTCACAAGTTACGATTTGTGTACATAA CATCATTAG rCATGGAGATCAATTGCC IT rATGCTTCCGI AACTCTCGCCTCCCCGGAGTCACGAGATCAATAGAAACC ACCGCCGTTGACCATTCGCGATGCTCTCACTGGCTGTAT GCTGTCGATAGCCATGGAGCCGTTCAAAGTATGGACCCT TTGGGTGAGGATCTCCCTCCAACCCCACGGGACGTACAC GAACAACCGAGCAGAGGCGGGGGAGGGCAAAGAGGCC GGCGCT GCAAAT CGGCTGGCAGATCAGT CGCGGC TCAG CAGAGACTCCCGA 1111 CCCTTCCGTTGCCTGGCTTTGCC TCGGGGTTCGAGAGGAGCCCGTCTGCCATAAATAAGCCT GCACTTCAACTCAAAAAAAAGGGAGATGACAGATCAAC C ACTTTCTCGACA AGAA A CA CTCTTCA CCC ATGGCG ATA CTTGAG TGAAGTAAG TGTGACTGT GACTGATAT TA IT IT CTTC TTCAGCCAT CC IT ITTCGATATAT TACCTTATAGT T GCTTATTTCATTTCGGAGGTAAGATGGTCTCCTTGGCAC CCACATTCCCGGCTGCACTTGGCGGCTGCGGAATTGCTT CTCCTGGCTGCATTTGCCGGTGTTAACTTCCGAACTCACC AGCTTCCTCCCCTCCCCCCACAAAAACAATCATGGGAGA GTCT C TTTTTAAGGGCCCACGCGAT TACAACCCTATTTCC T CGACTAT C TGI C ACC TGACTAATGAGTCCGACGGACAC ACCACGTCGCTATACGGAATTGGCTTTGGGCCGTTCATC ATTACAAACAAGCATCTCTTCCGGCGTAACAATGGCACC CTCTTGGTTCAGTCCCTCCATGGTGTCTTCAAGGTTAAGA ACACCACGACTCTCCAGCAGCATCTTATCGACGGGAGGG ACA TGAT CA TAA ITCG TATGCCCAAGGAC TTCCCCCC IT TCCCGCAAAAG ITGAAGT TCCGAGAGCCGCAGCGTGAA GAACGGATTTGCTTGGTCACTACCAACTTTCAGACCAAA AGCATGTCTTCTATGGTTTCAGATACCTCGTGCACCTTCC CTTCTTCGGACGGCATTrTCTGGAAGCACTGGATCCAGA CCAAGGACGGACAGTGTGGATCGCCCTTGGTCAGTACCC GCGACGGGTTTATCGT GGGT ATCCACTCT GCTAGCAA TT TTACTAATACAAATAATTACTTCACTTCTGTACCCAAGA A T T T 1 ATGGAGCTGCTCACCAACC AGGAGGCCCAGCAAT GGGTTAGTGGCTGGAGACTCAATGCCGATTCTGTCTTAT GGGGTGGCCACAAGGTGTTCATGGTCAAACCTGAGGAA CCCTTCCAGCCCGTGAAAGAAGCTACGCAGTTGATGAAC CGT CGACGACGACGCATCGAAAATCT CTACTTTC AGGGT GCCATGGGGGGATCCGGTGCGACAAACTTCTCCCTTCTT AAACAAGCGGGGGATGTCGAGGAGAACCCGGGTCCTAT GGCGTTCGATCTGAAGACCGAAGACGGCCTCATAACCTA CTTGACCAAACACCTATCACTGGATGTTGACACCAGCGG AGTCAAGCGCCTCAGTGGTGGTTTCGTGAATGTCACGTG GCGCATCAAA TTGAACGCTCCGTA TCAGGGAC A TACGA GCATTATCCTGAAGCATGCACAACCACACATGTCGACAG ACGAGGACTTTAAGATTGGGGTGGAGCGGAGCGTCTAC GAGTATCAAGCAATCAAGCTAATGATGGCCAACCGAGA AGTCTTAGGCGGTGTGGATGGTATTGTCTCTGTTCCCGA AGGT C IGAAT TA TGACT TGGAGAAC AATGCGC TTA TCAT GCAGGATGTTGGCAAGATGAAGACGCTCCTGGACTATGT TACTGCGAAACCGCCACTCGCCACGGACATAGCAAGGC TAGTGGGCACTGAAATCGGTGGCTTCGTGGCACGGCTCC ACAACATCGGACGTGAGCGACGGGATGATCCGGAGTTC AAATTCTTCTCCGGGAATATTGTCGGGCGCACGACCAGT GACCAGCTGTACCAGACTATTATACCAAATGCTGCAAAGTA TGGCGTCGATGACCCT ITGC TCCCAACAG IT GTGAAGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GATCTTGTGGATGATGTGATGCATTCTGAAGAAACACTG GTCATGGCTGACCTATGGTCAGGAAACATTCTGCTTCAA CTCGAGGAGGGAAATCCCAGCAAGCTTCAGAAGATCTA CATCCTCGACTGGGAGCTCTGCAAGTACGGCCCGGCCAG TCTGGATCTCGGGTATTTCCTAGGTGACTGCTATCTCATC TCCCGCTTTCAAGATGAACAGGTCGGTACCACCATGCGG CAGGCTTACTTGCAATCGTATGCGAGGACATCAAAACAT I CGATCAA ITATGCGAAAGTAACAGCGGGAATCGCT GCT CATATTGTTATGTGGACTGATTTCATGCAGTGGGGCTCG GAGGAAGAGAGGATCAACTTTGTCAAAAAGGGAGTAGC CGCTTTCCATGATGCTAGAGGCAACAACGACAACGGGG AGATCACTAGCACATTGCTTAAAGAGAGCAGCACCGCC GAAAAT TTATACTTCC AAGGCGCAAI GGGCGGGAGCGG AGCTACAAACTTTTCACT GT TGAAGCAGGCAGGCGATGT AGAGGAGAATCCTGGTCCGATGCACATACGTAACCCCTA CCGCACGCCAATCGACTACCAAGCACTTTCCGAAGCGTT TCCTCCGCTGAAGCCATTCGTGAGTGTCAACGCCGACGG AACGTCTTCTGTAGATCTCACAATCCCCGAGGCTCAAAG GGCATTTACGGC AGCACTGCTGCACCGGGACTTTGG ICT CACCATGACTAI TCCTGAGGATCGATTATG TCCC ACI GT GCCCAACCGCCTGAACTACGTCCTGTGGATTGAAGATAT CTTCAACTACACAAATAAGACTCTAGGCCTGTCCGACGA TCGCCCAATCAAGGGTGTGGACATCGGTACCGGTGCGA GTGCCATTTATCCCATGCTGGCCTGTGCCCGGTTCAAGG CTTGGI CCA TGGI TGGAACCGAGGTGGAAAGAAAATGC AT TGATACGGCTCGTC TTAATG ITGTTGCAAACAACCTC CAAGACAGGCTGTCCATCCTGGAGACCTCAATCGATGGG CCCATCCTTGTTCCTATATTTGAGGCCACGGAAGAATAT GAGTACGAGTTTACAATGTGCAATCCTCCATTCTACGAC GGCGCGGCAGATATGCAAACTTCGGATGCCGCCAAGGG CTTCGGTTTTGGCGTAGGCGCCCCTCATTCAGGGACGGT CAI CGAGATGTCCACTGAAGGGGGAGAATCAGCA ITCG TCGCTCAGATGGTGCGTGAAAGTTTGAAACTTCGGACGA GATGCCGCTGGTACACCTCTAACCTTGGAAAGTTAAAGT CCTTGAAGGAGATTGTGGGACTCCTAAAAGAGTTGGAA ATTTCCAACTACGCCATAAACGAGTATGTGCAGGGCTCC ACCCGCAGATATGCCGI TGCCTGGAGCT TCACCGATA IT CAATTGCCGGAAGAATTATCGCGACCATCCAATCCAGAG CTGTCGAGCCTATTTTAGCTAGTACAGCAGAAGAATCTC TCTCCGCTGTTGCTTCAGTGTCTGCCATGCATTAACTrCA TCCTACTGTCCTACCCGCAGTACCCATTCACATTTGCGGC AGATACCAGGTTGTTTTCTATTCCCTCGGTTCTTCAGTTCTrCAGATATTACATTACTCGAGAAATIGGCGGCGAIGCA GGAGTTTGGTTGG 1111 AATTGTTTCAGTCTC CTTGAC CT GATTTGTATGACATGCAATGTTTCGACGGAAGACTATCT CGGTGAATATACGTCATGAATCATGCCCATACCAATGAA AATTGTGGCTTCAGAAACCACTATGGCATACATACATAT GTA TGAA IAAAGTACACGTTTACAGCTTAACGATGTCGC AGC IGGTTTTC ATTC AC AGTTTTAGGGTAI AG TATCTTCC ACTGAGGATCGTGCCGCAAGTTCAATGTTACTTCATTTG GTACGCTGCAGGATCCTCTAAGTCCAGGGTCAGTATTCA TCGGCATATGTATCGTTCCGATCCGCTTCCTCAAACCCA ACATCTCGAGCGCTGGGAGAGGTAGCAAAATCATTCGA ACG TCGGACACGAGGATCACTA ICC TCGTACTTGGTAGCAGTATCCTIGGCAACCGCGTCACAGGC A TCC ACCCAA TCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence CGAGTATACATCAACAGCAGCGGAGAGATCTATGTATAT ATCATGAGCAAATGCCACTCACTTAGGAGAAATCATAA ACATGAACGCACAGTTTATGCCCGTCTGAAATCGCTGGC CACAGACTTTGCAGGACAAATTTCCTAGGCCAAGTTTCT TGTCTAG 11 11 ACGACGATGGAGTTCTCGTGATTG CAG A AAAGGCAGGCAAATGTCGTAGGCAACGGTTCTCTCTAGT TGAGTATTAGCGACGGTAACCCTGAAGAATCAGAAGGT GGTCACCTTTCTGGGT TGCTG rGGTTGCCTGCTGGACTTC TTCCGCTTACCCTAAATTCAAGGAAAGCTTAGAGAAAGG TACATTGGCGCTGTGTAGAGTGGCATACCATGCTTCAAA GTTTCTGGGTG ACGCGACCGGCAATTATAGCTGAC 11 11 GATACTGCAGGAAATCTGAAGCCCTTGGATTGACAGCCC AATAGCCGG TGTGAGATCAGCAGAGCAATGC ACGAAAC TGCI GC AAACTCGACCGCGTATTTA TGTTGTGAAGACAC AAGTCTAGTGGAACAAGGCAGTGCGAGCAAGTGACCGG ACCGA 1 11 1 ATCTG A ATGTGCTTCTG AATGCTTCAGTGG AAGACTAGAGATCTCCGGGGGAGTTAGACAGGTATAGC CTAATAGTCCACTACATGCACTCCCGGAGACTCCAAGAA CACTATTTGGTGGCATAAAGTGA TGGAAATGCAACCAGT I GGTTGACTGGCGGTAGAT TAGTC ATCGGAI AC AT TAGT AAC 1 T T 1 ATAAGTAATTAGTTAGTTAACTAATTAGTTCCC GCCCGAATCGCTATTCCGACTGAGATATCTGATATCGCG GCCGCGGTGATGACGGTGAAAACCTCTGACACATGCAG CTCCCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCC GGGAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGT TGGCGGGTG rCGGGGCTGGCTTAATGTGAAATTCCACAG CCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTG CGTTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGT CGTGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGG AGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCG CTCACTGACrCGCTGCGCTCGGTCGTTCGGCTGCGGCGA GCGGTATCAGCTCACTCAAAGGCGGTAATACGG ITATCC ACAGAATCAGGGGATAACGCAGGAAAGAACATGTGAGC AAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCC GCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGAC GAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCG AAACCCGACAGGACTAIAAAGAIACCAGGCGTTTCCCCC TGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCC GCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAG CGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAG TTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCA CGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGG TAAC IATCG rCTTGAGTCCAACCCGGIAAGACACGACI T ATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCA GAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGT GGTGGCCTAACTACGGCTACACTAGAAGGACAGTATTTG GTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAA GAGTTGG TAGCTCI TGATCCGGCAAACAAACCACCGCTGGrAGCGGIGGn’n’nTGTnGCAAGCAGCAGATrACGC GCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATC 1111 CTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTT AAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCA CCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAA I CTAAAGTATATATGAG TAAACTTGGTCTGAC AGTTAC CAATGC1TAATCAGIGAGGCACCTATCTCAGCGATCTGTCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTGTA GATAACTACGAT ACGGGAGGGCTTACCA TCTGGCCCCAG TGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCC AGATTTATCAGCAATAAACCAGCCAGCCGGAAGGGCCG AG CG CAG AAGTGGTCCTG CA ACTTTATCCGCCTCCATCC AGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTT CGCCAGTTAATAGTTTGCGCAACGTTGTTGCCATTGCTA CAGGCA TCGTGGTGTC ACGCTCGTCG IT TGGTATGGC IT CATTCAGCTCCGGTTCCCAACGATCAAGGCGAGTTACAT GATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCG GTCCTCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGT TATCACTCATGGTTATGGCAGCACTGCATAATTCTCTTAC I GTCAI GCC ATCCGTAAGATGC TITTCI GTGACTGG IGA GTAC I’CAACC AAGTCA T1 CI GAGAA FAGIGTATGCGGCG ACCGAGTTGCTCTTGCCCGGCGTCAATACGGGATAATAC CGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGG AAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACC GCTGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACC C AACTGA TCTTCAGC ATCmTACTITC ACCAGCG TTTCT GGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAA AGGGAATAAGGGCGACACGGAAATGTTGAATACTCATA CTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTT ATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGA AAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGA AAAGTGCC ACCTGACGTCTAAGAAACCATTATTAI C ATG ACATIAACCTAI AAAAATAGGCG TATCACGAGGCCCTIT CGTC23 pUC19: I CTCGTCT CC rGTTATAGAGICAGAAGITGCGGGAGGGC 5 'UI'R_uprT:: PbphA CGTCTGCCGCAGTTCI ATGTATTA TCAACAAGG ITAAAC:: RmINMT: CPtrpC.': AATAGGCGACGATTAATTCCTTAGCTGCTTCGACTCTGA PsucA:: psiK;: TcgrA: GCATTCCTATTGCTAGTTATCAGACACAATCCAAAATTA: PthiA::cpr:: TafnyB:: AGTATACTGCAATGGAGTTACCCATGTCAGAGGCTAGAG 3'UTR_? / / ?rF (FIG. AGGGCGAACTTCAGCGATTATGTCATATCGGCGGAAGG 5D) GTI’ATGTATTAGCCTC TTGTTATGGATGCAIT ITIGCATG GTTATACGCGTTCTCCTACCGTGTTGGTAAAGGAAGCTT TATAGTCAAGGCTAAGTGGTTTAGTGTGGGAAATGGCAC TTATAAAATCCTGTACACGGAGAATAGAAAGTACTATCA CCTAAGAGCAAAGTGCATGACCTGGAAGGAAAAAGGCC TTGTGTCAAACTTTCGCTCTTGATAGATATGCAATCCGTT GACGAAC TTTAGGCIT IGCTIGCAAATTAAAC CT TTTCAT TTTCCTTGACGATC AATTGCCAGTACCAGA U l i AGCTAC CCAGTATACAGCTACGTCGCAGGATCAGCCGGACTGATT ATGACAAATACACTCGGATGCTTATTTAGGAACTTATCA ATTGGGGTTTATTTTCACAAGGCGAAGTGATCCACAAGA CACATGCATGAAAGAACATTCATGAGCAATCCAGTCATT GGCTTTT CCAAAAGGT GGCCGGGGAACAGCAC IGTTCC A CCAGTCGGTACCCCGTAATGAGGGGAGAGGGTATTATTA TTAGCAATTATTTCCAGATGTATCAACTTAGGCAGAGAC CC AGGG A AATACTGGCCCTGAACTTG A AAGGC 11 11 GTT GAATGCTAGCTTGGGTCTTCTCTGCAGAAGATAGTTGAC GGTrCTAGATrAATrGCATGTGGTTGAACCCAC TCCTAC GAATAGTTTACCGCACTACTCCGTACTACCCGTGATACT GTATTACGCAGTCGACTACGGAGCACTCCGTACAGAATA GTCATTGTAATAGCCAACTACTTAAGTAGTCCCACTAACCGTCCCAATGAGGAAAATGTTCAACCCTCGCATATTAATWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TCCTTAGCTTTAAATGCCTGCGTTACTTCCTACACTTCAA CTCAACCCCACTACCTTTGGAACGGTTTACAGTTCGCTG CAGATATCCTTCATTTCTTGTTTCTTCACCTCTTAGTCGT ACTTTGCATCCGTGGAAGAAGGAGGGGGAAAGCTACCA TAGCCAAGACGAACGAGCGTGTCCGTTCTACAAGATCAT CCCTGGATTCTCCCTCTGTGTGGATGCATTTCGATACGG AGCCGTAGAGGGATGTAATGCGTACTTCCTTAGTCACTT CCACAGCGACCATIACATCGGCCI GACGGGG I’CGTGGCG CCATGGACCAATCTACTGCAGCAGACCTACGGCCAACTT GGTGTGCCAGCAACTGAAGGTCGACCGGAAGTGGCTTG TACCACTTGAGTTCGAGCGGAAGACGGAAATCCCGGAT ACAGGAGGAGCGCAGGTGACTTTGATCGAGGCTAATCA TTGTCCTGGGAGCGCCATCTTTCTCTTCGAGAAATCAAT GGGAI CGGGTCCCTCGCAGAGAACACATCG TGTCCI CCA CTGTGGTGACTTTCGCGCCTCGCCGCTTCATGTGCAACA TGCCCTTCTCCGCCCGGAGATTGCTGACCCCGCAACCGG CAAGGCTCGCCAGCAACGAATCGATGCCTGCTATCTGGA CACTACATATTTGAGCCCCAAGTATGCATTCCCTGGCCA AGAAGATGTCATACAAGCCTGCGCAGAACTTTGCGTTGA GCTCGATGGGGACGCCAACGACACCAATGGACGAGCGT TTGGACGACCAGTCAATGGAAAAAGCGGAATGCTGAGC AAGTTTGTTACGGCTGTGACTGGATCCCGCCCGTCTCCG ACGCAAGACAGCCGCCCCCTGGCCGGCTATTGGTAGTA ATAGGGACGTACAGCATCGGCAAAGAACGCATCTGTCT GGGGATCGCACGGGC ATTGAAGAGCAAGATC TACGCGA CGCCAGCTAAGCAGCGCGTCTGTGCGTGCCTCGAGGATG CTGAGCTGTCATCGCTGCTGACAGACGATCCCACGGAGG CGCAGGTGCATATGCAAACGCTATTCGAGATCCGGGCG GAAACGCTGGCGGATTACCTGGACTCGATGAAGCCGCA CTTCACGCGGGTGGTGGGATTTCGACCAACCGGGTGGAC GTATCGCCCGCCAGCTGGCCGAATGCTGGACAACCCACC GGTGTCGGTGGTGCTCAATTCGGCACATTGGAAGACGCC CTTTTCTGCGAAAGACCTGGTGCCACAGCGAGGGAGTAC GCGGGAAAGCGCATGCTTTGGAGTGCCGTACAGTGAGC ACAGCTCATTTCGGGAGTTGAGCATGTTCTGCTGCGCAC TCCGGATCGGACGGGTGATCCCGACAGTGAACGTAGGT AGCCGGAAAAGTCGGGAGCGCATGAAGGCGTGGATTGA GCGATGGGAGGCGGAGAAGCGGAAGAATGGGTTGTACC GCGTGGAGGGGAATAGCTGGTAGGGGATAGATAGACGG CTCTACCAACGTCCAAAGTACTGCTGGAACACAAGGATC AGCAGGATCAGAAGGATTGCGAAAGACGGGTCGGAACA TGTTGCCTAATAGAGTAAGTAAGGAGTTGGTGCTGTAAC TAGTCACAAGTTACGATTTGTGTACATAACATCATTAGT CATGGAGATCAATTGCCTTTATGCTTCCGTAACTCTCGCC TCCCCGGAGTCACGAGATCAATAGAAACCACCGCCGTTG ACCATTCGCGATGCTCTCACTGGCTGTATGCTGTCGATA GCCATGGAGCCGTTCAAAGTATGGACCCTTTGGGTGAGG ATCTCCCTCCAACCCCACGGGACGTACACGAACAACCGA GC AGAGGCGGGGGAGGGC AAAGAGGC CGGC GC IGC AA ATCGGCTGGCAGATCAGTCGCGGCTCAGCAGAGACTCCC GATTTTCCC1TCCGTTGCCTGGCTTTGCCTCGGGGTTCGA GAGGAGCCCGTCTGCCATAAATAAGCCTGCACTTCAACT CAAAAAAAAGGGAGATGACAGATCAACCACTTTCTCGA CAAGAAACACTCTI’CACCC ATGGCGA lACTIGAGI GAAGTAAGTGTGACTGTGACTGATATATTTTCTTCTTCAGCCAWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TCCTTTTTCGATATATTACCTTATAGTTGCTTATTTCATTT CGGAGGTAAGATGGTCTCCTTGGCACCCACATTCCCGGC TGCACTTGGCGGCTGCGGAATTGCTTCTCCTGGCTGCAT TTGCCGGTGTTAACTTCCGAACTCACCAGCTTCCTCCCCT CCCCCCACAAAAACAATCATGGAGAACTCATACTCTGCA CAGATGTACATTGATGAATTTGATCCTGTACACTACTAC CAGACATACTATTCTTCGGGGAAAGGAGGTATCGCTAGA GAATGGAC AGACTTTGCCT TACAGAAI CTGCAI GAAACA TTTGGTCCAGGAGGTGTGAAAGGAGACATACTAATTGAC TTTGGAGCTGGACCCACAATTTATCAACTGCTCTCTGCTT GTGAAGTGTTCAACAGCATTATAACCTCTGATTTTCTTG AGCAAAACCGAGAGCAATTGGAAAAATGGCTGAGAAAG GACCCAGATGCCTTAGACTGGTCTCATTTTACCAAATAT GTGTGTGAACTGGAAGGTAAC AGAGA TAACTGGGAAAA AAAGGAAGAAACGCTGAGGAGAAAAGTAACCAAAGTGT TGAAGTGTGACGCTCTTGCGGAGAAGCCATTTGACGACG TGCCTATGCCAGAAGCCGACTGTCTGATTAGCTGCCTCT GCTTAGAAAATCCTTGTCAAGACCAAGAAGCTTATATCA ATATATTGAAAAAGCTTAAGGAGCTACTTAAACCCGGTG GTCACATTATAATTCAGAGTATTCTTAATTGTTCATACTA CCATATTGGTAACAGCTGTTTTTCCCATCTGTCCTTATCT AAGGATGACGTGGAAAAATCATTTAAAGAGGCCGGGTA TGAAATTGTTAAATTAAAGGTGCTGCCACGATCTGTAAT GTCAGAAATGGAGATCAGTGATTCTAATGGCTATTACTT TATCCATGCTCGTAAACCACAGAAAGAGTAAGGATCCA CTTAACGTTACTGAAATCATCAAACAGCTTGACGAATCT GGATATAAGATCGTTGGTGTCGATGTCAGCTCCGGAGTT GAGACAAATGGTGTTCAGGATCTCGATAAGATACGTTCA TTTGTCCAAGCAGCAAAGAGTGCCTTCTAGTGATTTAAT AGCTCCATGTCAACAAGAATAAAACGCGTTTCGGGTTTA CCTCTTCCAGATACAGCTCATCTGCAATGCATTAATGCATTGGACCTCGCAACCCTAGTACGCCCTTCAGGCTCCGGC GAAGCAGAAGAATAGCTTAGCAGAGTCTATTTTCATTTT CGGGAGACGAGATCAAGCAGATCAACGGTCGTCAAGAG ACCTACGAGACTGAGGAATCCGCTCTTGGCTCCACGCGA GTAGTGATATGTCGGCTCTAGTTCCTTGCTGTAAGTAAG GAGACGGGTATAI GTCAACG I’AGTATAAAGTGAAGCAG GCGAATTTTAAAGAATTTGCAATGGCCCATCTGTGTTCC ATCTTCGCACAACATTTAATTATTTTATATGATTTGTCAT AGACCCACCAACTTCAACTCGAACTACATCACTTGGACC AACATCACGCGTTCAACATGGACAAGGGTTGATAACCC GGGATGCATTCATTGTCTGCCTCAAGTGTCGCTACTAGT TCCATCTTTTGTAAATTTGGATATGTCCGTTTCTTCTAT CGCAACAAGCCATCCAACAAGAGAATACCGACCTGGAT CATGTAATTCTGGCAATGGTCAACAGCCCCGTCCCGCAG AGCATACGGATTCTTGTTTTGCGACCCCCCTGGAACGAT ATAATAATTTCGCAGTCTCCACTATATTCCGGCCCGGGAAACACCCTGGGTCCTCCCTAGGCACGACCGATTGAGAAAGATATCGTAAGAAGGACAACCCTTGGGCTGAGGGCCTGC CACCCATCTTCCATGATAAGACATCTTTCTGGACGATCA GCGCTGTCACAGGTGACGGGCCAGTGTGAACAAATCAC ATCGAAGGCACACATTGCGCGATGAAGACTCTGCACTCT ATTGCGTCAAACACGCAAACCATTATACCTGAAGCATCA CCTCGTGTCCTATACGAGTCGTTAAACTTTCTTCCTCTATTCTGCCCACTTTCATTTCTTTTATACTCCCGTTCTTGCTWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence CGATCTCCACCGCTTCATACCGACAAACCTCCGGCTTTC AGTTTCTTCTTACGGTAAAACCAAAGCACCCCACGAGCA AGCTAGATTCCACACCAGGTAACTTCAGTCAAGCCAACA GAACCTCGGTGGGTCTCAAGTTGAAGATCGGCAGCATCA TAACCTCGTTGCGAGAACTCGGGGGAAATCTCGGGGAA TCCGCGCTGAATCTGCCCCCGCGAACCCTAAGCGGACTT CCTCCGCAATCCTCAATTTCCCCGAGGATACGGACTATT CATTCCAGCATTCCAACCATTCTAGTTCTAGTGATCGGAA ATTCCCCGGCACCCCTGCATCAACAGAAGCATACCATAT ATAATGTCACAATTTCCCCTCTGCCAAGGGAGGGGAAGT GAGTGTCCCCTCCTCTGCTATTATGGCCTTTGATCTCAAA ACAGAAGACGGCCTGATTACCTACCTGACAAAACATCTG TCTCTCGATGTCGATACAAGTGGAGTGAAGCGTCTATCA GGCGGGTTTGTAAATG ITAC ATGGCGCATC AAAT TGAAT GCTCCGTACCAAGGGCATACCTCAATAATTCTTAAGCAC GCTCAGCCCCACATGAGCACCGACGAAGATTTCAAAAT AGGTGTCGAAAGGAGTGTCTACGAGTATCAGGCCATCA AGCTCATGATGGCGAATCGGGAAGTCCTCGGTGGTGTGG ATGGC ATTGTCAGCGTGCCGGAGGG TCTCAACTATGATT TAGAGAATAACGCCTTGATCATGCAAGACGTTGGAAAG ATGAAGACCTTGCTAGACTATGTCACCGCCAAGCCCCG TTGGCTACAGACATTGCTCGACTAGTAGGGACTGAGATC GGAGGCTTTGTTGCTCGACTGCACAACATTGGTAGAGAA AGGCGTGATGACCCTGAATTCAAGTTCTTCTCCGGAAAT A TAGTGGGTAGAACCACCTCCGATCAAC TCTACCAGACC ATCA TCCCCAACGCTGCCAAATA TGGGGTGGACGATCCT CTGTTGCCTACCGTTGTGAAGGACCTGGTTGATGATGTG ATGCACTCAGAAGAGACGTTGGTTATGGCTGACCTCTGG TCCGGCAACATCCTCCTTCAACTGGAGGAGGGCAATCCA AGCAAGTTGCAGAAGATCTACATCCTGGACTGGGAGCT GTGCAAGTACGGCCCAGCGTCTCTIGATC ITGGGTACTT I C1TGGCGACTGITATCT lATTAGICGCITCCAGGATGAG CAGGTCGGAACGACGATGCGCCAGGCATACCTCCAATC GTATGCACGGACTTCCAAGCATTCCATCAACTACGCGAA GGTCACTGCCGGCATCGCAGCACACATCGTCATGTGGAC GGACTTCATGCAGTGGGGTTCGGAGGAAGAACGCATTA ACTTCGTCAAGAAAGGGGTGGCAGCCTTCCATGACGCCC GGGGAAACAATGACAACGGCGAGATTACGTCTACTCTG CTGAAGGAGAGCTCGACTGCGTAGCTAGTACAGCAGAAGAATCTCTCTCCGCTGTTGCTTCAGTGTCTGCCATGCATT AACTTCATCCTACTGTCCTACCCGCAGTACCCATTCACAT TTGCGGCAGATACCAGGTTGTTTTCTATTCCCTCGGTTCT TCAGTTCTTCAGATATTACATTACTCGAGAAATTGGCGG CGATGCAGGAGTTTGGTTGGTTTTAATTGTTTCAGTCTCC TTGACCTGATTTGTATGACATGCAATGTTTCGACGGAAG ACTATCTCGGTGAATATACGTCATGAATCATGCTTCGGT AAATACACTATCACACACCGAACGTGCCCTGATTGCCTT GATACTCTG TGAGCGCTGGGCAGGGGACCI TGCACCCAC CGA IGAAGAATTTCACCGGCAATTGAGCCGG TGTGTCTC TAAGCAGGAGGCATGGTGGTGTCAGTACTTGGGTCGGGT AG CG ACCCTAATTGGAG ACGTGC ATCCATCCG GCCG CGT GTCGGACATGCATTGGAGGATCCGATTGGAAACTGAAT GGGAATCCATTGTGAAGAAGAAAGACGAGTGCGATATG CTGCGTCTCAAAGTGAAATGCAACAACGATGTGGCTGTCGCCGCGTTCTCTCTTGACAGCTTACAGGAAAGGGCGGAGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence AAAGTCGAGAAAGTCGGAAAGAAAAAGAACTGGATCAA GGATTATGGAGTGCGAGTGGGGGTTAACGATTATTTGCTA ATACTTAGGTTTCACTATTGAAAAGGTTCCAGTCGTGGA GATTTTCTGTTTTTGGATAAATGTTAACTAACCGTGGAC AGAGTACTATGTTATATAGTGGATCAGATGATCCACCAT TCCTCGATCTGACAGACGGGCAATTGATTACGGGATCCC ATTGGTAACGAAATGTAAAAGCTAGGAGATCGTCCGCC GATGTCAGGATGATTTCACTTGTTCTTGTCCGGCTCACC GGTCAAAGCTAAAGAGGAGCAAAAGGAACGGATAGAAT CGGGTGCCGCTGATCTATACGGTATAGTGCCCTTATCAC GTTGACTCAACCCATGCTATTTAACTCAACCCCTCCTTCT GAACCCCACCATCTTCTTCCTTTTCCTCTCATCCCACACA ATTCTCTATCTCAGATTTGAATTCCAAAAGTCCTCGGAC GAAACTGAACAAGTCTTCCTCCCTTCGATAAACCTTTGG TGATTGGAATAACTGACCATCTTCTATAGTTCCCAAACC AACCGACAATGTAAATACACTCCTCGATTAGCCCTCTAG AGGGCATACGATGGAAGTCATGGAATACTTTTGGCTGGA CTCTCACAATGATCAAGGTATCTTAGGTAACGTCTTTGG CGTGGGCCGGTGTTCGTTCCCAGTCAI CGATGC A T1 CAC A TGCCCTCCCTAAGCTGGGCCCTAGACTCTAGGATCCTA GTCTAGAAGGACATGGCATCGATGGACTGGGTTCGTTCT GAGATTATACGGCTAAAACTTGATCTGGATAATACCAGC GAAAAGGATCATGCCTTCTCTCGTTCTTCCTGTTGATGG AATGGCTAACAGATGATAGTCATTGCAACTTGAAACATG ACCGACCCTAATCGTACCACCTTCTCTTCAGCACTACAT CCTCTAGCTGTGGTCTCAATGGCCTCCTCTTCCTCAGACGTTTCGTCTTGGGCTTGGGTGTCGTCCTCGCTGCCCTTTA TATATTCCGCGACCAGCTTITCGCTGCGTCCAAACCAAA GGTCGCCCCAGTATCCACCACCAAACCCGCCAATGGCTC TGCCAACCCTCGCGACTTCATCGCAAAGATGAAGCAGG GTAAAAAGCGC ATTGIC ATI TT ITACGGTI’CTCAGACGG G rACTGCAGAAGAGIATGCCAITCGICTCGCAAAGGAG GCTAAGCAGAAGTTTGGTTTGGCGTCCCTTGTGTGCGAT CCAGAGGAATACGACTTTGAGAAACTTGACCAACTGCC AGAGG A CTCCATCGCTTTCTTCGTCGTTGCCA CCTATGGT G AGGG AGA A CCTACCGA CAACGCCGTCCAGCTTITGCA GAACTTGCAAGACGAGTCTTTCGAGTTCAGCAGTGGAGA GCGCAAATTGAGTGGCCTCAAATATGTCGTCTTTGGTCT TGGGAACAAAACTTACGAGCACTACAATCTTATTGGACG CACTGTTGACGCTCAACTCGCCAAGATGGGAGCTATCCG TATCGGCGAACGCGGTGAAGGTGACGATGATAAGAGCA TGGAGGAGGATTACCTTGAATGGAAGGACGGTATGTGG GAGGCTTTCGCTACTGCCATGGGTGTCGAAGAGGGACA GGGCGGCGACTCTGCCGACTTCGTTGTTTCGGAACTCGA GTCTCATCCTCCCGAGAAGGTTTACCAAGGTGAATTCTC GGCTCGCGCTCTTACAAAGACCAAAGGAATCCATGACG CCAAGAACCCCTTCGCTGCACCTATCACTGTCGCCCGTG AACTITI CCAGTCTG IT GTCGACAGGAACTGTGTCCAI G I CGAATTCAACATTGAAGGCTCTGGC ATTACGTACCAAC ATGGTGACCACGTCGGTCTTTGGCCCTTGAACCCGGATG TCGAAGTGGAGCGTCTCCTGTGCGTTCTGGGATTGACCG AAAAGCGCGACGCTGTTATCAGCATCGAATCTCTCGATC CCGCTCTGGCCAAGGTACCATTCCCTGTCCCTACTACCT ACGGTGCTGTCCTTCGCCACI ACATCGACA TCAGCGCTGTIGCTGG I’CGTCA AATTCTTGGGACATrGTCGAAGTTCGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence CTCCTACTCCGGAGGCCGAGGCTTTCCTCAGGAATCTCA ATACCAACAAGGAAGAATACCACAACGTTGTCGCTAAT GGATGCCTCAAGTTGGGCGAAATTCTCCAAATCGCTACT GGTAACGATATCACTGTCCCACCTACTACTGCCAATACC ACCAAGTGGCCTATACCCTTTGATATCATCGTCTCTGCC ATTCCCCGTCTTCAACCCCGGTACTACTCCATTTCCTCGA GCCCCAAAATCCACCCCAACACTATCCACGCTACCGTTG I TG TCCTCAAGTACGAGAACGTTCCCACCGAGCCAAT TC CTCGTAAATGGGTATACGGTGTTGGATCCAACTTCTTAC TTAACCTCAAGTATGCCGTCAACAAGGAGCCCGTACCTT ACATCACTCAGAACGGTGAACAACGTGTTGGCGTTCCGG AATACCTTATTGCAGGACCTCGTGGCTCGTACAAGACTG AGACTTTCTACAAGGCCCCCATCCATGTTAGGCGCTCGA CC I’TCAGAC ITCCCACTAACCCCAAGAGCCCTGTTATCA TGATCGGTCCTGGAACTGGAGTTGCTCCTTTCCGTGGATTTGTGCAAGAACGTGTTGCCCTTGCCCGCCGCTCCATTGAGAAGAACGGACCTGATTCACTTGCTGACTGGGGTCGCATCTCTCTGTTCTACGGTTGCCGCCGATCGGATGAAGATTTCTTGTACAAGGACGAATGGCCACAATACGAGGCTGAACTCAAGGGCAAATTCAAACTTCACTGCGCCTTCTCTCGAC AGAACTACAAGCCTGATGGAAGCAAGATTTACGTCCAG GATCTCATTTGGGAAGACAGGGAGCACATTGCTGACGCT ATTCTCAATGGCAAAGGTTACGTGTATATCTGTGGTGAG GCGAAGAGCATGAGCAAGCAGGTCGAGGAGGTGTTAGC CAAAATCTTGGGAGAGGCCAAGGGTGGATCTGGCCCTG TTGAGGGTGTCGCTGAAGTTAAGCTATTGAAGGAGAGAT CAAGGCTCATGTTGGATGTCTGGAGTTAAAGGGTGGAG AGTATATGATGGTACTGCTATTCAATCTGGCATTGGACA GTGAGTTTGAGTTTGATGTAACTTGTCTATTCTATGATGT ATGGTCTTTTTGTTCTATAGTTGGAAATCGGAATGATCTC AAATCTTGAATAAATATAAAAAGGATAATACTCACATCC A I’CACAACCTTAC AAGGTTAAI TCCGAGCTATA T1 CCAC CGACACAAATAGGCAGTATCTTCTCTCGCCAGAGAATCG CGATATTATTGGCATGCAAATAACGATAACTGTCTCCAG AAGGTAAATATATGCAGTCTTGAAACCTAAACAAGGCTT CTCAATCCATTGATTCTCAGTGATATCCTCTTACGAGAAT AGGGAAGGTATATAACCGTTGCTGGGGTTGCGTTTAGGCT AAATTCGTATGATAGTTGAATCTGTTTGGATGGGTATGC TGTGGTTTTATTTGGCATATCATTAGGGTTTGACCTGGTG GTTGCTCGCGACTATAGAATGAAGTGGAATGGGGGAAA GAAAGCAGGAAAAACAGCTTGGAGAGGAGCTATATCAT AAAATATTATACGATTGTGGGCATAATGTCAAATGTATT AGGTCTAGGTTTAAGTTTATGTTAGTATATCATGGAGAT ATAGTAAAAGGGAACTCTTTCCACTGATGTATGTTCTCT TCTCACAAAGCCAGAAGGGTATAGTGATATCCCGAGCCT GATAGCGTATrAGGATTCAGTTTTGGTGAGATACCATAA GTTTTTCATACACAAACCGATGTCTAGAGAGAGGGGAA GAGGGGTAGGAGGGGAAGGGCGAG TGTTGC C GC C I TGC CTAACAC AAGACAGG TATACGTACTACTGACCAGCTAC A TGTATCAATACAGTAATGGTCCTCAAGAATTCCATACCA ATGAAAATTGTGGCTTCAGAAACCACTATGGCATACATA CATATGTATGAATAAAGTACACGTTTACAGCTTAACGAT GTCGCAGCTGGTTTTCATTCACAGTTTTAGGGTATAGTAT CTTCCACTGAGGATCGTGCCGCAAGTTCAATGTTACTTCATTTGGTACGCTGCAGGATCCTCTAAGTCCAGGGTCAGTWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence ATTCATCGGCATATGTATCGTTCCGATCCGCTTCCTCAAA CCCAACA TCTCGAGCGCI GGGAGAGGTAGCAAAATCA T TCGAACGTCGGACACGAGGATCACTATCCTCGTACTTGG TAGCAGTATCCTTGGCAACCGCGTCACAGGCATCCACCC AATCCGAGTATACATCAACAGCAGCGGAGAGATCTATG TATATATCATGAGCAAATGCCACTCACTTAGGAGAAATC ATAAACATGAACGCACAGTTTATGCCCGTCTGAAATCGC TGGCCACAGACTTTGCAGGACAAATTTCCTAGGCCAAGT TTCTTGTCTAGTTTTACGACGATGGAGTTCTCGTGATTGC AGAAAAGGCAGGCAAATGTCGTAGGCAACGGTTCTCTC TAGTTGAGTATTAGCGACGGTAACCCTGAAGAATCAGA AGGTGGTCACCTTTCTGGGTTGCTGTGGTTGCCTGCTGG ACTTCTTCCGCTTACCCTAAATTCAAGGAAAGCTTAGAG AAAGGTACATTGGCGCTGTGTAGAGTGGCATACCATGCT TCAAAGTTTCTGGGTGACGCGACCGGCAATTATAGCTGA CTTTTGATACTGCAGGAAATCTGAAGCCCTTGGATTGAC AGCCCAATAGCCGGTGTGAGATCAGCAGAGCAATGCACGAAACTGCTGCAAACTCGACCGCGTATTTATGTTGTGAAGACACAAGTCTAGTGGAACAAGGCAGTGCGAGCAAGTGACCGGACCGATTTTATCTGAATGTGCTTTCTGAATGCTTC AGTGGAAGACTAGAGATCTCCGGGGGAGTTAGACAGGT ATAGCCTAATAGTCCACTACATGCACTCCCGGAGACTCC AAGAACACTATTTGGTGGCATAAAGTGATGGAAATGCA ACCAGTTGGTTGACTGGCGGTAGATTAGTCATCGGATAC ATTAGTAACTTTATAAGTTAATTAGTTAGTTAACTAATTAGTTCCCGCCCGAATCGCTATTCCGACTGAGATATCTGAT ATCGGTGATGACGGTGAAAACCTCTGACACATGCAGCTC CCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGG GAGCAGACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTG GCGGGTGTCGGGGCTGGCTTAATGTGAAATTCCACAGCC TGGGGTGCCTAATGAGTGAGC TAACTCACA ITAATIGCG I TGCGCTCAC TGCCCGCTTTCC AGTCGGGAAACCTGI CG TGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAG AGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTC ACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCG GTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACA GAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAA AGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGT TGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGC ATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAAC CCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGA AGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTA CCGGATACCTGTCCGCCTTTCTCCCTrCGGGAAGCGTGG CGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGT GTAGGTCGITCGCTCCAAGCTGGGCTGTGTGCACGAACC CCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTA TCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCC ACTGGC AGC AGC C AC I GG TAAC AGGATTAGC AGAGCGA GGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGC CTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCT GCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTG GTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCG GTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAA AAAAAGGATCTCAAGAAGATCCTTTGATCTTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence ATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAG ATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAA AGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGC TTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTC GTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAA CTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTG CAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATT TATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGC AGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCT ATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCA GTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGC ATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCA GCI CCGG TI CCCAACGA TCAAGGCGAGTTACATGA TCCC CCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTC CGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCAC TCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCAT GCC ATCCGTA AG ATGC 11 11 CTGTGACTGGTG AGTACTC AACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGA GTTGCTCTTGCCCGGCGTCAATACGGGATAAT ACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAAC GTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGT TGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACT GATCTTCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTG AGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGA ATAAGGGCGACACGGAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCT CATGAGCGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCATTATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCGATATCGATATC24 pUC19; TRE- TGCGGCCGCCGCGCGTTTGATATCGGTACCGAGCTCGAC Pmin::RmINMT::Ttr TTTCACTTTTCTCTATCACTGATAGGGAGTGGTAAACTCG pc, ACTTTCACTTTTCTCTATCACTGATAGGGAGTGGTAAACT PgpdA::T5H::Tamy CGACTTTCACTTTTCTCTATCACTGATAGGGAGTGGTAA B::PbphA::ASMT::T ACTCGACTTTCACTTTTCTCTATCACTGATAGGGAGTGGT cgrA::pyrGwt (FIG. AAACTCGACTTTCACTTTTCTCTATCACTGATAGGGAGT 7) GGTAAACTCGACTTTCACTTTTCTCTATCACTGATAGGG AGTGGTAAACTCGACTTTCACTTTTCTCTATCACTGATAG GGAGTGGTAAACTCGACCTATATAAGCAGAGCTCGTTTA GTGAACCGTCAGATCGCCTGGAGACGCCATCCACGCTGT TTTGACCTCCATAGAAGACACCGGGACCGATCCAGCCTC CGCGGCCCCGAATTGCCCATCTTCAGTATATTCATCTTCC CATCCAAGAACCTTTATTTCCCCTAAGTAAGTACTTTGCT ACA I’CCATACTCCA ICC TTCCCATCCCTTATTCCTITGAA CC rTrCAGTrCGAGCTTTCCCACTrCATCGCAGCITGAC T AACAGCTACCCCGCTTGAGCAGACATCACATGGAGAAC TCATACTCTGCACAGATGTACATTGATGAATTTGATCCT GTACACTACTACCAGACATACTATTCTTCGGGGAAAGGA GGTATCGCTAGAGAATGGACAGACTTTGCCTTACAGAAT CTGCATGAAACATTTGGTCCAGGAGGTGTGAAAGGAGA CATACTAATTGACTTTGGAGCTGGACCCACAATTTATCA ACTGCTCTCTGCTTGTGAAGTGTTCAACAGCATTATAAC CTCTGATTTTCTTGAGCAAAACCGAGAGCAATTGGAAAAATGGCTGAGAAAGGACCCAGATGCCTTAGACTGGTCTCAWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TTTTACCAAATATGTGTGTGAACTGGAAGGTAACAGAGA TAACTGGGAAAAAAAGGAAGAAACGCTGAGGAGAAAA GTAACCAAAGTGTTGAAGTGTGACGCTCTTGCGGAGAA GCCATTTGACGACGTGCCTATGCCAGAAGCCGACTGTCT GATTAGCTGCCTCTGCTTAGAAAATCCTTGTCAAGACCA AGAAGCTTATATCAATATATTGAAAAAGCTTAAGGAGCT ACTTAAACCCGGTGGTCACATTATAATTCAGAGTATTCTTAATTGTTCATACTACCATATTGGTAACAGCTGTTTTTCC CATCTGTCCTTATCTAAGGATGACGTGGAAAAATCATTT AAAGAGGCCGGGTATGAAATTGTTAAATTAAAGGTGCT GCCACGATCTGTAATGTCAGAAATGGAGATCAGTGATTC TAATGGCTATTACTTTATCCATGCTCGTAAACCACAGAA AGAGTAAGGATCCACTTAACGTTACTGAAATCATCAAAC AGCTTGACGAATCTGGATATAAGATCGTTGGTGTCGATG TCAGCTCCGGAGTTGAGACAAATGGTGTTCAGGATCTCG ATAAGATACGTTCATTTGTCCAAGCAGCAAAGAGTGCCT TCTAGTGATTTAATAGCTCCATGTCAACAAGAATAAAAC GCGTTTCGGGTTTACCTCTTCCAGATACAGCTCATCTGCA ATGCATTAATGCATTGGACCTCGCAACCCTAGTACGCCCTTCAGGCTCCGGCGAAGCAGAAGAATAGCTTAGCAGAGTCTATTTTCATTTTCGGGAGACGAGATCAAGCAGATCAA CGGTCGTCAAGAGACCTACGAGACTGAGGAATCCGCTCT TGGCTCCACGCGTCGGAGAATATGGAGCTTCATCGAATCACCGGCAGTAAGCGAAGGAGAATGTGAAGCCAGGGGTGTATAGCCGTCGGCGAAATAGCATGCCATTAACCTAGGTACAGAAGTCCAATTGCTTCCGATCTGGTAAAAGATTCACG AGATAGTACCTTCTCCGAAGTAGGTAGAGCGAGTACCCG GCGCGTAAGCTCCCTAATTGGCCCATCCGGCATCTGTAG GGCGTCCAAATATCGTGCCTCTCCTGCTTTGCCCGGTGT ATGAAACCGGAAAGGCCGCTCAGGAGCTGGCCAGCGGC GCAGACCGGGAACACAAGC TGGCAGI CGACCCATCCGG I GCTCTGCAC rCGACCTGCTGAGGTCCCTCAGTCCCTGG TAGGCAGCTTTGCCCCGTCTGTCCGCCCGGTGTGTCGGC GGGGTTGACAAGGTCGTTGCGTCAGTCCAACATTTGTTG CCATATTTTCCTGCTCTCCCCACCAGCTGCTCTTTTCTTTT CTCTTTCTTTTCCCATCTTCAGTATATTCATCTTCCCATCC AAGAACCTn'AITICCCCTAAGTAAGTACITIGCTACAIC CATACTCCATCCTTCCCATCCCTTATTCCTTTGAACCTTT CAGTTCGAGCTTTCCCACTTCATCGCAGCTTGACTAACA GCTACCCCGCTTGAGCAGACATCACCATGGAGCTGACGA TGGCTTCTACAATGAGTCTAGCACTGCTCGTTCTGTCAG CAGCATATGTCCTTGTGGCCTTACGACGATCGAGGAGTA GCAGCAGCAAACCGAGACGGC ITCCGCCCTCCCC TCCCG GCTGGCCCGTCATCGGCCATCTCCATTTGATGTCTGGCA TGCCTCACCACGCGTTAGCGGAGCTGGCGCGCACCATGA GAGCACCTTTGTrCCGCATGCGTCTGGGCTCCGTGCCAG CAGTTGTCATTTCCAAACCAGACTTGGCGCGGGCGGCGT TGACGACAAATGATGCTGCCI TGGCATCACGCCCCCACC I CC TGTCCGG I’CAATTCCTCTCG ITCGGGTGI TCCGAI GT TACGTTCGCTCCGGCTGGGCCATATCACCGGATGGCCAG GAGAGTGGTGGTAAGCGAGTTGCTTTCTGCGCGACGCGT TGCTACCTACGGGGCGGTGCGTGTTAAGGAATTGCGTCG CCTCCTGGCTCATCTGACCAAGAACACTTCGCCAGCCAA GCCTGTCGACCTCTCGGAGTGCTTCCTCAATCTAGCAAACGACGTGCI ATGTCGGGI AGCCTTTGG TCGGCGGT TTCCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GCATGGCGAAGGTGATAAGTTGGGAGCTGTGCTCGCCG AGGCTCAGGATCTGTTTGCCGGCTTCACCATAGGCGACT TCTTCCCCGAGCTTGAGCCTGTCGCTTCAACAGTCACTG GACTCAGACGCCGGTTGAAGAAGTGCTTGGCGGATCTCC GTGAGGCCTGTGACGTAATCGTCGATGAACACATATCGG GAAATCGCCAGCGTATCCCCGGTGACCGAGACGAGGAC TTTGTGGATGTTTTGCTCCGAGTGCAGAAGTCACCGGAT CTGGAGGI TCCACTCACTGATGACAACC TGAAAGCCCTA GTGCTTGACATGTTTGTCGCCGGGACCGATACCACTTTT GCCACGCTCGAATGGGTAATGACCGAACTCGTCCGCCAT CCGCGCATTCTAAAAAAGGCCCAGGAGGAAGTAAGACG TGTGGTGGGAGACAGTGGACGGGTCGAGGAATCCCATC I TGGAGAGTTACACTACATGCGCGCCATCAI C AAAGAGA CC ITCCGACTGCATCCTGC TGT TCCC TTGCI CGTCCCTCG CGAGTCTGTTGCGCCTTGCACACTCGGGGGTTATGATAT TCCTG CTAGGACAAGG GTCTTC ATCA ACACGTTCG CCAT GGGCCGAGATCCAGAAATCTGGGACAATCCGCTGGAGT ACAGCCCCGAAAGGTTCGAATCTGCAGGAGGCGGTGGA GAGAI TGATCTGAAGGACCCCGACTACAAGCTGCTTCCG I TCGG TGGTGGGAGAAGGGGCTGCCCAGGCTACACCTTT GCGCTGGCTACAGTGCAAGTCTCCCTCGCTTCTCTCCTGT ACCACTTTGAGTGGGCCCTTCCCGCTGGAGTAAGGGCAG AGGATGTCAACCTGGATGAGACTTTCGGTCTTGCCACGC GTAAAAAGGAACCACTGTTCGTCGCAGTTCGCAAGTCAG ACGCCTATGAATTCAAGGGCGAAGAGC ITAGCGAAGTT AGGGI GGAGAGTATATGATGG TACTGCI AT TC AATCI GG CATTGGACAGTGAGTTTGAGTTTGATGTAACTTGTCTATT CTATGATGTATGGTCTTTTTGTTCTATAGTTGGAAATCGG AATGATCTCAAATCTTGAATAAATATAAAAAGGATAATA CTCACATCCATCACAACCTTACAAGGTTAATTCCGAGCT ATATTCCACCGACACAAA TAGGCAG TATCI TCTCTCGCC AGAGAATCGCGATAITATTGGCATGCAAATAACGAIAA CTGTCTCCAGAAGGTAAATATATGCAGTCTTGAAACCTA AACAAGGCTTCTCAATCCATTGATTCTCAGTGATATCCT CTTACGAGAATAGGGAAGGTATATACCGTTGCTGGGGTT GCGTTTAGGCTAAATTCGTATGATAGTTGAATCTGTTTG GATGGG TATGCTGTGGT IT IATTTGGC ATAI C ATIAGGG TTTGACCTGGTGGTTGCTCGCGACTATAGAATGAAGTGG AATGGGGGAAAGAAAGCAGGAAAAACAGCTTGGAGAG GAGCTATATCATAAAATATTATACGATTGTGGGCATAAT GTCAAATGTATTAGGTCTAGGTTTAAGTTTATGTTAGTAT ATCATGGAGATATAGTAAAAGGGAACTCTTTCCACTGAT GTATGTTCTCI TCTC AC AAAGCCAGAAGGGTAI AGTGAT ATCCCGAGCCTGATAGCGTATTAGGATTCAG 1111 GGTG AGATACCATAAGTTTTTCATACACAAACCGATGTCTAGA GAGAGGGGAAGAGGGGTAGGAGGGGAAGGGCGAGTGT TGCCGCCTTGCCTAACACAAGACAGGTATACGTACTACT GACCAGCTACAI GTATCAATAC AGTAATGG TCCTCAAGA A I’TCG rGTCCGTTCTACAAGATCATCCCTGGA ITCI CCCT CTGTGTGGATGCATTTCGATACGGAGCCGTAGAGGGATG TAATGCGTACTTCCTTAGTCACTTCCACAGCGACCATTA CATCGGCCTGACGGGGTCGTGGCGCCATGGACCAATCTA CTGCAGCAGACCTACGGCCAACTTGGTGTGCCAGCAACT GAAGGTCGACCGGAAGTGGCITGTACCACITGAGITCGAGCGGAAGACGGAAATCCCGGAIACAGGAGGAGCGCAGGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TGACTTTGATCGAGGCTAATCATTGTCCTGGGAGCGCCATCTTTCTCTTCGAGAAATCAATGGGATCGGGTCCCTCGC AGAGAACACATCGTGTCCTCCACTGTGGTGACTTTCGCG CCTCGCCGCTTCATGTGCAACATGCCCTTCTCCGCCCGG AGATTGCTGACCCCGCAACCGGCAAGGCTCGCCAGCAA CGAATCGATGCCTGCTATCTGGACACTACATATTTGAGC CCCAAGTATGCATTCCCTGGCCAAGAAGATGTCATACAA GCCTGCGCAGAACTTTGCGTTGAGCTCGATGGGGACGCC AACGACACCAATGGACGAGCGTTTGGACGACCAGTCAA TGGAAAAAGCGGAATGCTGAGCAAGTTTGTTACGGCTGT GACTGGATCCCGCCCGTCTCCGACGCAAGACAGCCGCCC CCCTGGCCGGCTATTGGTAGTAATAGGGACGTACAGCAT CGGCAAAGAACGCATCI GTCTGGGGA TCGC ACGGGCAT TGAAGAGCAAGATCTACGCGACGCCAGCTAAGCAGCGC GTCTGTGCGTGCCTCGAGGATGCTGAGCTGTCATCGCTG CTGACAGACGATCCCACGGAGGCGCAGGTGCATATGCA AACGCTATTCGAGATCCGGGCGGAAACGCTGGCGGATT ACCTGGACTCGATGAAGCCGCACTTCACGCGGGTGGTGG GATTTCGACCAACCGGGTGGACGIATCGCCCGCCAGCTG GCCGAA TGCTGGAC AACCC ACCGG TGTCGGTGG TGCTCA ATTCGGCACATTGGAAGACGCCCTTTTCTGCGAAAGACC TGGTGCCACAGCGAGGGAGTACGCGGGAAAGCGCATGC TTTGGAGTGCCGTACAGTGAGCACAGCTCATTTCGGGAG TTGAGCATGTTCTGCTGCGCACTCCGGATCGGACGGGTG A I CC CGAC AGTGAACGTAGGTAGCCGGAAAAGTCGGGA GCGCATGAAGGCGTGGAT I GAGCGA I GGGAGGCGGAGA AGCGGAAGAATGGGTTGTACCGCGTGGAGGGGAATAGC TGGTAGGGGATAGATAGACGGCTCTACCAACGTCCAAA GTACTGCTGGAACACAAGGATCAGCAGGATCAGAAGGA TTGCGAAAGACGGGTCGGAACATGTTGCCTAATAGAGT AAGTAAGGAGTTGGTGCTGTAAC TAGTC AC AAGT TACGA TTTGTGTACATAACATCATTAGTCATGGAGATCAATTGC CTTTATGCTTCCGTAACTCTCGCCTCCCCGGAGTCACGA GATCAATAGAAACCACCGCCGTTGACCATTCGCGATGCT CTCACTGGCTGTATGCTGTCGATAGCCATGGAGCCGTTC AAAGTATGGACCCTTTGGGTGAGGATCTCCCTCCAACCC CACGGGACGTACACGAACAACCGAGCAGAGGCGGGGGA GGGCAAAGAGGCCGGCGCTGCAAATCGGCTGGCAGATC AGTCGCGGCTCAGCAGAGACTCCCGATTTTCCCTTCCGT TGCCTGGCTTTGCCTCGGGGTTCGAGAGGAGCCCGTCTG CCATAAATAAGCCTGCACTTCAACTCAAAAAAAAGGGA GATGACAGATCAACCACTTTCTCGACAAGAAACACTCTT C ACC CAI GGCGATACTTGAGTGAAGTAAGTGTGACTGTG ACTGATATTATTTTCTTCTTCAGCCATCC 1111 TCGATAT ATTACCTTATAGTTGCTTATTTCATTTCGGAGGTAAGATG GTCTCCTTGGCACCCACATTCCCGGCTGCACTTGGCGGC TGCGGAATTGCTTCTCCTGGCTGCATTTGCCGGTGTTAAC TICCGAACTCACCAGCTICCrCCCCTCCCCCCACAAAAA CAA rCATGGGATCCTCI GAAGACCAGGCI TA I’CGGTTGC TGAACGACTACGCCAATGGCTTCATGGTCTCCCAAGTGC TCTTCGCCGCTTGTGAGCTCGGGGTTTTTGACCTCCTCGC GGAGGCGCCCGGACCTCTCGATGTTGCTGCCGTCGCTGC TGGAGTTCGAGCATCGGCACATGGCACGGAGCTACTTTT GGATATCTGTGTTAG CCTGAAGCTACTCAAGGTCGAGACGCGTGGTGGGAAGGCGTTCTACCGCAACACCGAACTTAWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GCTCAGATTATCTCACTACAGTGTCTCCCACATCACAAT GCTCCATGCTTAAGTACA TGGGCAGAACATCCTACAGAT GCTGGGGCCACCTAGCAGATGCTGTCCGCGAAGGACGG AATCAGTACCTTGAAACTTTCGGTGTACCTGCCGAGGAG TTATTCACCGCGATATACCGTAGTGAGGGTGAGCGCCTT CAATTTATGCAGGCCCTGCAAGAGGTCTGGTCGGTCAAC GGCCGATCAGTGCTGACGGCCTTCGATCTCAGTGTATTT CCGCTTATGTGCGACCTGGGAGGGACCTGGATCAAATTG GAGACCATCATCTTGAGCAAGCTCTCCCAAGGTCAGAAG ACCAAGCACAGGGTTTTTTCTCTCATTGGAGGTGCCGGA GCACTGGCGAAGGAGTGCATGTCGCTGTACCCAGGCTGC AAGATCACTGTCTTCGACATTCCAGAGGTGGTGTGGACA GCCAAGCAGC ACTTITCCT TTCAGGAGGAAGAGCAGATC GACT ITCAAGAAGGCGACTTCTTC AAAGACCCGCTGCCC GAAGCCGATCTATATATCCTCGCACGTGTATTACATGAC TGGG CAGATGG CAAATGTTCG CATCTGTTGG A ACGA ATA TATCATACGTGTAAACCAGGTGGTGGCATTCTGGTCATC GAGAGTCTGCTCGACGAAGATCGCAGAGGCCCGTTGTTG ACTCAACTGTATAGCTTGAACATGCTCGTGCAGACCGAA GGGCAGGAAAGGACTCCTACCCACTACCACATGCTATTA AGTTCTGCCGGGTTCCGCGATTTCCAGTTCAAGAAGACA GGAGCTATTTATGATGCCATTTTGGCGCGGAAACTAGTA CAGCAGAAGAATCTCTCTCCGCTGTTGCTTCAGTGTCTG CCATGCATTAACTTCATCCTACTGTCCTACCCGCAGTACC CATTCACATTTGCGGCAGATACCAGGTTGTTTTTCTATTCC CTCGGTTCT I’CAGTTCT TCAGATA1TACAT TACTCGAGAA ATTGGCGGCGATGCAGGAGTTTGGTTGGTTTTAATTGTT TCAGTCTCCTTGACCTGATTTGTATGACATGCAATGTTTC GACGGAAGACTATCTCGGTGAATATACGTCATGAATCAT GCCCTCGGTCGCTCACTGTTCCTTTACGGATATGTGTACT CCGGCAAGCCGCGGGGTCGCGGTCGTTTGTACGGCAGCTTCTACTTGCTTGCACAGGGAGCTCTCTGGGGCTTGACGT CTTTTGGAGTTGCGAGGGAGTTGATTTCCTACTTCTAAGT TTGGACTGAATCCGTGGTGTGATTGAGGTGATTGGCGAT GTTTGGCTATACCAGCTATATGTAATAATCTCTACTGTAT ACTACTATTCAACGCATTTTACTATGCGTGCTGCTAGGG TCGGCAATGACAATGGCAATCTGACTGACGTGGTCTATT TCTCCATGTGCAGCAGGGAATACGAGCTCCAATGGACCT CGGGAGTGGCACAGTCAATGGCAAGGAAACTCCGCCTT TGCAGGTGTGGCTGAACCCCACGGGTCGGAGGCGGAGC AATCCACCCCCGATGTGGCTGGTGCGTGGAGGGGCTCGC GATGATTTTACTGAGCTTGCTTTTCTTGTCGACATTGAAC AT IGTCCTTGG I’CTTCC ITCAGATTTAAGGGTCAG I’CACT GCTACATTTTTCAGTAGTATCCGCGCACGTCTCTGGATTT ACGAATCAGGGTCCACCAGTCGAAACTTCGAACTACTCT CATTATACAATCCTCTTTCCATTCCCGCATTAACCCCTCC ATCAACACCATGTCCTCCAAGTCGCGATTGACCTACACT GCCCGTGCCAGCAAGCATCCCAATGCTCTGGCGAAGAG GCTGTTCGAGATTGCCGAGGCCAAGAAGACCAATGTGA CTGTCTCGGCTGACGTTACCACCACTAAGGAGCTACTAG ATCTTGCTGACCGTAGGCCGACCCGCTACTCTGCCTGAT TATGCTGCATGCAAACTTATTAACGGTGATACCGGACTG CAGGTCTCGGTCCCTACATTGCCGTGATCAAAACCCACA TCGATATCCTCTCTGATTTCAGCAACGAGACCATTGAGGGACTTAAGGCTCTCGCGCAGAAGCACAACTTTCTCATCTWSGR Docket No. 66180-701.601SEQ ID NO. Vector SequenceTCGAGGACCGCA AGTTCA TTG AC ATCGGCA A CA CGGTCC AGAAGCAATACCACGGCGGTACCCTCCGTATCTCGGAAT GGGCCCACATCATCAACTGCAGCATTCTCCCTGGTGAGG GTATCGTCGAGGCTCTCGCTCAGACGGCGTCTGCACCGG ACTTCGCCTACGGCCCCGAACGCGGTCTGTTGATCTTGG CAGAGATGACCTCTAAGGGCTCCTTGGCTACCGGCCAGT ACACTACTTCCTCGGTCGATTATGCCCGGAAATACAAGA ACTTCGTTATGGGATTCGTGTCGACGCGCGCGTTGGGTG AGGTGCAGTCGGAAGTCAGCTCTCCTTCGGATGAGGAG GACTTTGTGGTCTTCACGACTGGTGTGAACATTTCTTCCA AGGGAGATAAGCTTGGTCAGCAGTACCAGACGCCCGGA TCGGCTATCGGCCGGGGTGCTGACTTCATTATCGCGGGT CGCGGTATCTACGCCGCGCCGGATCCGGTGCAGGCTGCG CAACAGTATCAGAAGGAGGGGTTGGGAAGCCTACCTGGC CCGTGTCGGCGGAAAACTAATACTATAAAAGGAGGATC GAAGTTCTGATGGTTATGAATGATATAGAAATGCAACTT GCCGCAACGGATACGGAAGCGGAAACGGACCAATGTCG AGCACGGGTAGTCAGACTGCGGCATCGGATGTCCAAAC GGTATTGATCCTGCAGGCTACTATGGTGIGGCACAAGGA I C AATGCGGTACGACGA IT TGATGC AGATAAGC AGGCTG CGAAGTAGTAACTCTTGCGTAGAGAAAATGGCGACGGG TGGCTGATAAGGGCGGTGATAAGCTTAATTGTCATCGCA GATAAGCACTGCTGTCTTGCATCCAAGTCAGCGTCAGCA GAAATACGGGACTTCCGAAAGTATATGGCAAAATTAAA GAACTTGACTCTCCAGCAATGTTTTGCCCTGACCGTCGCTAAAACGTTACTACCCCTATACCCGTCTGTTTGTCCCAGC CCGAGGCATTAGGTCTGACTGACAGCACGGCGCCATGC GGGCTTGGGACGCCATGTCCGTCGCGTGATAAGGGTTGA TCCATGCAGCTACTATCCTTCCATCGTTCCATTCCCATCC TTGTCCTATCTCCATCCTTGAAACTTTACTAGTTTAGTTG GATGCTCGAGCTTGCTCTCGGCTACTCCGTCGGCGGCCG CCGGCCGCGATATCCGGTGATGACGGTGAAAACCI’CTGA CACATGCAGCTCCCGGAGACGGTCACAGCTTGTCTGTAA GCGGATGCCGGGAGCTCGAGCAGACAAGCCCGTCAGGG CGCGTCAGCGGGTGTTGGCGGGTGTCGGGGCTGGCTTAA TGTGAAATTCCACAGCCTGGGGTGCCTAATGAGTGAGCT AAC rCACATIAATTGCGITGCGCTCACIGCCCGC ITI’CCA GTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAATCGG CCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCT CTTCCGCTTCCTCGCTCACTGACTCGCTGCGCTCGGTCGT TCGGCTGCGGCGAGCGGTATCAGCTCACTCAAAGGCGGT AATACGGTTATCCACAGAATCAGGGGATAACGCAGGAA AGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAAC CGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTC CGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGT CAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCA GGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTT CCGACCCTGCCGC ITACCGGATACCTGTCCGCC TTTCTCC CTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTG TA GGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGG GCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCG CCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAA GACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACA GGATTAGCAGAGCGAGGTAI GTAGGCGGTGC IACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence ACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACC TTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAA ACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAG CAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCC TTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGA AAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAA AAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAG TTTAAATCAATCTAAAGTATATATATGAGTAAACTTGGTC TGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTC AGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTC CCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCA TCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGC TCACCGGCTCCAGATTTATCAGCAATAAACCAGCCAGCC GGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATC CGCCTCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAG AGTAAGTAGTTCGCCAGTTAATAGTTTGCGCAACGTTGT TGCCATTGCTACAGGCATCGTGGTGTCACGCTCGTCGTT TGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAG GCGAGTTACATGATCCCCCATGI TG TGCAAAAAAGCGGT TAGCTCCTTCGGTCCTCCGATCGTTGTCAGAAGTAAGTT GGCCGCAGTGTTATCACTCATGGTTATGGCAGCACTGCA TAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCT GTGACTGGTGAGTACTCAACCAAGTCATTCTGAGAATAG TGTATGCGGCGACCGAGTTGCTCTTGCCCGGCGTCAATA CGGGATAA TACCGCGCCACA TAGCAGAAC IT TAAAAGT GCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTC AAGGATCTTACCGCTGTTGAGATCCAGTTCGATGTAACC CACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTC ACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAA TGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTT GAATACTCATACTCTTCCTTTTTCAATATTATTGAAGCAT TTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGA ATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCA CATTrCCCCGAAAAGTGCCACCTGACGTCTAAGAAACCA TTATTATCATGACATTAACCTATAAAAATAGGCGTATCA CGAGGCCCTTTCGTC36 pyrG_5 UTR PfraA ATGCGACCGTAGAGCAGTGCAAGACCAACGTAAGCCAA:: tTS / rt'TA: T cgrA:p CCTCACACAAACAGGATTCCTCGAGCTAACATACATTCC yrGJ' UTR GAACCGTGCAGCCCAAGGCCGAGCAGTTCAACTGCGCT CAGCGCGCTCA TGCCAACT TCCTTGAGAACTCCAGCCAA ACTATGCTCTTCCTCCTGGTAGCTGGACTGAAGTACCCC CAGTTGGCGACTGGCCTCGGAAGCATCTGGGTCCTCGGT CGCTCACTGTTCCTTTACGGATATGTGTACTCCGGCAAG CCGCGGGGTCGCGGTCGTTTGTACGGCAGCTTCTACTTG CTTGCACAGGGAGCTCTCrGGGGCTTGACGrCTTTTGGA GT rGCGAGGGAGTrGATTTCCTACTTC TAAGI T TGGACT GAATCCGTGGTGTGATTGAGGTGATTGGCGATGTTTGGC TATACCAGCTATATGTAATAATCTCTACTGTATACTACTA TTC AACGC A U l i ACTATG CGTGCTGCTAGGGTCGGCA A TGACAATGGCAATCTGACTGACGTGGTCTATTTCTCCAT GTGCAGCAGGGAATACGAGCTCCAA IGGACCTCGGGAG TGGCACAGTCAATGGCAAGGAAACTCCGCCTTTGCAGGT GTGGCTGAACCCCACGGGTCGGAGGCGGAGCAATCCAC CCCCGATGTGGCTGGTGCGTGGAGGGGCTCGCGATGATTTTACTGAGCTTGCTTTTCTTGTCGACATTGAACATTGTCCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TTGGTCTTCCTTCAGATTTAAGGGTCAGTCACTGCTACAT TTTTCAGTAGTATCCGCGCACGTCTCTGGATTTACGAATC AGGGTCCACCAGTCGAAACTTCGAACTACTCTCATTATA CAATCCTCTTTCCATTCCCGCATTAACCCCTCCATCAACA CCTCGCGCGTTTAAGCTTCCCTCGGCTGGTCTGTCTTACA CAAGATCACACGCTTTGATCTACAATCACCCCAAGTATG GACCTCAGGCCCACCAACGCCCAGTGGAGGCACGTATCT I GCGCCCCAGAGGACGGAAGGGCAAGAACACGAAGGCC ATTGCAGGTGTGGCTGGTATTGCCGTGGAAGACTTGAAT ACTGTCACCTTTACCGAGCAGGACTCTCCGGCCGGCCTT GCCTACTTTGACGCCTCTATCCCCGGTGGTGCTAAGTAC TGGGCCACCCCTATCCGGGCCTTTGTCGACTCGGAAGGC AAGATTGGCCTGGCTTCTTACCGCGCTAGCGCTACTGCT AAAGCCCCTTACGGAATCGATAGCCAGAAGAAGCCCGG ATCGTACAGCATCTCTGACGTGGCTCGCGGCGACCAGCG CGTGGTCCCGAGACTGGATAGACAGCGGAACGCCGCAG CGGAGACTGAGGAGGTTGCGCGTAACCTCATGAAGAGC CTTGGCTCCTAGAATACAGGTGTTTCAGTCCCAAGCAAT TTTTGTCTCATGTGTCAGACATGTTCTATCTTCCACTTAG AGAGCTTTGCTGTA TGATTAGGTT 1TTGGATGGTAAATG TATAGTTATTTTCGCACTTGTTCTCATTTGTTTGTGATATA AGCCGG CTAC ATCTCATTCTAAGTATAA ATTAAATTG C AATTTCAAAGACGTCTCAGTAATTACTGATCACTATAAA CCTGGTTTTGCCATACCGTAAGGCAACAGCCATCTTCAT AACTAACTAGTCCGTIACATATGAAATACATAAATGGCG CTTAATAATCCAGCGCAACGCCCGACCGCITIGACAGGI AAGCGCACGTGACATTAAATAGGGCATCCACATCAGGGTAGA TACGCATCACATGACCCGCACATCCTAAGCGAGG GACGGGTAAGTTGAAGGAGCGAAAGACATCAGAACATC TTGGACGGTTTTTCGAACATCCATCCAGCCAGCAACAAA CCGCCAAAGAATTCACCATGTCTAGATTAGATAAAAGTA AAGTGA I’TAAC AGCGC ATTAGAGCTGC ITAATGAGGTCG GAATCGAAGGTTTAACAACCCGTAAACTCGCCCAGAAG CTAGGTGTAGAGCAGCCTACAITGTATTGGCACGTGCGC AACAAGCAGACTCTTATGAACATGCTTTCAGAGGCAATA CTGGCGAAGCATCACACCCGTTCAGCACCGTTACCGACT GAGAGT TGGCAGCAG ITI’CTCCAGGAAAATGCI CTGAGT TTCCGTAAAGCATTACTGGTCCATCGTGATGGAGCCCGA TTGCATATAGGGACCTCTCCTACGCCCCCCCAGTTTGAA CAAGCAGAGGCGCAACTACGCTGTCTATGCGATGCAGG GTTTTCGGTCGAGGAGGCTCTTTTCATTCTGCAATCTATC AGCCATTTTACGTTGGGTGCAGTATTAGAGGAGCAAGCA ACAAACCAGATAGAAAATAATCATGTGATAGACGCTGC ACCACCATTATTACAAGAGGCATTTAATATTCAGGCGAG AACCTCTGCTGAAATGGCCTTCCATTTCGGGCTGAAATC ATTAATATTTGGATTTTCTGCACAGTTAGATGAAAAAAA GCATACACCCATTGAGGATGGTAATAAACCAAAAAAGA AGAGAAAGCTAGC AGTGTC AGTGAC ATTTGAAGATGI G GCTGTGCTCTTTACTCGGGACGAGTGGAAGAAGCTGGAT CTGTCTCAGAGAAGCCTGTACCGTGAGGTGATGCTGGAG AATTACAGCAACCTGGCCTCCATGGCAGGATTCCTGTTT ACCAAACCAAAGGTGATCTCCCTGTTGCAGCAAGGAGA GGATCCCTGGGAGGGCAGGGGAAGTCTTCTAACATGCG GGGACGTGGAGGAAAATCCCGGCCCCATGTCTAGACTGGACAAGAGC AAAGTCA TAAACGGCGCTC IGGAATTAC TWSGR Docket No. 66180-701.601SEQ ID NO. Vector SequenceCAATGGAGTCGGTATCGAAGGCCTGACGACAAGGAAAC TCGCTCAAAAGCTGGGAGTTGAGCAGCCTACCCТGTACT GGCACGTGAAGAACAAGCGGGCCCTGCTCGATGCCCTG CCAATCGAGATGCTGGACAGGCATCATACCCACTTCTGC CCCCTGGAAGGCGAGTCATGGCAAGACTTTCTGCGGAAC AACGCCAAGTCATTCCGCTGTGCTCTCCTCTCACATCGC GACGGGGCTAAAGTGCATCTCGGCACCCGCCCAACAGA GAAACAGTACGAAACCCTGGAAAATCAGCTCGCGTTCCT GTGTCAGCAAGGCTTCTCCCTGGAGAACGCACTGTACGC TCTGTCCGCCGTGGGCCACTTTACACTGGGCTGCGTATT GGAGGAACAGGAGCATCAAGTAGCAAAAGAGGAAAGA GAGACACCTACCACCGATTCTATGCCCCCACTTCTGAGA CAAGCAATTGAGCTG ITCGACCGGCAGGGAGCCGAACC TGCCTTCCTTTTCGGCCTGGAACTAATCATATGTGGCCTG GAGAAACAGCTAAAGTGCGAAAGCGGCGGGCCGGCCGA CGCCCTTGACGATTTTGACTTAGACATGCTCCCAGCCGA TGCCCTTGACGACTTTGACCTTGATATGCTGCCTGCTGAC GCTCTTGACGATTTTGACCTTGACATGCTCCCCGGGTAA CTAGTACAGCAGAAGAATCTCTCTCCGCTGTTGCTTCAGT GTCTGCCATGCATTAACTTCATCCTACTGTCCTACCCGC AGTACCCATTCACATTTGCGGCAGATACCAGGTTGTTTT CTATTCCCTCGGTTCTTCAGTTCTTCAGATATTACATTAC TCGAGAAATTGGCGGCGATGCAGGAGTTTGGTTGGTTTT AATTGTTTCAGTCTCCTTGACCTGATTTGTATGACATGCAATGTTTCGACGGAAGACTATCTCGGTGAATATACGTCAT GAATCATGCGGCCAAGGAGGATCGAAGTTCTGATGGTTATGAATGATATAGAAATGCAACTTGCCGCAACGGATAC GGAAGCGGAAACGGACCAATGTCGAGCACGGGTAGTCA GACTGCGGCATCGGATGTCCAAACGGTATTGATCCTGCA GGCTACTATGGTGTGGCACAAGGATCAATGCGGTACGA CGAT ITGATGCAGA TAAGCAGGC TGCGAAG TAGTAACTC TTGCGTAGAGAAAATGGCGACGGGTGGCTGATAAGGGC GGTGATAAGCTTAATTGTCATCGCAGATAAGCACTGCTG TCITGCATCCAAGTCAGCGTCAGCAGAAATACGGGACTT CCGAAAGTATATGGCAAAATTAAAGAACTTGACTCTCCA GCAATGTTTTGCCCTGACCGTCGCTAAAACGTTACTACC CCTATACCCGTCTGTTTGTCCCAGCCCGAGGCATTAGGT CTGACTGACAGCACGGCGCCATGCGGGCTTGGGACGCCATGTCCGTCGCGTGATAAGGGTTGATCCATGCAGCTACT ATCCTTCCATCGTTCCATTCCCATCCTTGTCCTATCTCCA TCCTTGAAACTTTACTAGTTTAGTTGGATGCTCGAGCTTG CTCTCGGCTACTCCGTCCAATGGATAAGACCCCGATGCCGGTCCTCATTGGTCTCCAGCTGGTATCGCCCCAACCTTC GTGTGATCGCCTCTCTGCTTCCCCTCATCATCATTACTAA CTAGTACATCCAAAAGCCATCCCAGTGCTTCCCCTCACC CTTGCCCAAGACATTCCAAGTGGGCCTTCGGCTGGAAAA CATGGACCCATTGGTTCCATCGATAAGCTAGCTCCTCGT CCGTTACCCCAGA ITGATACCAGAI AACATTGACCAGCG GCI TA TCACCGAGGTCI GCGGGTGAGACCCCCCCTGCGA CAAGTTAGATAAAAGAAACTCGCCTCATTGTGCTTCCGA TGGGGTCGGATGACGAGCCTTCGGAAAGAGCTGGCGCC TCTGGTGATGACGGTGAAAACCTCTGACACATGCAGCTC CCGGAGACGGTCACAGCTTGTCTGTAAGCGGATGCCGG GAGC AGACAAGCCCGTCAGGGCGCGTCAGCGGGTGT TGGCGGGTGTCGGGGCTGGCTTAATGTGAAATTCCACAGCCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCG TTGCGCTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCG TGCCAGCTGCATTAATGAATCGGCCAACGCGCGGGGAG AGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTC ACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCG GTATCAGCTCACTCAAAGGCGGTAATACGGTTATCCACA GAATCAGGGGATAACGCAGGAAAGAACATGTGAGCAAA AGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGT TGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGC ATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAAC CCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGA AGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTA CCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGT GTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACC CCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTA TCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCC ACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGA GGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGC CTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCT GCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTG GTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAG ATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAA AGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGC TTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTC GTTCATCCATAGTTGCCTGACTCCCCGTCGTGTAGATAA CTACGAI ACGGGAGGGCTTACCA TCTGGCCCCAGTGCTG CAA IGATACCGCGAGACCCACGCI CACCGGC I’CCAGATT TATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGC AGAAGTGGTCCTGCAACTTTATCCGCCTCCATCCAGTCT ATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCA GTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGC ATCGTGGTGTCACGCTCGTCGTTTGGTATGGCTTCATTCA GCTCCGGTTCCCAACGATCAAGGCGAGTTACATGATCCC CCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTC CGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCAC TCATGGTTATGGCAGCACTGCATAATTCTCTTACTGTCAT GCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGTACTC AACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGA GTTGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGC CACATAGCAGAACTTTAAAAGTGCTCATCATTGGAAAAC GTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGT TGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACT GATC I’TCAGCA rCTITrACTFTCACCAGCGTTTC IGGGIG AGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGA ATAAGGGCGACACGGAAATGTTGAATACTCATACTCTTC CTTTTrCAATATTATTGAAGCATTTATCAGGGTTATTGTC TCATGAGCGGATACATATTTGAATGTATTTAGAAAAATA AACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGC CACCTGACGTCTAAGAAACCATIATTATCATGACATTAACCTATAAAAATAGGCGTATCACGAGGCCCTTTCGTCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence37 TRE- TCGCGCGTTTGGTACCGAGCTCGACTTTCACTTTTCTCTA Pmin::psiH:: T trpC TCACTGATAGGGAGTGGTAAACTCGACTTTCACTTTТCT::pyrG wt CTATCACTGATAGGGAGTGGTAAACTCGACTTTCACTTT TCTCTATCACTGATAGGGAGTGGTAAACTCGACTTTCACTTTTCTCTATCACTGATAGGGAGTGGTAAACTCGACTTTCACTTTTCTCTATCACTGATAGGGAGTGGTAAACTCGACTTTCACTTTTCTCTATCACTGATAGGGAGTGGTAAACTCGACTTTCACTTTTCTCTATCACTGATAGGGAGTGGTAAACT CGACCTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGA TCGCCTGGAGACGCCATCCACGCTG 1111 GACCTCCATA GAAGACACCGGGACCGATCCAGCCTCCGCGGCCCCGAA TTGCCCATCTTCAGTATATTCATCTTCCCATCCAAGAACC TTATTTCCCCTAAGTAAGTACTTTGCTACATCCATACTCCATCCTTCCCATCCCTTATTCCTTTGAACCTTTCAGTCG AGCTTTCCCACTTCATCGCAGCTTGACTAACAGCTACCC CGCTTGAGCAGACATCACATGATCGCCGTTCTGTTTTCTT TTGTCATCGCAGGCTGCATCTACTACATTGTGTCTCGGA GGGTGCGCCGCTCCCGATTGCCCCCGGGACCCCCAGGTA TCCCCATTCCA IT rATAGGCAACATGTTTGACA I’GCCGG AGGAAAGCCCATGGC rCACCTTCCTTCAGTGGGGCCGCG ACTACAACACCGACATCCTGTATGTCGACGCGGGAGGTA CTGAGATGGTCATTCTCAACACTCTAGAGACCATCACTG ACCTTCTGGAGAAACGTGGGTCGATCTATTCCGGCCGTC TTGAATCGACCATGGTCAACGAGTTGATGGGCTGGGAGT TCGATТTAGGGTTCATCACCTATGGCGATCGGTGGAGAGAGGAGCGGCGCATGTTCGCTAAGGAATTCTCCGAGAAG GGGATCAAGCAATTCCGACATGCACAGGTCAAGGCAGC GCATCAGTTGGTACAGCAGCTGACGAAGACGCCAGACA GGTGGGCTCAGCACATAAGGCACCAGATTGCGGCCATG AGTTTGGATATAGGTTACGGAATTGATCTAGCCGAAGAC GACCCCT GGCTGGAGGCCACTCATC TGGCGAATGAGGG ACTCGCAATTGCTTCTGTGCCTGGGAAATTCTGGGTCGA CTCCTTCCCTTCCCTTAAATACCTCCCCGCATGGTTCCCC GGCGCGGTTTTCAAGCGGAAGGCCAAGGTCTGGCGTGA AGCTGCTGATCACATGGTGGATATGCCGTACGAGACGAT GCGAAAACTAGCACCACAAGGCCTGACAAGACCAAGCT ATGCCAGTGCTCGACTCCAAGCGATGGATTТGAATGGAG ATCTTGAACACCAAGAGCATGTCATCAAGAACACCGCC GCAGAGGTGAATGTTGGTGGTGGGGATACCACTGTGTCG GCTATGAGCGCTTTTATCCTCGCAATGGTTAAATATCCC GAGGTCCAACGAAAGGTTCAAGCCGAACTCGACGCTTT GACGAACAACGGTCAGATACCAGACTATGACGAAGAAG ACGATTCGCTGCCGTACCTCACGGCTTGTATCAAAGAGC TCTTTCGCTGGAACCAGATCGCCCCTCTGGCCATTCCGC ACAAGCTGATGAAGGATGATGTGTACCGTGGATATTTGA TTCCCAAGAATACGCTTGTGTTTGCCAACACATGGGCCG TGCTTAATGACCCTGAAGTGTATCCGGATCCAAGTGTCT TCAGACCTGAACGTIACCTAGGCCCTGATGGAAAGCCTG ACAACACAGTTAGGGATCCCCGCAAAGCAGCCITrGGCT ACGGTCGTCGCAATTGCCCGGGTATTCATCTTGCCCAAA GCACAGTGTGGATCGCTGGTGCGACTCTCTTGTCAGCGT TCAACATCGAGCGCCCGGTTGATCAGAATGGCAAGCCC ATCGATATTCCTGCGGACTTCACCACCGGGTTCTTCCGG CACCCTGTCCCGTTCCAGTGTCGGTTTGTTCCCAGAACAGAACAAGTCTCTCAGTCTGTATCAGGGCCATAAGGATCCWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence ACTTAACGTTACTGAAATCATCAAACAGCTTGACGAATC TGGATAI AAGA TCGTTGGTGTCGAI GTCAGCI CCGGAGT TGAGACAAATGGTGTTCAGGATCTCGATAAGATACGTTC ATTTGTCCAAGCAGCAAAGAGTGCCTTCTAGTGATTTAA TAGCTCCATGTCAACAAGAATAAAACGCGTTTCGGGTTT ACCTCTTCCAGATACAGCTCATCTGCAATGCATTAATGC ATTGGACCTCGCAACCCTAGTACGCCCTTCAGGCTCCGG CGAAGC AGAAGAATAGCTTAGC AGAGTCTATTTTC A TTT TCGGGAGACGAGATCAAGCAGATCAACGGTCGTCAAGA GACCTACGAGACTGAGGAATCCGCTCTTGGCTCCACGCG CCTCGGTCGCTCACTGTTCCTTTACGGATATGTGTACTCC GGCAAGCCGCGGGGTCGCGGTCGTTTGTACGGCAGCTTC TACTТGCTTGCACAGGGAGCTCTCTGGGGCTTGACGTCTTTTGGAGTTGCGAGGGAGTTGATTTCCTACTTCTAAGTTT GGACTGAATCCGTGGTGTGATTGAGGTGATTGGCGATGT TTGGCTATACCAGCTATATGTAATAATCTCTACTGTATAC TACTATTCAACGCATTTTACTATGCGTGCTGCTAGGGTC GGCAATGACAATGGCAATCTGACTGACGTGGTCTATTTC TCCATGTGCAGCAGGGAATACGAGCTCCAATGGACCTCG GGAGTGGCACAGTCAATGGCAAGGAAACTCCGCCTTTG CAGGTGTGGCTGAACCCCACGGGTCGGAGGCGGAGCAA TCCACCCCCGATGTGGCTGGTGCGTGGAGGGGCTCGCGA TGATTTTACTGAGCTTGCTTTTCTTGTCGACATTGAACAT TGTCCTTGGTCTTCCTTCAGATTTAAGGGTCAGTCACTGC TACATTTTTCAGTAGTATCCGCGCACGTCTCTGGATTTAC GAATCAGGGTCCACCAGTCGAAACTTCGAACTACTCTCA TTATACAATCCTCTTTCCATTCCCGCATTAACCCCTCCAT CAACACCATGTCCTCCAAGTCGCGATTGACCTACACTGC CCGTGCCAGCAAGCATCCCAATGCTCTGGCGAAGAGGCT GTTCGAGATTGCCGAGGCCAAGAAGACCAATGTGACTG TCTCGGCTGACGTTACCACCACTAAGGAGCTACTAGATCTTGCTGACCGTAGGCCGACCCGCTACTCTGCCTGATTAT GCTGCATGCAAACTTATTAACGGTGATACCGGACTGCAG GTCTCGGTCCCTACATTGCCGTGATCAAAACCCACATCG ATATCCTCTCTGATTTCAGCAACGAGACCATTGAGGGAC TTAAGGCTCTCGCGCAGAAGCACAACTTTCTCATCTTCG AGGACCGCAAGTTCATTGACATCGGCAACACGGTCCAG AAGCAATACCACGGCGGTACCCTCCGTATCTCGGAATGG GCCCACATCATCAACTGCAGCATTCTCCCTGGTGAGGGT ATCGTCGAGGCTCTCGCTCAGACGGCGTCTGCACCGGAC TTCGCCTACGGCCCCGAACGCGGTCTGTTGATCTTGGCA GAGATGACCTCTAAGGGCTCCTTGGCTACCGGCCAGTAC ACTACTTCCTCGGTCGATTATGCCCGGAAATACAAGAAC TTCGTTATGGGATTCGTGTCGACGCGCGCGTTGGGTGAG GTGCAGTCGGAAGTCAGCTCTCCTTCGGATGAGGAGGAC TTTGTGGTCTTCACGACTGGTGTGAACATTTCTTCCAAGG GAGATAAGCTTGGTCAGCAGTACCAGACGCCCGGATCG GCTATCGGCCGGGGTGCTGACTTCATTATCGCGGGTCGC GGTATCTACGCCGCGCCGGATCCGGTGCAGGCTGCGCAA CAGTATCAGAAGGAGGGGTGGGAAGCCTACCTGGCCCG TGTCGGCGGAAAACTAATACTATAAAAGGAGGATCGAA GTTCTGATGGTTATGAATGATATAGAAATGCAACTTGCC GCAACGGATACGGAAGCGGAAACGGACCAATGTCGAGC ACGGGTAGTCAGACTGCGGCATCGGATGTCCAAACGGTATTGATCCTGCAGGCTACTATGGTGTGGCACAAGGATCAWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence ATGCGGTACGACGATTTGATGCAGATAAGCAGGCTGCG AAGTAGTAACTCTTGCGTAGAGAAAATGGCGACGGGTG GCTGATAAGGGCGGTGATAAGCTTAATTGTCATCGCAGA TAAGCACTGCTGTCTTGCATCCAAGTCAGCGTCAGCAGA AATACGGGACTTCCGAAAGTATATGGCAAAATTAAAGA ACTTGACTCTCCAGCAATGTTTTGCCCTGACCGTCGCTA AAACGTTACTACCCCTATACCCGTCTGTTTGTCCCAGCCC GAGGCATTAGGTCTGACTGACAGCACGGCGCCATGCGG GCTTGGGACGCCATGTCCGTCGCGTGATAAGGGTTGATC CATGCAGCTACTATCCTTCCATCGTTCCATTCCCATCCTT GTCCTATCTCCATCCTTGAAACTTTACTAGTTTAGTTGGA TGCTCGAGCTTGCTCTCGGCTACTCCGTCCGGTGATGAC GGTGAAAACCT CTGACACAI GCAGCTCCCGGAGACGGT CACAGCTTGTCTGTAAGCGGATGCCGGGAGCTCGAGCA GACAAGCCCGTCAGGGCGCGTCAGCGGGTGTTGGCGGG TGTCGGGGCTGGCTTAATGTGAAATTCCACAGCCTGGGG TGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCG CTCACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCA GCTGCATTAATGAATCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTTCCTCGCTCACTGA CTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATC AGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATC AGGGGATAACGCAGGAAAGAACATGTGAGCAAAAGGCC AGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTG GCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGAC AGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTC CCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGA TACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTT CTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGG TCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTC TTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGG CAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTAT GTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAAC TACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCT CTGCTGAAGCCAG ITACCTTCGGAAAAAGAG I’TGGTAGC TCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGT TTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAA GGATCTCA AGA AG ATCCTTTG ATC 11 11 CTACGGGGTCT GACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTG GTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCAT CCATAGTTGCCTGACTCCCCGTCGTGTAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAATGATACCGCGAGACCCACGCTCACCGGCTCCAGATТTATCAGCAATAAACCAGCCAGCCGGAAGGGCCGAGCGCAGAAGT GGTCCTGCAACTTTATCCGCCTCCATCCAGTCTATTAATT GTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCAGTTAATA GTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGG TGTCACGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGG TTCCCAACGATC AAGGCGAGTTACATGATCCCCC ATG ITGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCCGATCGTWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGT TA TGGCAGCACTGCATAA TTCTCTTAC TGTCATGCCATCC GTAAGATGCTTTTCTGTGACTGGTGAGTACTCAACCAAG TCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCT TGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGC AGAACTTTAAAAGTGCTCATCATTGGAAAACGTTCTTCG GGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCC AGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCA GCATCTTTТACTTTCACCAGCGTTTCTGGGTGAGCAAAA ACAGGAAGGCAAAATGCCGCAAAAAAGGGAATAAGGG CGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCA ATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAG CGGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCACCTGA CGTCTAAGAAACCATTATTATCATGACATTAACCTATAA AAATAGGCGTATCACGAGGCCCTTTCGTC38 PbphA:: RmIKTM:: T CTTTCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATT trpC:: PsucA::psiK: ACCGCCTTTGAGTGAGCTGATACCGCTCGCCGCAGCCGA: T cgrA:: PthiA:: CP ACGACCGAGCGCAGCGAGTCAGTGAGCGAGGAAGCGGA R:: T tefl::pyrG_wt AGAGCGCCCAATACGCAAACCGCCTCTCCCCGCGCGTTG (FIG. IF) GCCGATTCATTAATGCAGCTGGCACGACAGGTTTCCCGA CTGGAAAGCGGGCAGI GAGCGCAACGCAATTAATACGC GTACCGCTAGCCAGGAAGAGTTTGTAGAAACGCAAAAA GGCCATCCGTCAGGATGGCCTTCTGCTTAGTTTGATGCC TGGCAGTТTATGGCGGGCGTCCTGCCCGCCACCCTCCGG GCCGTTGCTTCACAACGTTCAAATCCGCTCCCGGCGGAT TTGTCCTACTCAGGAGAGCGTTCACCGACAAACAACAGATAAAACGAAAGGCCCAGTCTTCCGACTGAGCCTTTCGTTTTATTTGATGCCTGGCAGTTCCCTACTCTCGCGTTAACGC TAGCATGGATGTTTTCCCAGTCACGACGTTGTAAAACGA CGGCCAGTCTTAAGCTCGGGCCCCA A ATAATGA 11 11 AT TTTGACTGATAGTGACCTGTTCGTTGCAACAAATTGATGAGCAATGCTTTTTTATAATGCCAACTTTGTACAAAAAAGCAGGCTGCGGCCGCCGTGTCCGTTCTACAAGATCATCCC TGGATTCTCCCTCTGTGTGGATGCATTTCGATACGGAGC CGTAGAGGGATGTAATGCGTACTTCCTTAGTCACTTCCA CAGCGACCATTACATCGGCCTGACGGGGTCGTGGCGCCA TGGACCAATCTACTGCAGCAGACCTACGGCCAACTTGGT GTGCCAGCAACTGAAGGTCGACCGGAAGTGGCTTGTAC CACTTGAGTTCGAGCGGAAGACGGAAATCCCGGATACAGGAGGAGCGCAGGTGACTTTGATCGAGGCTAATCATTGT CCTGGGAGCGCCATCTTTCTCTTCGAGAAATCAATGGGA TCGGGTCCCTCGCAGAGAACACATCGTGTCCTCCACTGT GGTGACTTTCGCGCCTCGCCGCTTCATGTGCAACATGCC CTTCTCCGCCCGGAGATTGCTGACCCCGCAACCGGCAAG GCTCGCCAGCAACGAATCGATGCCTGCTATCTGGACACTACATATTTGAGCCCCAAGTATGCATTCCCTGGCCAAGAA GATGTCATACAAGCCTGCGCAGAACTTTGCGTTGAGCTC GATGGGGACGCCAACGACACCAATGGACGAGCGTTTGG ACGACCAGTCAATGGAAAAAGCGGAATGCTGAGCAAGT TTGTTACGGCTGTGACTGGATCCCGCCCGTCTCCGACGC AAGACAGCCGCCCCCCTGGCCGGCTATTGGTAGTAATAG GGACGTACAGCATCGGCAAAGAACGCATCTGTCTGGGG ATCGCACGGGCATTGAAGAGCAAGATCTACGCGACGCCAGCTAAGCAGCGCGTCTGTGCGTGCCTCGAGGATGCTGAWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GCTGTCATCGCTGCTGACAGACGATCCCACGGAGGCGCA GGTGCATATGCAAACGCTATTCGAGATCCGGGCGGAAA CGCTGGCGGATTACCTGGACTCGATGAAGCCGCACTTCA CGCGGGTGGTGGGATTTCGACCAACCGGGTGGACGTATC GCCCGCCAGCTGGCCGAATGCTGGACAACCCACCGGTGT CGGTGGTGCTCAATTCGGCACATTGGAAGACGCCCTTTT CTGCGAAAGACCTGGTGCCACAGCGAGGGAGTACGCGG GAAAGCGCATGCTTTGGAGI GCCGTACAG TGAGCACAG CTCATTTCGGGAGTTGAGCATGTTCTGCTGCGCACTCCG GATCGGACGGGTGATCCCGACAGTGAACGTAGGTAGCC GGAAAAGTCGGGAGCGCATGAAGGCGTGGATTGAGCGA TGGGAGGCGGAGAAGCGGAAGAATGGGTTGTACCGCGT GGAGGGGAATAGCTGGTAGGGGATAGATAGACGGCTCT ACCAACGTCCAAAGTACTGCTGGAACACAAGGATCAGC AGGATCAGAAGGATTGCGAAAGACGGGTCGGAACATGT TGCCTAATAGAGTAAGTAAGGAGTTGGTGCTGTAACTAG TCACAAGTTACGATTTGTGTACATAACATCATTAGTCAT GGAGATCAATTGCCTTTATGCTTCCGTAACTCTCGCCTCC CCGGAGTCACGAGATCAA TAGAAACCACCGCCGT TGAC CAI TCGCGAI GCTCTC ACI GGCTGTATGCTGTCGATAGC CATGGAGCCGTTCAAAGTATGGACCCTTTGGGTGAGGAT CTCCCTCCAACCCCACGGGACGTACACGAACAACCGAG CAGAGGCGGGGGAGGGCAAAGAGGCCGGCGCTGCAAAT CGGCTGGCAGATCAGTCGCGGCTCAGCAGAGACTCCCG A IT ITCCCTTCCGTTGCC TGGCT TTGCCTCGGGGTTCGAG AGGAGCCCGTC TGCCATAAATAAGCCI GCACTTCAACTC AAAAAAAAGGGAGATGACAGATCAACCACTTTCTCGAC AAGAAACACTCTTCACCCATGGCGATACTTGAGTGAAGT AAGTGTGACTGTGACTGATATTATTTTCTTCTTCAGCCAT CCTTTTTCGATATATTACCTTATAGTTGCTTATTTCATTTC GGAGG TAAGATGGI CTCCTTGGCACCCACA ITCCCGGCT GCACTTGGCGGC IGCGGAA ITGCI TCTCCTGGCTGCA IT TGCCGGTGTTAACTTCCGAACTCACCAGCTTCCTCCCCTC CCCCCACAAAAACAATCATGGAGAACTCATACTCTGCAC AGATGTACATTGATGAATTTGATCCTGTACACTACTACC AGACATACTATTCTTCGGGGAAAGGAGGTATCGCTAGA GAATGGAC AGACTTTGCCTIACAGAAI CTGCAI GAAACA TTTGGTCCAGGAGGTGTGAAAGGAGACATACTAATTGAC TTTGGAGCTGGACCCACAATTTATCAACTGCTCTCTGCTT GTGAAGTGTTCAACAGCATTATAACCTCTGATTTTCTTG AGCAAAACCGAGAGCAATTGGAAAAATGGCTGAGAAAG GACCCAGATGCCTTAGACTGGTCTCATTTTACCAAATAT GTGTGTGAACTGGAAGGTAAC AGAGA IAACTGGGAAAA AAAGGAAGAAACGCTGAGGAGAAAAGTAACCAAAGTGT TGAAGTGTGACGCTCTTGCGGAGAAGCCATTTGACGACG TGCCTATGCCAGAAGCCGACTGTCTGATTAGCTGCCTCT GCTTAGAAAATCCTTGTCAAGACCAAGAAGCTTATATCA ATATATTGAAAAAGCTrAAGGAGCTACTTAAACCCGGTG G rCACATIATAATTC AGAGTATTC TTAATIGTTCATAC TA CCATATTGGTAACAGCTGT 1T1 TCCCATCTGTCCTTATCT AAGGATGACGTGGAAAAATCATTTAAAGAGGCCGGGTA TGAAATTGTTAAATTAAAGGTGCTGCCACGATCTGTAAT GTCAGAAATGGAGATCAGTGATTCTAATGGCTATTACTT TATCCATGCTCGTAAACCACAGAAAGAGTAAGGATCCACTTAACGTIACTGAAATCAI CAAACAGCTIGACGAA ICTWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence GGATATAAGATCGTTGGTGTCGATGTCAGCTCCGGAGTT GAGACAAATGGI GT TCAGGATCTCGATAAGATACGTICA TTTGTCCAAGCAGCAAAGAGTGCCTTCTAGTGATTTAAT AGCTCCATGTCAACAAGAATAAAACGCGTTTCGGGTTTA CCTCTTCCAGATACAGCTCATCTGCAATGCATTAATGCA TTGGACCTCGCAACCCTAGTACGCCCTTCAGGCTCCGGC GAAGCAGAAGAATAGCTTAGCAGAGTCTATTTTCATTTT CGGGAGACGAGAI C AAGCAGATC AACGGTCG TCAAGAG ACCTACGAGACTGAGGAATCCGCTCTTGGCTCCACGCGA GTAGTGATATGTCGGCTCTAGTTCCTTGCTGTAAGTAAG GAGACGGGTATATGTCAACGTAGTATAAAGTGAAGCAG GCGAATTTTAAAGAATTTGCAATGGCCCATCTGTGTTCC A TCTTCGC ACAACATTTAA ITATnTATAIGATlTGTCAT AGACCCACCAACTTCAAC rCGAACTACATCACTIGGACC AACATCACGCGTTCAACATGGACAAGGGTTGATAACCC GGGATGCATTCATTGTCTGCCTCAAGTGTCGCTACTAGT TCCATC IT' 1 " 1 G 1 AAA11 " 1 1 GG A11 Al G 1 ’CCG’ 111 " 111 CTTCTAT CGCAACAAGCCATCCAACAAGAGAATACCGACCTGGAT CATGIAATICTGGCAATGGTCAACAGCCCCGTCCCGCAG AGCATACGGA rTCTTGITITGCGACCCCCC IGGAACGAT ATAATAATTTCGCAGTCTCCACTATATTCCGGCCCGGGA AACACCCTTGGGTCCTCTCTAGGCACGACTGATTGATAA TGATATCGTAAGAAGTACAACCTTGGGCTGAGGGCCTGC CACCCATCTTCCATGATAAGACATCTTTCTGGACGATCA GCGCTGTCACAGG TGACGGGCCAGI GTGAACAAATC AC ATCGAAGGCACACA1TGCGCGATGAAGACTCTGCACTCT ATTGCGTCAAACACGCAAACCATTATACCTGAAGCATCA CCTCGTGTCCTATACG AGTCGTTAA AC 1 1 1 1 CTTCCTCTA TTCTGCCCACTTTTC ATTTC 1 1 1 1 ATACTCCCGTTCTTGCT CGATCTCCACCGCTTCATACCGACAAACCTCCGGCTTTC AGTTTCITCTTACGGI'AAAACCAAAGCACCCCACGAGCA AGCTAGAITCCACACCAGGTAACTTCAGTCAAGCCAACA GAACCTCGGTGGGTCTCAAGTTGAAGATCGGCAGCATCA TAACCTCGTTGCGAGAACTCGGGGGAAATCTCGGGGAA TCCGCGCTGAATCTGCCCCCGCGAACCCTAAGCGGACTT CCTCCGCAATCCTCAATTTCCCCGAGGATACGGACTATT CAI CCAGCATTCCAACCAI TCTAGTICTAG TGAI CGGAA ATTCCCCGGCACCCCTGCATCAACAGAAGCATACCATAT ATAATGTCACAATTTCCCCTCTGCCAAGGGAGGGGAAGT GAGTGTCCCCTCCTCTGCTATTCATGGCCTTTGATCTCAA AACAGAAGACGGCCTGATTACCTACCTGACAAAACATCT GTCTCTCGATGTCGATACAAGTGGAGTGAAGCGTCTATC AGGCGGG ITTGTAAATGTTAC ATGGCGCAI C AAATTGAA TGCTCCGTACCAAGGGCATACCTCAATAATTCTTAAGCA CGCTCAGCCCCACATGAGCACCGACGAAGATTTCAAAAT AGGTGTCGAAAGGAGTGTCTACGAGTATCAGGCCATCA AGCTCATGATGGCGAATCGGGAAGTCCTCGGTGGTGTGG ATGGC ATTGTCAGCGI GCCGGAGGG TCTCAACTATGATT TAGAGAATAACGCCTTGATCATGCAAGACGTTGGAAAG ATGAAGACCTTGCTAGACTATGTCACCGCCAAGCCCCG TTGGCTACAGACATTGCTCGACTAGTAGGGACTGAGATC GGAGGCTTTGTTGCTCGACTGCACAACATTGGTAGAGAA AGGCGTGATGACCCTGAATTCAAGTTCTTCTCCGGAAAT A IAGTGGGTAGAACCACCTCCGATCAAC TCTACCAGACCATCA TCCCCAACGCTGCCAAATA TGGGGTGGACGATCCTWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence CTGTTGCCTACCGTTGTGAAGGACCTGGTTGATGATGTG ATGC ACI C AGAAGAGACGTTGGT TATGGCTGACCTCT GG TCCGGCAACATCCTCCTTCAACTGGAGGAGGGCAATCCA AGCAAGTTGCAGAAGATCTACATCCTGGACTGGGAGCT GTGCAAGTACGGCCCAGCGTCTCTTGATCTTGGGTACTT TCTTGGCGACTGTTATCTTATTAGTCGCTTCCAGGATGAG CAGGTCGGAACGACGATGCGCCAGGCATACCTCCAATC G IATGCACGGACTTCCAAGCATTCCAI CAACTACGCGAA GGTCACTGCCGGCATCGCAGCACACATCGTCATGTGGAC GGACTTCATGCAGTGGGGTTCGGAGGAAGAACGCATTA ACTTCGTCAAGAAAGGGGTGGCAGCCTTCCATGACGCCC GGGGAAACAATGACAACGGCGAGATTACGTCTACTCTG CTGAAGGAGAGCTCGACTGCGTAGCTAGTAC AGC AGAA GAATCTCTCTCCGCI GT rGCTICAGTGTCTGCCAI GCAT I AACTTCATCCTACTGTCCTACCCGCAGTACCCATTCACAT TTGCGGCAGATACCAGGTTGTTTTCTATTCCCTCGGTTCT TCAGTTCTTCAGATATTACATTACTCGAGAAATTGGCGG CGATGCAGGAGTTTGGTTGGTTTTAATTGTTTCAGTCTCC ITGACCTGA IT TGTATGACA TGCAATGITTCGACGGAAG ACI ATCTCGGTGAATAI ACGTCAI GA Al C ATGCTTCGGT AAATACACTATCACACACCGAACGTGCCCTGATTGCCTT GATACTCTGTGAGCGCTGGGCAGGGGACCTTGCACCCAC CGATGAAGAATTTCACCGGCAATTGAGCCGGTGTGTCTC TAAGCAGGAGGCATGGTGGTGTCAGTACTTGGGTCGGGT AGCGACCCTAAT TGGAGACG TGCATCCAI CCGGCCGCG T GTCGGACATGCATTGGAGGATCCGA ITGGAAACTGAAT GGGAATCCATTGTGAAGAAGAAAGACGAGTGCGATATG CTGCGTCTCAAAGTGAAATGCAACAACGATGTGGCTGTC GCCGCGTTCTCTCTTGACAGCTTACAGGAAAGGGCGGAG AAAGTCGAGAAAGTCGGAAAGAAAAAGAACTGGATCAA GGATTATGGAGTGCGAGTGGGGGTTAACGATTATTTGCTA A TAClTAGGnTC ACTATTGAAAAGGTTCCAGTCG TGGA GATTTTCTGTTTTTGGATAAATGTrAACTAACCGTGGAC AGAGTACTATGTTATATAGTGGATCAGATGATCCACCAT TCCTCGATCTGACAGACGGGCAATTGATTACGGGATCCC ATTGGTAACGAAATGTAAAAGCTAGGAGATCGTCCGCC GATGTCAGGATGATrTCACTTGTTTCTTGTCCGGCTCACC GGTCAAAGCTAAAGAGGAGCAAAAGGAACGGATAGAAT CGGGTGCCGCTGATCTATACGGTATAGTGCCCTTATCAC GTTGACTCAACCCATGCTATTTAACTCAACCCCTCCTTCT GAACCCCACCATCTTCTTCCTTTTCCTCTCATCCCACACA ATTCTCTATCTCAGATTTGAATTCCAAAAGTCCTCGGAC GAAACTGAACAAGTCTTCCTCCCTTCGATAAACCTTTGG TGATTGGAATAACTGACCATCTTCTATAGTTCCCAAACC AACCGACAATGTAAATACACTCCTCGATTAGCCCTCTAG AGGGCATACGATGGAAGTCATGGAATACTTTTGGCTGGA CTCTCACAATGATCAAGGTATCTTAGGTAACGTCTTTGG CGTGGGCCGGTGTTCGTTCCCAGTCAI CGATGC A T1 CAC A TGCCCTCCCTAAGCTGGGCCCTAGACTCTAGGATCCTA GTCTAGAAGGACATGGCATCGATGGACTGGGTTCGTTCT GAGATTATACGGCTAAAACTTGATCTGGATAATACCAGC GAAAAGGATCATGCCTTCTCTCGTTCTTCCTGTTGATGG AATGGCTAACAGATGATAGTCATTGCAACTTGAAACATG ACCGACCCTAATCGTACCACCTTCTCTTCAGCACTACATCCTCTAGCTGTGGTCTCAATGGCCTCCTCTTCCTCAGACGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TTTTCGTCTTGGGCTTGGGTGTCGTCCTCGCTGCCCTTTA TA TATTCCGCGACC AGCTT TI CGCI GCGTCCAAACCAAA GGTCGCCCCAGTATCCACCACCAAACCCGCCAATGGCTC TGCCAACCCTCGCGACTTCATCGCAAAGATGAAGCAGG GTAAAAAGCGCATTGTCATTTTTTACGGTTCTCAGACGG GTACTGCAGAAGAGTATGCCATTCGTCTCGCAAAGGAG GCTAAGCAGAAGTTTGGTTTGGCGTCCCTTGTGTGCGAT CCAGAGGAATACGAC IT TGAGAAACTTGACCAACTGCC AGAGGACTCCATCGCTTTCTTCGTCGTTGCCACCTATGGT GAGGGAGAACCTACCGACAACGCCGTCCAGCTTTTGCA GAACTTGCAAGACGAGTCTTTCGAGTTCAGCAGTGGAGA GCGCAAATTGAGTGGCCTCAAATATGTCGTCTTTGGTCT I GGGAACAAAACTTACGAGCACTACAA TCTTAT TGGACG C ACTGTTGACGCTC AACTCGCCAAGAI GGGAGCT ATCCG TATCGGCGAACGCGGTGAAGGTGACGATGATAAGAGCA TGGAGGAGGATTACCTTGAATGGAAGGACGGTATGTGG GAGGCTTTCGCTACTGCCATGGGTGTCGAAGAGGGACA GGGCGGCGACTCTGCCGACTTCGTTGTTTCGGAACTCGA GTCTCATCCTCCCGAGAAGGTTTACCAAGGTGAATTCTC GGC TCGCGCTCT TACAAAGACCAAAGGAATCCA TGACG CCAAGAACCCCTTCGCTGCACCTATCACTGTCGCCCGTG A A 01" 1 T 1 C C AGTCTGTTGTCGAC AGG A A CTGTG TCC ATG TCGAATTCAACATTGAAGGCTCTGGCATTACGTACCAAC ATGGTGACCACGTCGGTCTTTGGCCCTTGAACCCGGATG I CGAAGTGGAGCGTC rCCTGTGCGTrCTGGGATTGACCG AAAAGCGCGACGCI GTTATCAGC ATCGAAI CTCTCGATC CCGCTCTGGCCAAGGTACCATTCCCTGTCCCTACTACCT ACGGTGCTGTCCTTCGCCACTACATCGACATCAGCGCTG TTGCTGGTCGTCAAATTCTTGGGACATTGTCGAAGTTCG CTCCTACTCCGGAGGCCGAGGCTTTCCTCAGGAATCTCA ATACCAACAAGGAAGAATACCACAACGTTGTCGCTAAT GGATGCCTCAAGTTGGGCGAAA ITCTCCAAATCGCTAC T GGTAACGATATCACTGTCCCACCTACTACTGCCAATACC ACCAAGTGGCCTATACCCTTTGATATCATCGTCTCTGCC ATTCCCCGTCTTCAACCCCGGTACTACTCCATTTCCTCGA GCCCCAAAATCCACCCCAACACTATCCACGCTACCGTTG I TG rCCTCAAGTACGAGAACGITCCCACCGAGCCAAT TC CTCGTAAATGGGTATACGGTGTTGGATCCAACTTCTTAC TTAACCTCAAGTATGCCGTCAACAAGGAGCCCGTACCTT ACATCACTCAGAACGGTGAACAACGTGTTGGCGTTCCGG AATACCTTATTGCAGGACCTCGTGGCTCGTACAAGACTG AGACTTTCTACAAGGCCCCCATCCATGTTAGGCGCTCGA CC ITCAGAC ITCCCACTAACCCCAAGAGCCCTGITATCA TGATCGGTCCTGGAACTGGAGTTGCTCCTTTCCGTGGATTTGTGCAAGAACGTGTTGCCCTTGCCCGCCGCTCCATTGAGAAGAACGGACCTGATTCACTTGCTGACTGGGGTCGCATCTCTCTGTTCTACGGTTGCCGCCGATCGGATGAAGATTTCTTGTACAAGGACGAATGGCCACAATACGAGGCTGAACTCAAGGGCAAATTCAAACTTCACTGCGCCTTCTCTCGAC AGAACTACAAGCCTGATGGAAGCAAGATTTACGTCCAG GATCTCATTTGGGAAGACAGGGAGCACATTGCTGACGCT ATTCTCAATGGCAAAGGTTACGTGTATATCTGTGGTGAG GCGAAGAGCATGAGCAAGCAGGTCGAGGAGGTGTTAGC CAAAATCT IGGGAGAGGCCAAGGG TGGAI CTGGCCCTGTIGAGGG TGTCGCT GAAG ITAAGCTATTGAAGGAGAGATWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence CAAGGCTCATGTTGGATGTCTGGAGTTAAGCGGACATTC GATTTATGCCGTTATGACTICCrTAAAAAAGCCTTTACG AATGAAAGAAATGGAATTAGACTTGTTATGTAGTTGATT CTACAATGGATTATGATTCCTGAACTTCAAATCCGCTGT TCATTATTAATCTCAGCTCTTCCCGTAAAGCCAATGTTGA AACTATTCGTAAATGTACCTCGTTTTGCGTGTACCTTGCT TATCACGTGATATTACATGACCTGGACAGAGTTCTGCGC GAAAGTC A TAACGTA AATC CCGGGCGGTAGG TGCGTCC CGGGCGGAAGGTAG 1111 CTCGTCCACCCCAACGCGTTT ATCAACCTCAACTTTCAACAACCATCATGCCACCAAAAG CGCGTAAAACAAAGCGAGATTTGATTGAGCAAGAGGGC AGGATCCAATGCGCGATTCAAGACATTAAAAATGGAAA A IT TCAAAAAATTGCGCCCGCAGCGCGTGCATACAAAAT TCAI CCCAA IACACCTCGGI CGCTCACTG T1 CCTTTACGG ATATGTGTACTCCGGCAAGCCGCGGGGTCGCGGTCGTTT GTACGGCAGCTTCTACTTGCTTGCACAGGGAGCTCTCTG GGGCTTGACGTCTTTTGGAGTTGCGAGGGAGTTGATTTC CTACTTCTAAGTTTGGACTGAATCCGTGGTGTGATTGAG GTGATTGGCGATGTTTGGCI ATACCAGCI ATATGTAATAA rCTCTACTGTATACTACTAI TCAACGCAITITACI ATGC GTGCTGCTAGGGTCGGCAATGACAATGGCAATCTGACTG ACGTGGTCTATTTCTCCATGTGCAGCAGGGAATACGAGC TCCAATGGACCTCGGGAGTGGCACAGTCAATGGCAAGG AAACTCCGCCTTTGCAGGTGTGGCTGAACCCCACGGGTC GGAGGCGGAGCAA ICCACCCCCGATGTGGC I GGTGCGT GGAGGGGCTCGCGATGAT IT lACTGAGCTTGCTnTCTT GTCGACATTGAACATTGTCCTTGGTCTTCCTTCAGATTTA AGGGTCAGTCACTGCTACATmTCAGTAGTATCCGCGC ACGTCTCTGGATTTACGAATCAGGGTCCACCAGTCGAAA CTTCGAACTACTCTCATTATACAATCCTCTTTCCATTCCC GCATIAACCCC TCCATCAACACCATGTCCTCCAAGI CGC GATTGACC IACACTGCCCGTGCCAGCAAGCATCCCAATG CTCTGGCGAAGAGGCTGTTCGAGATTGCCGAGGCCAAG AAGACCAATGTGACTGTCTCGGCTGACGTTACCACCACT AAGGAGCTACTAGATCTTGCTGACCGTAGGCCGACCCGC TACTCTGCCTGATTATGCTGCATGCAAACTTATTAACGG I GATACCGGACTGCAGG TCTCGGI CCCTACAT TGCCGTG ATCAAAACCCACATCGATATCCTCTCTGATTTCAGCAAC GAGACCATTGAGGGACTTAAGGCTCTCGCGCAGAAGCA CAACTTTCTCATCTTCGAGGACCGCAAGTTCATTGACAT CGGCAACACGGTCCAGAAGCAATACCACGGCGGTACCC TCCGTATCTCGGAATGGGCCCACATCATCAACTGCAGCAnCTCCCTGGI GAGGGTATCGTCGAGGCI CTCGCTCAGA CGGCGTCTGCACCGGACTTCGCCTACGGCCCCGAACGCG GTCTGTTGATCTTGGCAGAGATGACCTCTAAGGGCTCCT TGGCTACCGGCCAGTACACTACTTCCTCGGTCGATTATG CCCGGAAATACAAGAACTTCGTTATGGGATTCGTGTCGA CGCGCGCGTTGGGTGAGGTGCAGTCGGAAGTCAGCTC TC CTTCGGAI GAGGAGGACTITG TGGTC I’TCACGAC TGGTG TGAACATTTCTTCCAAGGGAGATAAGCTTGGTCAGCAGT ACCAGACGCCCGGATCGGCTATCGGCCGGGGTGCTGACT TCATTATCGCGGGTCGCGGTATCTACGCCGCGCCGGATC CGGTGCAGGCTGCGCAACAGTATCAGAAGGAGGGGTGG GAAGCC IACCTGGCCCGTGTCGGCGGAAAACTAATACTATAAAAGGAGGATCGAAGTTCI GATGGTIATGAATGATAIWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence AGAAATGCAACTTGCCGCAACGGATACGGAAGCGGAAA CGGACCAATGTCGAGCACGGG TAGTCAGACTGCGGCA T CGGATGTCCAAACGGTATTGATCCTGCAGGCTACTATGG TGTGGCACAAGGATCAATGCGGTACGACGATTTGATGCA GATAAGCAGGCTGCGAAGTAGTAACTCTTGCGTAGAGA AAATGGCGACGGGTGGCTGATAAGGGCGGTGATAAGCT TAATTGTCATCGCAGATAAGCACTGCTGTCTTGCATCCA AGTCAGCGTC AGCAGAAATACGGGACTTCCGAAAGI AT ATGGC AAAATTAAAGAACTTGACTCTC CAGC AATG 1111 GCCCTGACCGTCGCTAAAACGTTACTACCCCTATACCCG TCTGTTTGTCCCAGCCCGAGGCATTAGGTCTGACTGACA GCACGGCGCCATGCGGGCTTGGGACGCCATGTCCGTCGC G TGATAAGGG TTGATCCATGCAGC TACTATCCTTCCA TC GTTCCATTCCCATCC TTGTCCTATCTCCATCCTTGAAAC T TTACTAGTTTAGTTGGATGCTCGAGCTTGCTCTCGGCTAC TCCGTCCGCGGCCGCACCCAGCTTTCTTGTACAAAGTTG GCATTATAAGAAAGCATTGCTTATCAATTTGTTGCAACG AACAGGTCACTATCAGTCAAAATAAAATCATTATTTGCC ATCCAGCTGATATCCCCTATAGTGAGTCGTATTACATGG I CATAGCI GT ITCCTGGCAGCTCTGGCCCG TGTC TCAAA ATCTCTGATGTTACATTGCACAAGATAAAAATATATCAT CATGAACAATAAAACTGTCTGCTTACATAAACAGTAATA CAAGGGGTGTTATGAGTATTCAACATTTCCGTGTCGCCC TTATTCCCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTGCT CACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGA TC AG ITGGGTGCACGAGTGGG ITAC A TCGAACTGGATCT CAACAGCGGTAAGATCCTTGAGAG H l TCGCCCCGAAGA ACG i T 1 rCCAATGATGAGCACTTTTAAAGTTCTGCTATGT GGCGCGGTATTATCCCGTGTTGACGCCGGGCAAGAGCA ACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGT TGAGTACTCACCAGTCACAGAAAAGCATCTI’ACGGAIGG CAI GACAGTAAGAGAA TTATGCAG TGCTGCCAI AACC AT GAGTGATAACACTGCGGCCAACTTACTTCTGACAACGAT CGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACAT GGGGGATCATGTAACTCGCCTTGATCGTTGGGAACCGGA G CTG A ATGA AGCC ATA CC A A A CGA CGAGCGTGA C ACC A CGA TGCCTGCAGCAA IGGCAACAACGI TGCGCAAACTAT TAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAAT TAATAGACTGGATGGAGGCGGATAAAGTTGCAGGACCA CTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTG ATAAATCTGGAGCCGGTGAGCGTGGGTCACGCGGTATC ATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATC GTAGTTATCTAC ACGACGGGGAG TCAGGCAACTATGGA T GAACGAAATAGACAGATCGCTGAGATAGGTGCCTCACT GATTAAGCATTGGTAATCAGAATTGGTTAATTGGTTGTA ACACTGGCAGAGCAITACGCTGACTTGACGGGACGGCG CAAGCTCATGACCAAAATCCCTTAACGTGAGTTACGCGT CGTICCACTGAGCGTCAGACCCCGTAGAAAAGATCAAA GGATCTTCTrGAGArCCTTTTTTTCTGCGCGrAATCrGCT GCTTGCAAACAAAAAAACCACCGCTACCAGCGGTGGTTT GTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGG TAACTGGCTTCAGCAGAGCGCAGATACCAAATACTGTTC TTCTAGTGTAGCCGTAGTTAGGCCACCACTTCAAGAACT CTGTAGCACCGCCTACA TACCTCGCTCI GCTAA TCCTGI TACCAGTGGC TGCTGCCAG TGGCGATAAGTCGTGI C ITACWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence CGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGC AGCGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCC AGCTTGGAGCGAACGACCTACACCGAACTGAGATACCT ACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAG GGAGAAAGGCGGACAGGTATCCGGTAAGCGGCAGGGTC GGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGAA ACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCT CTGAClTGAGCGTCGATn’nGIGATGCrCGTCAGGGGG GCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTT ACGGTTCCTGGCCTTTTGCTGGCC 1111 GCTC ACATGTT 39 PRE Pmin:: RmENM CTTTCCTGCGTTATCCCCTGATTCTGTGGATAACCGTATT T::ftrpC:: Ptefl:: T5 ACCGCCTTTGAGTGAGCTGATACCGCTCGCCGCAGCCGA H:: Ttefl:: PbphA:: A ACGACCGAGCGCAGCGAGTCAGTGAGCGAGGAAGCGGA SMT:: T cgrA::pyrG_ AGAGCGCCCAATACGCAAACCGCCTCTCCCCGCGCGTTG wt GCCGATTCATTAATGCAGCTGGCACGACAGGTTTCCCGA C TGGAAAGCGGGCAGTGAGCGCAACGCAATTAATACGC GTACCGCTAGCCAGGAAGAGTTTGTAGAAACGCAAAAA GGCCATCCGTCAGGATGGCCTTCTGCTTAGTTTGATGCC TGGCAGTTTATGGCGGGCGTCCTGCCCGCCACCCTCCGG GCCGTTGCTTCACAACGTTCAAATCCGCTCCCGGCGGAT TTGTCCTACTCAGGAGAGCGTTCACCGACAAACAACAGA TAAAACGAAAGGCCCAGTCTTCCGACTGAGCCTTTCGTT TTATTTGATGCCTGGCAGTTCCCTACTCTCGCGTTAACGC TAGCATGGATGTTTTCCCAGTCACGACGTTGTAAAACGA CGGCC AGTCTTAAGCTCGGG CCCCA A ATAATG A 1 11 1 AT TTTGACTGATAGTGACCTGTTCGTTGCAACAAATTGATG AGC AATGC1TITTTATAA TGCC AACTTTGTACAAAAAAG CAGGCIGGTACCGAGCTCGACTITCACITITCTCrATCAC TGATAGGGAGTGGTAAAC TCGACTITC ACTTTTCTCT ATC ACTGATAGGGAGTGGTAA ACTCGACTTTC AC 1111 CTCT ATC A CTGATA GGG AGTGGTAAACTCG A CTTTC AC 1 11 1 C TCTATCACTGATAGGGAGTGGTAAACTCGACTTTCACTT TTCTCTATCACTGATAGGGAGTGGTAAACTCGACTTTCA CTTITCECTAIC ACTGAEAGGGAGTGGTAAACTCGACTTT CACTTTTCTCTATCACTGATAGGGAGTGGTAAACTCGAC CTATATAAGCAGAGCTCGTTTAGTGAACCGTCAGATCGC CTGGAGACGCCATCCACGCTGTTTTGACCTCCATAGAAG ACACCGGGACCGATCCAGCCTCCGCGGCCCCGAATTGCC CATCTTCAGTATATTCATCTTCCCATCCAAGAACCTTTAT I TCCCCTAAG TAAG TACTITGCI ACATCCATACTCCATCC TTCCCATCCCTTATTCCTTTGAACCTTTCAGTTCGAGCTT TCCCACTTCATCGCAGCTTGACTAACAGCTACCCCGCTT GAGCAGACATCACATGGAGAACTCATACTCTGCACAGA TGTACATTGATGAATTTGATCCTGTACACTACTACCAGA C Al ACTAI TCTTCGGGGAAAGGAGGTATCGC TAGAGAAT GGACAGACITIGCC T1 ACAGAATCI GCATGAAACAT ITG GTCCAGGAGGTGTGAAAGGAGACATACTAATTGACTTTG GAGCTGGACCCACAATTTATCAACTGCTCTCTGCTTGTG AAGTGTTCAACAGCATTATAACCTCTGATTTTCTrGAGC AAAACCGAGAGCAATTGGAAAAATGGCTGAGAAAGGAC CCAGATGCCTTAGACI GGTC rCATITIACC AAATATGIG TGTGAACTGGAAGGTAACAGAGATAACTGGGAAAAAAA GGAAGAAACGCTGAGGAGAAAAGTAACCAAAGTGTTGA AGTGTGACGCTCTTGCGGAGAAGCCATTTGACGACGTGCCTATGCCAGAAGCCGACTGTCTGATTAGCTGCCTCTGCTWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TAGAAAATCCTTGTCAAGACCAAGAAGCTTATATCAATA TA ITGAAAAAGCTTAAGGAGCTACTTAAACCCGG TGGTC ACATTATAATTCAGAGTATTCTTAATTGTTCATACTACCA TATTGGTAACAGCTGTTTTTCCCATCTGTCCTTATCTAAG GATGACGTGGAAAAATCATTTAAAGAGGCCGGGTATGA AATTGTTAAATTAAAGGTGCTGCCACGATCTGTAATGTC AGAAATGGAGATCAGTGATTCTAATGGCTATTACTTTAT CCATGCTCGTAAACCACAGAAAGAGTAAGGATCCACTI AACGTTACTGAAATCATCAAACAGCTTGACGAATCTGGA TATAAGATCGTTGGTGTCGATGTCAGCTCCGGAGTTGAG ACAAATGGTGTTCAGGATCTCGATAAGATACGTTCATTT GTCCAAGCAGCAAAGAGTGCCTTCTAGTGATTTAATAGC I CCATGTCAACAAGAAI AAAACGCGTTTCGGGT TTACCT CTTCCAGATACAGCTCATCTGCAATGCAI TAATGCATTG GACCTCGCAACCCTAGTACGCCCTTCAGGCTCCGGCGAA GCAGAAGAATAGCTTAGCAGAGTCTA IT 1 T'CA IT 1 TCGG GAGACGAGATCAAGCAGATCAACGGTCGTCAAGAGACC TACGAGACTGAGGAATCCGCTCTTGGCTCCACGCGCGAG ACAGCAGAA rCACCGCCCAAGTTAAGCCTTTGTGCTGAI CAI GCTCTCGAACGGGCCAAGT I’CGGGAAAAGC AAAGG AGCGTTTAGTGAGGGGCAATTTGACTCACCTCCCAGGCA ACAGATGAGGGGGGC AAA A AGA AAG A AA 1 " 1 1 " 1 CGTG AG TCAATATGGATTCCGAGCATCATTTTCTTGCGGTCTATCT TGCTACGTATGTTGATCTTGACGCTGTGGATCAAGCAAC GCCACTCGCTCGCTCC ATCGCAGGCI GGTCGCAGAC AAA TTAAAAGGCGGCAAACTCGTACAGCCGCGGGGTTGTCC GCTGCAAAGTACAGAGTGATAAAAGCCGCCATGCGACC ATCAACGCGTTGATGCCCAGCTTTTTCGATCCGAGAATC CACCGTAGAGGCGATAGCAAGTAAAGAAAAGCTAAACA AAAAAAAATTTCTGCCCCTAAGCCATGAAAACGAGATG GGGTGGAGCAGAACCAAGGAAAGAGTCGCGCTGGGCTG CCGTTCCGGAAGG IGTTGI AAAGGCTCGACGCCCAAGGT GGGAGTCTAGGAGAAGAATTTGCATCGGGAGTGGGGCG GGTTACCCCTCCATATCCAATGACAGATATCTACCAGCC AAGGGTTTGAGCCCGCCCGCTTAGTCGTCGTCCTCGCTT GCCCCTCCATAAAAGGATTTCCCCTCCCCCTCCCACAAA A IT rTCTTTCCCTTCCTCTCC I TG TCCGC ITCAGTACGTAT ATCTTCCCTTCCCTCGCTTCTCTCCTCCATCCTTCTTTCAT CCATCTCCTGCTAACTTCTCTGCTCAGCACCTCTACGCAT TACTAGCCGTAGTATCTGAGCACTTCTCCCTTTTATATTC CACAAAACATAACACAACCTTCACCATGGAGCTGACGA TGGCTTCTACAATGAGTCTAGCACTGCTCGTTCTGTCAG CAGCATA IGTCCTTGI GGCCTIACGACGATCGAGGAGTA GCAGCAGCAAACCGAGACGGCTTCCGCCCTCCCCTCCCG GCTGGCCCGTCATCGGCCATCTCCATTTGATGTCTGGCA TGCCTCACCACGCGTTAGCGGAGCTGGCGCGCACCATGA GAGCACCTTTGTTCCGCATGCGTCTGGGCTCCGTGCCAG C AGT TGTCA IT I CC AAACC AGACTI GGCGCGGGCGGCGI I GACGACAAA IGATGCTGCCTIGGCATC ACGCCCCC ACC TCCTGTCCGGTCAATTCCTCTCGTTCGGGTGTTCCGATGT TACGTTCGCTCCGGCTGGGCCATATCACCGGATGGCCAG GAGAGTGGTGGTAAGCGAGTTGCTTTCTGCGCGACGCGT TGCTACCTACGGGGCGGTGCGTGTTAAGGAATTGCGTCG CCTCCTGGCTCATC TGACCAAGAACACTTCGCCAGCCAAGCCTGTCGACC rCTCGGAGTGCTTCCTCAAI CTAGCAAAWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence CGACGTGCTATGTCGGGTAGCCTTTGGTCGGCGGTTTCC GCATGGCGAAGGTGATAAGTIGGGAGCI GTGC TCGCCG AGGCTCAGGATCTGTTTGCCGGCTTCACCATAGGCGACT TCTTCCCCGAGCTTGAGCCTGTCGCTTCAACAGTCACTG G ACTCAGACGCCGGTTGAAG A AGTG CTTGG CG GATCTCC GTGAGGCCTGTGACGTAATCGTCGATGAACACATATCGG GAAATCGCCAGCGTATCCCCGGTGACCGAGACGAGGAC ITIGTGGATG IT ITGCI CCGAGTGCAGAAGTCACCGGAT CTGGAGGTTCCACTCACTGATGACAACCTGAAAGCCCTA GTGCTTGACATGTTTGTCGCCGGGACCGATACCAC 1111 GCCACGCTCGAATGGGTAATGACCGAACTCGTCCGCCAT CCGCGCATTCTAAAAAAGGCCCAGGAGGAAGTAAGACG I GTGGTGGGAGACAGTGGACGGGTCGAGGAA TCCCA TC TIGGAGAGTTACAC TACATGCGCGCCA TCATCAAAGAGA CCTTCCGACTGCATCCTGCTGTTCCCTTGCTCGTCCCTCG CGAGTCTGTTGCGCCTTGCACACTCGGGGGTTATGATAT TCCTGCTAGGACAAGGGTCTTCATCAACACGTTCGCCAT GGGCCGAGATCCAGAAATCTGGGACAATCCGCTGGAGT ACAGCCCCGAAAGGTTCGAATCTGCAGGAGGCGGTGGA GAGATIGATCTGAAGGACCCCGACTACAAGCTGCTTCCG TTCGGTGGTGGGAGAAGGGGCTGCCCAGGCTACACCTTT GCGCTGGCTACAGTGCAAGTCTCCCTCGCTTCTCTCCTGT ACCACTTTGAGTGGGCCCTTCCCGCTGGAGTAAGGGCAG AGGATGTCAACCTGGATGAGACTTTCGGTCTTGCCACGC G TAAAAAGGAACCACTG ITCGTCGCAGTICGCAAGTC AG ACGCCTATGA ATTCAAGGGCGAAGAGCT IAGCGAAGTTT AGAGCGGACATTCGATTTATGCCGTTATGACTTCCTTAA AAAAGCCTTTACGAATGAAAGAAATGGAATTAGACTTG TTATGTAGTTGATTCTACAATGGATTATGATTCCTGAACT TCAAATCCGCTGTTCATTATTAATCTCAGCTCTTCCCGTA AAGCCAATGTrGAAACTATICGTAAATGTACCTCGT IT T GCG IGTACCITGCTTA rCACGTGATATTACAI GACCTGG ACAGAGTTCTGCGCGAAAGTCATAACGTAAATCCCGGG CGGTAGGTGCGTCCCGGGCGGAAGGTAGTTTTCTCGTCC ACCCCAACGCGTTTATCAACCTCAACTTTCAACAACCAT CATGCCACCAAAAGCGCGTAAAACAAAGCGAGATTTGA TTGAGCAAGAGGGCAGGATCCAATGCGCGATrCAAGAC ATTAAAAATGGAAAATTTCAAAAAATTGCGCCCGCAGC GCGTGCATACAAAATTCATCCCAATACA CGTGTCCGTTCTACAAGATCATCCCTGGATTCTCCCTCTG TGTGGATGCATTTCGATACGGAGCCGTAGAGGGATGTAA TGCGTACTTCCTTAGTCACTTCCACAGCGACCATTACATC GGCCTGACGGGGTCGTGGCGCCATGGACCAATCTACT GC AGCAGACCTACGGCCAACTTGGTGTGCCAGCAACTGAA GGTCGACCGGAAGTGGCTTGTACCACTTGAGTTCGAGCG GAAGACGGAAATCCCGGATACAGGAGGAGCGCAGGTGA CTTTGATCGAGGCTAATCATTGTCCTGGGAGCGCCATCTTrCTCTrCGAGAAATCAATGGGATCGGGTCCCTCGCAGA GAACACATCGTGTCCTCCACTGTGGIGACTITCGCGCCT CGCCGCTTCATGTGCAACATGCCCTTCTCCGCCCGGAGA TTGCTGACCCCGCAACCGGCAAGGCTCGCCAGCAACGA ATCGATGCCTGCTATCTGGACACTACATATTTGAGCCCC AAGTATGCATTCCCTGGCCAAGAAGATGTCATACAAGCC I GCGCAGAACTTTGCGTTGAGCTCGAI GGGGACGCCAACGACACC AATGGACGAGCGTTTGGACGACC AGTCAATGGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence AAAAAGCGGAATGCTGAGCAAGTTTGTTACGGCTGTGA CTGGATCCCGCCCGTCTCCGACGCAAGACAGCCGCCCCC CTGGCCGGCTATTGGTAGTAATAGGGACGTACAGCATCG GCAAAGAACGCATCTGTCTGGGGATCGCACGGGCATTG AAGAGCAAGATCTACGCGACGCCAGCTAAGCAGCGCGT CTGTGCGTGCCTCGAGGATGCTGAGCTGTCATCGCTGCT GACAGACGATCCCACGGAGGCGCAGGTGCATATGCAAA CGC TATTCGAGATCCGGGCGGAAACGCTGGCGGAT IACC TGGACTCGATGAAGCCGCACTTCACGCGGGTGGTGGGAT TTCGACCAACCGGGTGGACGTATCGCCCGCCAGCTGGCC GAATGCTGGACAACCCACCGGTGTCGGTGGTGCTCAATT CGGCACATTGGAAGACGCCCTTTTCTGCGAAAGACCTGG I GCCACAGCGAGGGAGTACGCGGGAAAGCGCATGCTTT GGAGTGCCGTACAGTGAGCACAGCTCATTTCGGGAGTTG AGCATGTTCTGCTGCGCACTCCGGATCGGACGGGTGATC CCGACAGTGAACGTAGGTAGCCGGAAAAGTCGGGAGCG CATGAAGGCGTGGATTGAGCGATGGGAGGCGGAGAAGC GGAAGAATGGGTTGTACCGCGTGGAGGGGAATAGCTGG TAGGGGATAGATAGACGGCTCTACCAACGTCCAAAGTA C TGCTGGAACACAAGGATCAGCAGGATCAGAAGGATTG CGAAAGACGGGTCGGAACATGTTGCCTAATAGAGTAAG TAAGGAGTTGGTGCTGTAACTAGTCACAAGTTACGATTT GTGTACATAACATCATTAGTCATGGAGATCAATTGCCTT TATGCTTCCGTAACTCTCGCCTCCCCGGAGTCACGAGAT CAA TAGAAACCACCGCCGT TGACCAT TCGCGATGC TCTC ACTGGCTGTATGCTGTCGATAGCCATGGAGCCGTTCAAA GTATGGACCCTTTGGGTGAGGATCTCCCTCCAACCCCAC GGGACGTACACGAACAACCGAGCAGAGGCGGGGGAGG GCAAAGAGGCCGGCGCTGCAAATCGGCTGGCAGATCAG TCGCGGCTCAGCAGAGACTCCCGATTTTCCCTTCCGTTG CCrGGCTITGCCTCGGGGTTCGAGAGGAGCCCGTCTGCC ATAAAIAAGCCTGCACITCAACTCAAAAAAAAGGGAGA TGACAGATCAACCACTTTCTCGACAAGAAACACTCTTCA CCCATGGCGATACTTGAGTGAAGTAAGTGTGACTGTGAC TGATATTATTTTCTTCTTCAGCCATCCTTTTTCGATATATT ACCTTATAGTTGCTTATTTCATTTCGGAGGTAAGATGGTC I CC ITGGCACCCACATTCCCGGCTGCACTTGGCGGCI GC GGAATTGCTTCTCCTGGCTGCATTTGCCGGTGTTAACTTC CGAACTCACCAGCTTCCTCCCCTCCCCCCACAAAAACAA TCATGTCCTCAGACCAGCTTTCCAAGTTCCTGGACCGCA ACAAGATGGAGGACAATAAACGCAAGGTGCTTGACGAA GAAGCCAAGGCCAGCTTGGACATTTGGAAGTACGTCTTC GGCT ITGCAGAC ATTGCTGCGGCGAAATGIGCTA TCGAC CTCAAGATCCCCGAGGCGATTGAGAACCACCCATCCTCC CAACCAGTGACGCTAGCTGAACTTAGCAGCGCCGTGTCT GCAAGTCCCAGCCATCTCCGAAGAATCATGCGCTTCTTG GTGCACCAAGGCATTTTCAAGGAGATTCCCACCAAGGAT GGCT TGGCCACTGG ITATGTCAACACCCCTC IT TCAAGA AGGTTGATGATTACACGACGCGATGGGAAArCGTrAGCC CCCTTTGTTCTGTTCGAGACCACTCCGGAGATGCTGGCT CCCTGGCTGCGTTTGTCAAGTGTTGTTTCGTCGCCTGTCA ATGGGTCTACACCACCGCCTTTTGATGCCGTCCACGGAA AAGATGTCTGGTCTTTTGCCCAGGACAACCCCTTCCTCTC CGACAI GATC AACGAAGCCATGGC ITGTGAI GCGCGGAGGGTGGTGCCGAGAGTAGCAGGAGCTTGCCATGGCCI CTWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence TCGACGGAGTGACCACCATGGTGGATGTAGGGGGTGGA ACTGGCGAGACAATGGGCATGITGGTCAAGGAATITCCG TGGATCAAGGGCTTCAACTTCGATCTTCCTCATGTTATCG AGGTGGCCGAAGTCCTGGATGGTGTTGAAAATGTTGAG GGTGATATGTTCGACTCCATACCAGCATGCGATGCAATC TTCATCAAGTGGGTGCTACACGACTGGGGTGACAAAGA CTGCATCAAAATCCTGAAGAACTGCAAGGAAGCGGTAC CTCCGAATAI AGGCAAGGTTCI C ATTGTCGAAAGTGTCA TTGGAGAGAATAAGAAGACGATGATCGTGGATGAACGG GATGAGAAGCTGGAGCATGTTCGTCTCATGCTCGACATG GTCATGATGGCGCACACCTCGACGGGGAAGGAGCGGAC TTTAAAAGAATGGGATTTTGTCTTGAAAGAGGCTGGTTT CGCACGAI ATGAGGTCCGI GATATTGATGATGIGCAGTC TCTGATCAI CGCC TACCGCAGCTAACT AGTACAGCAGAA GAATCTCTCTCCGCTGTTGCTTCAGTGTCTGCCATGCATT AACTTCATCCTACTGTCCTACCCGCAGTACCCATTCACAT TTGCGGCAGATACCAGGTTGTTTTCTATTCCCTCGGTTCT TCAGTTCTTCAGATATTACATTACTCGAGAAATTGGCGG CGATGCAGGAGTITGGTIGGTI’n'AAITGITrCAGTCrCC ITGACCTGATITGTATGACATGCAATGnTCGACGGAAG ACTATCTCGGTGAATATACGTCATGAATCATGCCCTCGG TCGCTCACTGTTCCTTTACGGATATGTGTACTCCGGCAA GCCGCGGGGTCGCGGTCGTTTGTACGGCAGCTTCTACTT GCTTGCACAGGGAGCTCTCTGGGGCTTGACGTCTTTTGG AGTTGCGAGGGAG ITGATFTCCTACI TCTAAGT TTGGAC TGAATCCGTGGTG I’GAT TGAGGTGA ITGGCGATG IT EGG CTATACCAGCTATATGTAATAATCTCTACTGTATACTACT ATTCA ACGCA 11 11 ACTATGCGTGCTGCTAGGGTCGGCA ATGACAATGGCAATCTGACTGACGTGGTCTATTTCTCCA TGTGCAGCAGGGAATACGAGCTCCAATGGACCTCGGGA GTGGC ACAGTCAAI GGCAAGGAAACTCCGCCTTTGCAG G TGTGGCTGAACCCCACGGGTCGGAGGCGGAGC AATCC ACCCCCGATGTGGCTGGTGCGTGGAGGGGCTCGCGATG AT 1 E 1 ACTGAGCTTGCTTTTCTTGTCGACATTGAACATTG TCCTTGGTCTTCCTTCAGATTTAAGGGTCAGTCACTGCTA CATTTTTCAGTAGTATCCGCGCACGTCTCTGGATTTACGAA rCAGGGICCACCAG rCGAAACITCGAACTACTCTCA IT ATACAATCCTCTTTCCATTCCCGCATTAACCCCTCCATCA ACACCATGTCCTCCAAGTCGCGATTGACCTACACTGCCC GTGCCAGCAAGCATCCCAATGCTCTGGCGAAGAGGCTGT TCGAGATTGCCGAGGCCAAGAAGACCAATGTGACTGTCT CGGCTGACGTTACCACCACTAAGGAGCTACTAGATCTTG CTGACCGTAGGCCGACCCGC TACTCTGCC TGATTA TGCT GCATGCAAACTTATTAACGGTGATACCGGACTGCAGGTC TCGGTCCCTACATTGCCGTGATCAAAACCCACATCGATA TCCTCTCTGATTTCAGCAACGAGACCATTGAGGGACTTA AGGCTCTCGCGCAGAAGCACAACTTTCTCATCTTCGAGG ACCGCAAGTICATIGACATCGGCAACACGGTCCAGAAG CAA rACCACGGCGGTACCCTCCGIATCI CGGAATGGGCC CACATCATCAACTGCAGCATTCTCCCTGGTGAGGGTATC GTCGAGGCTCTCGCTCAGACGGCGTCTGCACCGGACTTC GCCTACGGCCCCGAACGCGGTCTGTTGATCTTGGCAGAG ATGACCTCTAAGGGCTCCTTGGCTACCGGCCAGTACACT ACTTCCTCGG 1’CGATTATGCCCGGAAATAC AAGAAC1TCGTrATGGGATTCGTGTCGACGCGCGCGTTGGGTGAGGTGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence CAGTCGGAAGTCAGCTCTCCTTCGGATGAGGAGGACTTT GTGGTCTTCACGACTGGTGI GAACATTTC TTCCAAGGGA GATAAGCTTGGTCAGCAGTACCAGACGCCCGGATCGGCT ATCGGCCGGGGTGCTGACTTCATTATCGCGGGTCGCGGT ATCTACGCCGCGCCGGATCCGGTGCAGGCTGCGCAACA GTATCAGAAGGAGGGGTGGGAAGCCTACCTGGCCCGTG TCGGCGGAAAACTAATACTATAAAAGGAGGATCGAAGT I CTGAI GGTTATGAATGATATAGAAATGCAAC TTGCCGC AACGGATACGGAAGCGGAAACGGACCAATGTCGAGCAC GGGTAGTCAGACTGCGGCATCGGATGTCCAAACGGTATT GATCCTGCAGGCTACTATGGTGTGGCACAAGGATCAATG CGGTACGACGATTTGATGCAGATAAGCAGGCTGCGAAG I AGTAACTCT TGCGTAGAGAAAATGGCGACGGGTGGCT GATAAGGGCGGI GATAAGCTIAATTGTC ATCGC AGAI AA GCACTGCTGTCTTGCATCCAAGTCAGCGTCAGCAGAAAT ACGGGACTTCCGAAAGTATATGGCAAAATTAAAGAACT TGACTCTCCAGCAATG 111 " 111 GCCCTG ACCGTCGCTA A AA CGTTACTACCCCTATACCCGTCTGTTTGTCCCAGCCCGAG GCAT TAGGI CTGACTGACAGCACGGCGCC ATGCGGGC IT GGGACGCCATGTCCG rCGCGTGATAAGGGTIGATCCAI G CAGCTACTATCCTTCCATCGTTCCATTCCCATCCTTGTCC TATCTCCATCCTTGAAACTTTACTAGTTTAGTTGGATGCT CGAGCTTGCTCTCGGCTACTCCGTCCACCCAGCTTTCTTG TACAAAGTTGGCATTATAAGAAAGCATTGCTTATCAATT TGTTGCAACGAACAGGTCACTATCAGTCAAAATAAAATC AT IATTTGCCA ICC AGCTGA TATCCCCTA TAG! GAGTCGT ATTACATGGTCATAGCTGTTTCCTGGCAGCTCTGGCCCG TGTCTCAAAATCTCTGATGTTACATTGCACAAGATAAAA ATATATCATCATGAACAATAAAACTGTCTGCTTACATAA ACAGTAATACAAGGGGTGTTATGAGTATTCAACATTTCC GTGTCGCCCITAlTCCCn’n’n'GCGGCAn’nGCCnCCT G IT IT TGCTCACCCAGAAACGCTGGTGAAAGTAAAAGAT GCTGAAGATCAGTTGGGTGCACGAGTGGGTTACATCGA ACTGGATCTCAACAGCGGTAAGATCCTTGAGAGTTTTCG CCCCGAAGAACGTTTTCCAATGATGAGCACTTTTAAAGT TCTGCTATGTGGCGCGGTATTATCCCGTGTTGACGCCGG GCAAGAGCAACTCGG rCGCCGCATACACTATTCTCAGAA TGACTTGGTTGAGTACTCACCAGTCACAGAAAAGCATCT TACGGATGGCATGACAGTAAGAGAATTATGCAGTGCTG CCATAACCATGAGTGATAACACTGCGGCCAACTTACTTC TGACAACGATCGGAGGACCGAAGGAGCTAACCGCTTTTT TGCACAACATGGGGGATCATGTAACTCGCCTTGATCGTT GGGAACCGGAGC TGAA TGAAGCCATACCAAACGACGAG CGTGACACCACGATGCCTGCAGCAATGGCAACAACGTT GCGCAAACTATTAACTGGCGAACTACTTACTCTAGCTTC CCGGCAACAATTAATAGACTGGATGGAGGCGGATAAAG TTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCT GGTTTATTGCTGAI AAAI CTGGAGCCGGTGAGCG IGGGI CACGCGGI ATCATTGCAGCACT GGGGCCAGA TGGTAAG CCCTCCCGTATCGTAGTTATCTACACGACGGGGAGTCAG GCAACTATGGATGAACGAAATAGACAGATCGCTGAGAT AGGTGCCTCACTGATTAAGCATTGGTAATCAGAATTGGT TAATTGGTTGTAACACTGGCAGAGCATTACGCTGACTTG ACGGGACGGCGCAAGCTCAI GACCAAAAI CCCTTAACGTGAGTTACGCGTCGTTCCACTGAGCGTCAGACCCCGTAGWSGR Docket No. 66180-701.601SEQ ID NO. Vector Sequence AAAAGATCAAAGGATCTTCTTGAGATCCTTTTTTTCTGC GCGTAATCTGCI GCTTGCAAACAAAAAAACCACCGC TAC CAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTC THU CCGAAGGTAACTGGCTTC AGCAGAGCGCAGATAC CAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGGCCACC ACTTCAAGAACTCTGTAGCACCGCCTACATACCTCGCTC TGCTAATCCTGTTACCAGTGGCTGCTGCCAGTGGCGATA AGTCGTGTCT TACCGGGTTGGACI C AAGACGAI AGTTAC CGGATAAGGCGCAGCGGTCGGGCTGAACGGGGGGTTCG TGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGA ACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCA CGCTTCCCGAAGGGAGAAAGGCGGACAGGTATCCGGTA AGCGGCAGGG TCGGAACAGGAGAGCGCACGAGGGAGC T TCCAGGGGGAAACGCCTGGTATC1TI ATAGTCCTGTCGG GTTTCGCCACCTCTGACTTGAGCGTCGATTTTTGTGATGC TCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAA CGCGGCCTTTTTACGGTTCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTT

[0099] A system provided herein can comprise a vector provided herein. A composition provider herein can comprise a vector provided herein.

[0100] In some embodiments, a vector provided herein is stably inserted in the genome of a host cell (e.g., a host cell provided herein). In some embodiments, a vector provided herein is stably inserted in the genome of a host cell (e.g,, a host cell provided herein) through homologous recombination. Compositions

[0101] In some embodiments, provided herein are compositions of tryptamine alkaloids comprising one or more vectors (e.g., a vector provided herein). In some embodiments, a composition can comprise a vector comprising a system for regulating the expression of one or more enzymes (e.g., an enzyme provided herein) that mediate the biosynthesis of one or more tryptamine alkaloids (e.g., a tryptamine alkaloid provided herein). In certain embodiments, a composition can comprise two different vectors (e.g., two different vectors provided herein), the two vectors comprising a system for regulating the expression of one or more enzymes (e.g., an enzyme provided herein) that mediates the biosynthesis of one or more tryptamine enzymes. In certain embodiments, a composition can comprise three different vectors (e.g., three different vectors provided herein), the three vectors comprising a system for regulating the expression of one or more enzymes (e.g., an enzyme provided herein) that mediates the biosynthesis of one or more tryptamine enzymes. In certain embodiments, a composition can comprise four or more different vectors (e.g., four or more different vectors provided herein), the four or more vectors comprising a system for regulating the expression of one or more enzymes (e.g., an enzyme provided herein) that mediates the biosynthesis of one or more tryptamine enzymes.

[0102] In some embodiments, composition provided herein can comprise a biological reservoir (e.g., a host cell). In some embodiments, a biological reservoir can comprise a biological reservoir provided herein. In some embodiments, a biological reservoir can comprise a cell of the species AspergillusWSGR Docket No. 66180-701.601niger. In some embodiments, a biological reservoir can comprise a cell of the species Escherichia coli. In some embodiments, a biological reservoir can comprise a cell of the species Saccharomyces cerevisiae. A biological reservoir provided herein can be inactivated.

[0103] In some embodiments, a composition provided herein can comprise a chemical compound that is associated with a system for regulating the expression of a gene. In some embodiments, a composition provided herein can be exposed to a chemical compound that is associated with a system regulating the expression of a gene for a duration of at least about 1 hour or more. In some embodiments, a composition provided herein can be exposed to a chemical compound that is associated with a system regulating the expression of a gene for a duration of at most about to about 1 week or less. A composition provided herein can be exposed to a chemical compound that is associated with a system regulating the expression of a gene for a duration of about I hour to about 1 week. In some embodiments, a composition provided herein can be exposed to a chemical compound that is associated with a system regulating the expression of a gene for a duration of about 6 hours to about 5 days. In some embodiments, a composition provided herein can be exposed to a chemical compound that is associated with a system regulating the expression of a gene for a duration of about 12 hours to about 48 hours.

[0104] In some embodiments, a composition provided herein comprises an antibiotic (e.g., tetracycline or doxycycline) associated with a system for regulating the expression of a gene. For example, a composition can comprise an antibiotic whose presence induces expression of a nucleic acid sequence in a tetracycline-controlled transcriptional activation system. In some embodiments, a composition provided herein can be exposed to an that is associated with a system regulating the expression of a gene for a duration of at least about 1 hour or more. In some embodiments, a composition provided herein can be exposed to an antibiotic that is associated with a system regulating the expression of a gene for a duration of at most about to about I week or less. A composition provided herein can be exposed to an antibiotic that is associated with a system regulating the expression of a gene for a duration of about 1 hour to about 1 week. In some embodiments, a composition provided herein can be exposed to an antibiotic that is associated with a system regulating the expression of a gene for a duration of about 6 hours to about 5 days. In some embodiments, a composition provided herein can be exposed to an antibiotic that is associated with a system regulating the expression of a gene for a duration of about 12 hours to about 48 hours.

[0105] In certain embodiments, a composition provided herein comprises tetracycline or a derivative of tetracycline (e.g., doxycycline). In certain embodiments, tetracycline is present in the composition at a concentration of at least about 0.1 µg / ml or greater. In certain embodiments, tetracycline is present in the composition at a concentration of at most 500 µg / ml or less. In certain embodiments, tetracyclineWSGR Docket No. 66180-701.601is present in the composition at a concentration of about 0.1 µg / ml to about 500 µg / ml. In certain embodiments, tetracycline is present in the composition at a concentration of about 1 µg / ml to about 250 µg / ml. In certain embodiments, tetracycline is present in the composition at a concentration of about 10 µg / ml to about 100 µg / ml. In certain embodiments, doxycycline is present in the composition at a concentration of at least about 0.1 µg / ml or greater. In certain embodiments, doxycycline is present in the composition at a concentration of at most 500 µg / ml or less. In certain embodiments, doxycycline is present in the composition at a concentration of about 0.1 µg / ml to about 500 µg / ml. In certain embodiments, doxycycline is present in the composition at a concentration of about 1 µg / ml to about 250 µg / ml. In certain embodiments, doxycycline is present in the composition at a concentration of about 10 µg / ml to about 100 µg / ml.

[0106] In some embodiments, a composition provided herein can comprise an aromatic compound (e.g., an aromatic compound with a structure similar to benzoic acid). For example, a composition can comprise an aromatic compound whose presence induces expression of a nucleic acid sequence in a benzoic acid inducible promoter system. In certain embodiments, a composition provided herein comprises an aromatic compound with a structure similar to benzoic acid. In some embodiments, a composition provided herein comprises benzoate. In certain embodiments, a composition provided herein comprises benzoic acid. Benzoic acid can be present in a composition at a concentration of at least about 0.01 mM or greater. Benzoic acid can be present in a composition at a concentration of at most about 100 mM or less. Benzoic acid can be present in composition at a concentration of about 0.01 mM to about 100 mM. Benzoic acid can be present in composition at a concentration of about 0.1 mM to about 50 mM. Benzoic acid can be present in composition at a concentration of about 0.1 mM to about 25 mM. Benzoic acid can be present in composition at a concentration of about 0.5 mM to about 10 mM. Benzoic acid can be present in composition at a concentration of about 0.8 mM to about 8 mM.

[0107] In some embodiments, a composition provided herein comprises a vitamin associated with a system for regulating the expression of a gene. For example, a composition can comprise a vitamin whose presence reduces expression of a nucleic acid sequence in a thiamine-repressed promoter system. In certain embodiments, a composition provided herein comprises thiamine (vitamin Bl). In certain embodiments, a composition can comprise thiamine at a concentration of at least about 0.001 uM or greater. In certain embodiments, a composition can comprise thiamine at a concentration of at least about 0.001 uM or greater. In certain embodiments, a composition can comprise thiamine at a concentration of at most about 50.0 mM or less. In certain embodiments, a composition can comprise thiamine at a concentration of about 0.001 uM to about 50.0 mM. In certain embodiments, a composition can comprise thiamine at a concentration of about 0.01 uM to about 10.0 mM. In certainWSGR Docket No. 66180-701.601embodiments, a composition can comprise thiamine at a concentration of about 0.1 uM to about 1.0 mM. In certain embodiments, a composition can comprise thiamine at a concentration of about 1 uM to about 0.1 mM.

[0108] In some embodiments, a composition provided herein comprises a sugar associated with a system for regulating the expression of a gene. For example, a composition can comprise a sugar (e.g., sucrose or glucose) whose presence induces expression of a nucleic acid sequence in a sucrose-induced promoter system. In certain embodiments, a composition provided herein comprises sucrose. In certain embodiments, a composition can comprise a sugar at a concentration of at least about 0.1 mM or greater. In certain embodiments, a composition can comprise a sugar at a concentration of at most 1 M or less. In certain embodiments, a composition can comprise a sugar at a concentration of about 0.1 mM to about 1 M. In certain embodiments, a composition can comprise a sugar at a concentration of about 1 mM to about 200 mM. In certain embodiments, a composition can comprise a sugar at a concentration of about 10 mM to about 100 mM. In certain embodiments, a composition can comprise a sugar at a concentration of about 20 mM to about 80 mM.

[0109] In some embodiments, a composition provided herein comprises a tryptamine alkaloid. In some embodiments, a composition provided herein comprises one or more tryptamine alkaloids. In some embodiments, a composition provided herein comprises two or more tryptamine alkaloids. In some embodiments, a composition provided herein comprises three or more tryptamine alkaloids.

[0110] In certain embodiments, a composition provided herein comprises tryptamine. In some embodiments, a composition provided herein can be exposed to for a duration of at least about 1 hour or more. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) for a duration of at most about to about 1 week or less. A composition provided herein can be exposed to a tryptamine alkaloid (e g., tryptamine) for a duration of about 1 hour to about 1 week. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) of about 6 hours to about 5 days. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) for a duration of about 12 hours to about 3 days. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) for a duration of about 24 hours to about 48 hours. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) at a concentration of at least 0.01 mM or more. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) at a concentration of at most 100 mM or less. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) at a concentration of about 0.01 mM to about 100 mM. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) at aWSGR Docket No. 66180-701.601concentration of about 0.1 mM to about 10 mM. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) at a concentration of about 1 mM to about 5 mM. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) at a concentration of about 2 mM to about 3 mM. In some embodiments, a composition provided herein can be exposed to a tryptamine alkaloid (e.g., tryptamine) at a concentration of about 2.5 mM.

[0111] In certain embodiments, a composition provided herein comprises tryptamine, N-methyltryptamine (NMT), AAV-dimethyltryptamine (DMT), A(A(AMrimethyltryptamine (TMT), 4-hydroxy-tryptamine, 4-hydroxy-AAiiethyltryptamine (norpsilocin), 4-hydroxy-A, A'r-di methyltryptamine (psilocin), 4-phosphory I oxy -tryptamine (norbaeocystin), 4-phosphoryloxy-A-methyltryptamine (baeocystin), 4-phosphoryloxy-A(A'-dimethyltryptamine (psilocybin), 4-phosphoryloxy-AAV, A rimethyl tryptamine (aeruginascin), A(A-dimethyl-5-hydroxytryptamine (bufotenine), 5-hydroxytryptamine (serotonin, 5-HT), Ar-m ethyl serotonin, A, A^V-trimethyl serotonin, 5-methoxyserotonin (5-MeO-serotonin), 5-methoxy-A-methyltiy'ptamine (5-MeO-NMT), 5-methoxy-A^V-dimethyltryptamine (5-MeO-DMT), 5-methoxy-A, A, Ar-methyltryptamine (5-MeO-TMT), or combinations thereof. A composition can comprises a tryptamine alkaloid that is substantially purified. A composition can comprises a tryptamine alkaloid that is not substantially purified. A composition can comprise a tryptamine alkaloid that is not purified.Biological reservoirs

[0112] A tryptamine alkaloid synthesized according to a system or method provided herein can be synthesized in a biological reservoir. In certain embodiments, a biological reservoir can maintain a compound (e.g., protect a compound synthesized in the biological reservoir from decomposing, degrading, or breaking down for a period of time). A biological reservoir can maintain a mixture of compounds (e.g., a composition comprising a plurality of tryptamine alkaloids). The biological reservoir can increase the stability of the compound (e.g., a tryptamine alkaloid). In some embodiments, the biological reservoir can increase the duration of time the compound (e.g., a tryptamine alkaloid) is stable. In some embodiments, a biological reservoir can protect its metabolites from the environment (e.g., from degradation associated with exposure to the environment).

[0113] In some embodiments, a biological reservoir provided herein can increase the stability of a compound (e.g., a tryptamine alkaloid disclosed herein) within the biological reservoir. Increasing the stability of a compound can comprise increasing the duration of time until a compound degrades, for example, in comparison to the time to degradation of the compound outside of the biological reservoir. In certain embodiments, a biological reservoir can increase the stability of a biological compound byWSGR Docket No. 66180-701.601at least about 10%, by at least about 25%, by at least 50%, by at least 75%, or by at least about 100%. In some embodiments, the stability of a compound in a biological reservoir can be at least 2 fold, at least 3 fold, at least 5 fold, or at least 10 fold greater than the stability of the compound outside of the biological reservoir.

[0114] Maintaining a compound (e.g., a tryptamine alkaloid) in a biological reservoir can comprise stably maintaining the compound. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater than a year. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater than 9 months. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater than a 6 months. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater than 5 months. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater than 4 months. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater than 3 months. In some embodiments, a biological reservoir can maintain a compound (e g., a tryptamine alkaloid disclosed herein) for at least greater than 2 months. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater 1 month. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater than 3 weeks. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater 2 weeks. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater a week. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater than 5 days. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater 3 days. In some embodiments, a biological reservoir can maintain a compound (e.g., a tryptamine alkaloid disclosed herein) for at least greater than 1 day.

[0115] A biological reservoir provided herein can be a cell (e.g., a host cell). In some embodiments, a cell is a plurality of cells (e.g., a plurality of eukaryotic cells or a plurality of prokaryotic cells). In some embodiments, a cell is a prokaryotic cell (e.g., a bacterial cell). In some embodiments, a prokaryotic cell comprises a cell of the species Escherichia coli, Bacillus subtilis, Corynebacterium glutamicum, Vibrio natriegens, Bacillus megaterium, Escherichia coli Nissle 1917, Clostridium acetobutlyicum, Streptomyces coelicolor, Lactococcus lactis. Pseudomonas putida, Streptomyces clavuligerus, and Streptomyces venezuelae. In certain embodiments, a prokaryotic cell comprises aWSGR Docket No. 66180-701.601cell of the species Escherichia coli. In certain embodiments, a prokaryotic cell comprises a cell of the species Bacillus subtilis. In certain embodiments, a cell is a eukaryotic cell. A eukaryotic cell can be a fungal cell or a plant cell. In certain embodiments, a biological reservoir comprises a fungal cell. In certain embodiments, a biological reservoir comprises a plant cell. A biological reservoir can comprises a cell of the species Aspergillus niger. A biological reservoir can comprise a cell of the species Saccharomyces cerevisiae.

[0116] In some embodiments, a biological reservoir can comprise a cell that has been genetically modified (e.g., to produce an enzyme disclosed herein). In some embodiments, a biological reservoir can comprise a cell that has been deactivated. A biological reservoir provided herein can comprise a system for regulating the production of a compound (e.g., a tryptamine alkaloid).

[0117] In some embodiments provided herein, a biological reservoir can by an Aspergillus niger cell that has been genetically modified to express an enzyme provided herein. A tryptamine alkaloid provided herein can be produced in a biological reservoir comprising an Aspergillus niger cell that has been modified to produce an enzyme disclosed herein.Tryptamine alkaloids

[0118] Provided herein are systems and methods for the synthesis of tryptamine alkaloids. In some embodiments, a system or method provided herein can comprise a system or method of regulating the synthesis of tryptamine alkaloids. i tryptamine alkaloid can be an alkaloid (e.g., a naturally occurring alkaline organic compound that contains at least one nitrogen atom) that is derived from tryptamine (e.g., an indolamine metabolite of the essential amino acid, tryptophan). A tryptamine alkaloid provided herein can be synthesized in a biological reservoir. A biological reservoir can be a host cell (e.g., Aspergillus niger) engineered to express one or more enzymes (e.g., an exogenous enzyme) that mediate the biosynthesis of one or more tryptamine alkaloids provided herein. In some embodiments, a biological reservoir can comprise a system for regulating the expression of the enzymes that mediate the biosynthesis of the tryptamine alkaloids.

[0119] Examples of tryptamine alkaloids provided herein include, but are not limited to, tryptamine alkaloids provided in Table 4. A tryptamine alkaloid can comprise one or more tryptamine alkaloids. In certain embodiments, a tryptamine alkaloid is tryptamine, A-methyltryptamine (NMT), N, N~ dimethyl tryptamine (DMT), A(A’, Ar-trimethyltryptamine (TMT), 4-hydroxy -tryptamine, 4-hydroxy-A-methyltryptamine (norpsilocin), 4-hydroxy-A, A-dimethyltryptamine (psilocin), 4-phosphoiyloxy-tryptamine (norbaeocystin), 4-phosphoryloxy-A-methyltryptamine (baeocystin), 4-phosphoryloxy-AyV-dimethyltryptamine (psilocybin), 4-phosphoryloxy-A, A, A-trimethyltryptamine (aeruginascin), -dimethyl -5 -hydroxy tryptamine (bufotenine), 5-hydroxytryptamine (serotonin, 5-HT), N-WSGR Docket No. 66180-701.601methylserotonin, N, N, A rimethylserotonin, 5-methoxyserotonin (5-MeO-serotonin), 5-methoxy -methyltryptamine (5-MeO-N T), S-methoxy-A^-dimethyltryptamine (5-MeO-DMT), 5-methoxy-AfAAV-methyltryptamine (5-MeO-TMT), or combinations thereof, A tryptamine alkaloid can be tryptamine. In certain embodiments, a tryptamine alkaloid is A-methyltryptamine (NMT). In certain embodiments, a tryptamine alkaloid is AAV-dimethyltryptamine (DMT). In certain embodiments, a tryptamine alkaloid is A(A-dimethyltryptamine (DMT). In certain embodiments, a tryptamine alkaloid is A’. A. A'-trimethyltryptamine (TMT). In certain embodiments, a tryptamine alkaloid is 4-hydroxy-tryptamine. In certain embodiments, a tryptamine alkaloid is 4-hydroxy-V-m ethyltryptamine (norpsilocin). In certain embodiments, a tryptamine alkaloid is 4-hydroxy-A(A-dimethyltryptamine (psilocin). In certain embodiments, a tryptamine alkaloid is 4-phosphoryloxy-tryptamine (norbaeocystin). In certain embodiments, a tryptamine alkaloid is 4-phosphoryloxy-?f-methyl tryptamine (baeocystin). In certain embodiments, a tryptamine alkaloid is 4-phosphoryloxy-A-methyltryptamine (baeocystin). In certain embodiments, a tryptamine alkaloid is 4-phosphoryloxy-AAV-dimethyltryptamine (psilocybin). In certain embodiments, a tryptamine alkaloid is 4-phosphoryloxy-A^ACV-trimethyltryptamine (aeruginascin). In certain embodiments, a tryptamine alkaloid is AAV-dimethyl-S-hydroxytryptamine (bufotenine). In certain embodiments, a tryptamine alkaloid is 5-hydroxytryptamine (serotonin, 5-HT). In certain embodiments, a tryptamine alkaloid is A’-methylserotonin. In certain embodiments, a tryptamine alkaloid is A(A(A’-trimethylserotonin. In certain embodiments, a tryptamine alkaloid is 5-methoxyserotonin (5-MeO-serotonin). In certain embodiments, a tryptamine alkaloid is 5-methoxy-A-methyltryptamine (5-MeO-NMT). In certain embodiments, a tryptamine alkaloid is 5-methoxy -N, A'-dimethyl tryptamine (5-MeO-DMT) In certain embodiments, a tryptamine alkaloid is 5-methoxy-A(A(Ar-methyltryptamine (5-MeO-TMT).

[0120] Table 4: Tryptamine alkaloidsNO Tryptamine Alkaloid Chemical Structure1 tryptamineWSGR Docket No. 66180-701.601NO Tryptamine Alkaloid Chemical Structure 2 N-methyltryptamine (NMT)HNH3 N,N-dimethyltryptamine (DMT)4 N,N,N-trimethyltryptamine (TMT)y;>*N5 4-hydroxy -tryptamineQhHH6 4-hydroxy-N-methyltryptamine(norpsilocin)O: H6 / KhWSGR Docket No. 66180-701.601NO Tryptamine Alkaloid Chemical Structure 7 4-hydroxy-N,N-dimethyltryptamine(psilocin)CH8 4-phosphoryloxy -tryptamine(norbaeocystin).? " G... J HO f £KB9 4-phosphoryloxy-N-methyltryptamine(baeocystin) 0 t-x r%...HOu10 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) o" "-■■■ F"' HO- 9 / •*“*’NH11 4-phosphoryloxy -N, N, N~trimethy 1 tryptami ne (aeruginasci n) 0004H / HO | r'"NWSGR Docket No. 66180-701.601NO Tryptamine Alkaloid Chemical Structure 12 N,N-dimethyl-5-hydroxytryptaminef W-' (bufotenine)Az"" NH13 5-hydroxytryptamine (serotonin, 5-HT) / NH2rA1 / '■" NH14 N-methylserotonin / V"'VH15 N,N,N-trimethylserotonin / _HO x / 4^ XX / / (A / vAH16 5-methoxy serotonin (5-MeO-serotonin) \6XJNH;2io"' NH17 5 -m ethoxy -A’-methyltryptamine (5 - MeO-NMT)° ' * IF & $ <18 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)WSGR Docket No. 66180-701.601NO Tryptamine Alkaloid Chemical Structure19 5-methoxy-N,N,N-methyltryptamine (5-MeO-TMT)0NEnzymes

[0121] Provided herein are systems and methods for regulating the synthesis of tryptamine alkaloids (e.g., psilocybin and serotonin) by a biological reservoir (e.g., a host cell, e.g., Aspergillus niger) engineered to express exogenous enzymes. An enzyme can comprise one or more enzymes. An enzyme (e.g., an enzyme provided herein) can mediate the biosynthesis of one or more tryptamine alkaloids (e.g., a tryptamine alkaloid provided herein). An enzyme can mediate the biosynthesis of one or more tryptamine alkaloids selected from the group consisting of tryptamine, N-methyltryptamine (NMT), N, N-dimethyltryptamine (DMT), N, N, N-trimethyltryptamine (TMT), 4-hydroxy-tryptamine, 4-hydroxy-N-methyltryptamine (norpsilocin), 4-hydroxy-N, N-dimethyltryptamine (psilocin), 4-phosphoryloxy-tryptamine (norbaeocystin), 4-phosphoryloxy-N-methyltryptamine (baeocystin), 4-phosphoryloxy-N, N-dimethyltryptamine (psilocybin), 4-phosphoryloxy-N, N, N-trimethyltryptamine (aeruginascin), N,N-dimethyl-5-hydroxytryptamine (bufotenine), 5-hydroxytryptamine (serotonin, 5-HT), N-methylserotonin, N, N, N-trimethylserotonin, 5-methoxyserotonin (5-MeO-serotonin), 5- methoxy -N-methyltryptamine (5-MeO-NMT), 5 -methoxy-N, N-dimethyl tryptamine (5-MeO-DMT), 5 -methoxy -N, N, N-methyltryptamine (5-MeO-TMT), or combinations thereof. In some embodiments, an enzyme is associated with the biosynthesis of psilocybin, and derivatives and intermediaries of the synthesis thereof. In some embodiments, an enzyme is associated with the biosynthesis of serotonin, and derivatives and intermediaries of the synthesis thereof.

[0122] An enzyme can be a biosynthetic enzyme in eukaryotes (e.g., plants or fungi) or in prokaryotes. In certain embodiments, an enzyme comprises an enzyme endogenous to a fungus. In certain embodiments, an enzyme comprises an enzyme endogenous to a mushroom of the genus Psilocybe (e.g., P. cubensis, P. azurescens, P. semilanceata, or P. cyanescens). In certain embodiments, an enzymes is an enzyme endogenous to a plant.

[0123] In some embodiments, an enzyme provided herein has A^V-methylation activity (e.g., of tryptamine to dimethyltryptamine). In some embodiments, an enzymes provided herein has hydroxylation activity (e.g., of dimethyltryptamine to psilocin or of tryptamine to serotonin). In some embodiments, an enzyme provided herein has phosphorylation activity (e.g., of psilocin to psilocybin).WSGR Docket No. 66180-701.601In some embodiments, an enzyme provided herein has methyltransferase activity (e.g., of serotonin to 5-MeO-serotonin or of 5-MeO-serotonin to 5-MeO-DMT). In some embodiments, an enzyme has kinase activity (e.g., transfer of phosphate groups). In some embodiments, an enzyme has monooxygenase activity (e.g., insertion of an oxygen atom). In some embodiments, an enzyme has synthase activity (e.g., catalyzes a synthesis process). In some embodiments, an enzyme has reductase activity (e.g., promotes reduction).

[0124] In some embodiments, an enzyme provided herein is a methylase. In some embodiments, an enzymes provided herein is a hydroxylase. In some embodiments, an enzyme provided herein is a phosphorylase. In some embodiments, an enzyme provided herein is a methyltransferase. In some embodiments, an enzyme is a kinase. In some embodiments, an enzyme is a monooxygenase. In some embodiments, an enzyme is a synthase. In some embodiments, an enzyme is a reductase.

[0125] In some embodiments, an enzyme described herein is a subtype of another enzyme provided herein or of the same class of enzymes. For example, an enzyme provided herein, 5-OH-INMT is a subtype of the ASMT enzyme.Examples of exogenous enzymes provided herein include, but are not limited to, enzymes provided in Table 5. In certain embodiments, an enzyme associated with the production of a tryptamine alkaloid in a method or system provided herein comprises tryptamine 4-monooxygenase (PsiH), hydroxytryptamine kinase (PsiK), Rhinella marina indolethylamine N-methyltransferase (RmINMT), Psilocybin synthase (PsiM), tryptamine 5-hydroxylase (T5H), acetyl serotonin methyltransferase (ASMT), 5-hydroxy-indolethylamine-N-methyltransferase (5OH-INMT), ora combination thereof. In certain embodiments, an enzyme comprises tryptamine 4-monooxygenase (PsiH). In certain embodiments, an enzyme comprises hydroxytryptamine kinase (PsiK). In certain embodiments, an enzyme comprises psilocybin synthase (PsiM). In certain embodiments, an enzyme com prises Rhinella marina indolethylamine N-methyltransferase (RmINMT). In certain embodiments, an enzyme comprises tryptamine 5-hydroxylase (T5H). In certain embodiments, an enzyme comprises acetyl serotonin methyltransferase (ASMT). In certain embodiments, an enzyme comprises 5-hydroxy-indolethylamine-N-methyltransferase (5OH-INMT).

[0126] A vector provided herein can comprise a nucleic acid sequence encoding an enzyme provided herein (e.g., an enzyme that mediates the biosynthesis of one or more tryptamine alkaloids). In some embodiments, provided herein are vectors (e.g., a first vector or a second vector) comprising a nucleic acid sequence encoding an enzyme (e.g., an enzyme provided herein). In some embodiments, provided herein are vector systems comprising a first vector, a second vector, and a third vector, the first vector comprising a nucleic acid sequence encoding an enzyme provided herein and the third vector comprising a second nucleic acid sequence encoding an enzyme provided herein. In certainWSGR Docket No. 66180-701.601embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 1. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 2. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 3. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 4. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 5. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 6. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 17. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 40. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 41. In certain embodiments, a vector provide herein can comprise a nucleic acid sequence (e.g., a nucleic acid sequence of the first vector or a second nucleic acid sequence of the third vector) comprising SEQ ID NO: 42. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 1. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 2. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 3. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40%WSGR Docket No. 66180-701.601sequence identity to SEQ ID NO: 4. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 5. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 6. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 17. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 40. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 41. In some embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a sequence of nucleic acids having at least about 99%, 97%, 95%, 93%, 90%, 87%, 85%, 83%, 80%, 77%, 75%, 73%, 70%, 67%, 65%, 63%, 60%, 57%, 55%, 53%, 50%, 45%, or 40% sequence identity to SEQ ID NO: 42.

[0127] In some embodiments, a vector provided herein comprises a nucleic acid encoding a plurality of nucleic acid sequences encoding one or more enzymes provided herein. For example, a vector provided herein can comprise nucleic acid sequences encoding PsiM and PsiK In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising SEQ ID NO: 2 and a nucleic acid sequence comprising SEQ ID NO: 3. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 70% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 70% sequence identity SEQ ID NO: 3. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 80% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 80% sequence identity SEQ ID NO: 3. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 85% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 85% sequence identity SEQ ID NO:WSGR Docket No. 66180-701.6013. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 90% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 90% sequence identity SEQ ID NO: 3. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 95% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 95% sequence identity SEQ ID NO: 3.

[0128] In certain embodiments, a vector provided herein can comprise nucleic acid sequences encoding ASMT, T5H, and 5OH-INMT. In certain embodiments, a vector provided herein can comprise nucleic acid sequences comprising SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 70% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 75% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 80% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 85% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 90% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 95% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6.

[0129] In some embodiments provided herein are vector systems for regulating the biosynthesis of tryptamine alkaloids, the vector systems comprising a first vector, a second vector, and, optionally, a third vector. For example, a vector systems provided herein can comprise a first vector comprising nucleic acid sequences encoding ASMT, T5H, and 5OH-INMT, and a second vector. For example, a vector systems provided herein can comprise a first vector comprising nucleic acid sequences comprising SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, and a second vector.

[0130] In certain embodiments, a vector system provided herein can comprise a first vector comprising a nucleic acid sequence encoding Psill and a second vector. In certain embodiments, a vector system provided herein can comprise a first vector comprising SEQ ID NO: 1 and a second vector.

[0131] In certain embodiments, a vector system provided herein can comprise a first vector comprising nucleic acid sequences encoding PsiK and PsiM and a second vector. In certain embodiments, a vectorWSGR Docket No. 66180-701.601system provided herein can comprise a first vector comprising nucleic acid sequences comprising SEQ ID NO: 2 and SEQ ID NO: 3 and a second vector.

[0132] In certain embodiments, a vector system provided herein can comprise a first vector, the first vector comprising a nucleic acid sequence encoding PsiH, a second vector, and a third vector, the third vector comprising nucleic acid sequences encoding PsiK and PsiM. In certain embodiments, a vector system provided herein can comprise a first vector, the first vector comprising a nucleic acid sequence comprising SEQ ID NO: 1, a second vector, and a third vector, the third vector comprising nucleic acid sequences comprising SEQ ID NO: 2 and SEQ ID NO: 3.

[0133] In some embodiments, a vector provided herein comprises a nucleic acid encoding a plurality of nucleic acid sequences encoding one or more enzymes provided herein. For example, a vector provided herein can comprise nucleic acid sequences encoding RmINMT and PsiK. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising SEQ ID NO: 2 and a nucleic acid sequence comprising SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 70% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 70% sequence identity SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 80% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 80% sequence identity SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 85% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 85% sequence identity SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 90% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 90% sequence identity SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising a nucleic acid sequence having at least about 95% sequence identity with SEQ ID NO: 2 and a nucleic acid sequence comprising a nucleic acid sequence having at least about 95% sequence identity SEQ ID NO: 17.

[0134] In certain embodiments, a vector provided herein can comprise nucleic acid sequences encoding RmINMT, T5H, and ASMT. In certain embodiments, a vector provided herein can comprise nucleic acid sequences comprising SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 70% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 17. In certainWSGR Docket No. 66180-701.601embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 75% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 80% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 85% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 90% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 95% sequence identity to each of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 17.

[0135] In some embodiments provided herein are vector systems for regulating the biosynthesis of tryptamine alkaloids, the vector systems comprising a first vector, a second vector, and, optionally, a third vector. For example, a vector systems provided herein can comprise a first vector comprising nucleic acid sequences encoding RmINMT, T5H, and ASMT, and a second vector. For example, a vector system provided herein can comprise a first vector comprising nucleic acid sequences comprising SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 17 and a second vector.

[0136] In certain embodiments, a vector system provided herein can comprise a first vector comprising a nucleic acid sequence encoding PsiH and a second vector. In certain embodiments, a vector system provided herein can comprise a first vector comprising SEQ ID NO: 1 and a second vector.

[0137] In certain embodiments, a vector system provided herein can comprise a first vector comprising nucleic acid sequences encoding PsiK and RmINMT and a second vector. In certain embodiments, a vector system provided herein can comprise a first vector comprising nucleic acid sequences comprising SEQ ID NO: 2 and SEQ ID NO: 17 and a second vector,

[0138] In certain embodiments, a vector system provided herein can comprise a first vector, the first vector comprising a nucleic acid sequence encoding PsiH; a second vector; and a third vector, the third vector comprising nucleic acid sequences encoding PsiK and RmINMT. In certain embodiments, a vector system provided herein can comprise a first vector comprising a nucleic acid sequence comprising SEQ ID NO: 1, a second vector, and a third vector comprising nucleic acid sequences comprising SEQ ID NO: 2 and SEQ ID NO: 17.

[0139] In certain embodiments, a vector described herein can comprise a nucleic acid sequence encoding PsiH. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence comprising SEQ ID NO: 40, In certain embodiments, a vector provided herein can comprise a nucleic acid sequence having at least about 70% sequence identity to a nucleic acid sequence set forth in SEQ ID NO: 40. In certain embodiments, a vector provided herein can comprise a nucleic acid sequenceWSGR Docket No. 66180-701.601having at least about 75% sequence identity to a nucleic acid sequence set forth in SEQ ID NO: 40. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence having at least about 80% sequence to a nucleic acid sequence set forth in SEQ ID NO. 40. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence having at least about 85% sequence identity to a nucleic acid sequence set forth in SEQ ID NO: 40. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence having at least about 90% sequence identity to a nucleic acid sequence set forth in SEQ ID NO: 40. In certain embodiments, a vector provided herein can comprise a nucleic acid sequence having at least about 95% sequence identity to a nucleic acid sequence set forth in SEQ ID NO: 40.

[0140] In some embodiments provided herein are vector systems for regulating the biosynthesis of tryptamine alkaloids, the vector systems comprising a first vector, a second vector, and, optionally, a third vector. For example, a vector system provided herein can comprise a first vector comprising a nucleic acid sequence encoding PsiH, and a second vector. For example, a vector system provided herein can comprise a first vector comprising a nucleic acid sequence comprising SEQ ID NO: 40 and a second vector.

[0141] In certain embodiments, a vector provided herein can comprise nucleic acid sequences encoding RmINMT, PsiK, and NADPH-ferrihemoprotein reductase (CPR). In certain embodiments, a vector provided herein can comprise nucleic acid sequences comprising SEQ ID NO: 41, SEQ ID NO: 18, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 70% sequence identity to each of SEQ ID NO: 41, SEQ ID NO: 18, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 75% sequence identity to each of SEQ ID NO: 41, SEQ ID NO: 18, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 80% sequence identity to each of SEQ ID NO: 41, SEQ ID NO: 18, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 85% sequence identity to each of SEQ ID NO: 41, SEQ ID NO: 18, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 90% sequence identity to each of SEQ ID NO: 41, SEQ ID NO: 18, and SEQ ID NO: 17. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 95% sequence identity to each of SEQ ID NO: 41, SEQ ID NO: 18, and SEQ ID NO: 17.

[0142] In some embodiments provided herein are vector systems for regulating the biosynthesis of tryptamine alkaloids, the vector systems comprising a first vector, a second vector, and, optionally, a third vector. For example, a vector system provided herein can comprise a first vector comprisingWSGR Docket No. 66180-701.601nucleic acid sequences encoding Am INMT, PsiK, and CPR, and a second vector. For example, a vector system provided herein can comprise a first vector comprising nucleic acid sequences comprising SEQ ID NO: 41, SEQ ID NO: 18, and SEQ ID NO: 17 and a second vector.

[0143] In certain embodiments, a vector provided herein can comprise nucleic acid sequences encoding / ?mINMT, T5H, and ASMT. In certain embodiments, a vector provided herein can comprise nucleic acid sequences comprising SEQ ID NO: 17, SEQ ID NO: 4, and SEQ ID NO: 42. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 70% sequence identity to each of SEQ ID NO: 17, SEQ ID NO: 4, and SEQ ID NO: 42. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 75% sequence identity to each of SEQ ID NO: 17, SEQ ID NO: 4, and SEQ ID NO: 42. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 80% sequence identity to each of SEQ ID NO: 17, SEQ ID NO: 4, and SEQ ID NO: 42. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 85% sequence identity to each of SEQ ID NO: 17, SEQ ID NO: 4, and SEQ ID NO: 42. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 90% sequence identity to each of SEQ ID NO: 17, SEQ ID NO: 4, and SEQ ID NO: 42. In certain embodiments, a vector provided herein can comprise nucleic acid sequences having at least about 95% sequence identity to each of SEQ ID NO: 17, SEQ ID NO: 4, and SEQ ID NO: 42.

[0144] In some embodiments provided herein are vector systems for regulating the biosynthesis of tryptamine alkaloids, the vector systems comprising a first vector, a second vector, and, optionally, a third vector. For example, a vector system provided herein can comprise a first vector comprising nucleic acid sequences encoding RmINMT, T5H, and ASMT, and a second vector. For example, a vector system provided herein can comprise a first vector comprising nucleic acid sequences comprising SEQ ID NO: 17, SEQ ID NO: 4, and SEQ ID NO: 42 and a second vector.

[0145] Table 5: EnzymesSEQ ID NO. Enzyme Sequence1 Tryptamine 4- ATGATCGCTGTACTA ITTTCTTITGTCATC GCTGGATGCATCTACTACATTGTATCACG monooxygenase (PsiH)CCGAGTGCGAAGATCACGGCTTCCTCCCG GGCCGCCCGGCATACCTATACCGTTCATT GGCAACATGTTTGATATGCCTGAAGAATC CCCATGGCTCACCTICCTCCAATGGGGTC GAGACTACAATACCGATATCCTGTATGTT GACGCCGGAGGCACGGAGATGGTTATTT GAATACGCTCGAGACCATCACTGATTTAC TGGAGAAGCGGGGCAGCATCTATTCCGGT CGTCTGGAATCCACTATGGTTAACGAATT GATGGGGTGGGAGTTTGACCTTGGATTCATCACTTACGGAGATCGCTGGCGGGAAGAGWSGR Docket No. 66180-701.601SEQ ID NO. Enzyme Sequence CGTCGCATGTTCGCCAAAGAATTCAGCGA AAAGGGGATCAAACAATTCCGGCATGCCC AGGTGAAGGCCGCACACCAACTAGTGCA ACAGCTGACAAAGACCCCTGATCGATGGG CACAGCACATCCGCCATCAGATCGCCGCC ATGTCGCTGGACATCGGATACGGGATTGA CCTCGCTGAAGACGACCCGTGGCTAGAGG CGACCCACCTCGCCAACGAGGGTCTCGCG ATAGCAAGCGTGCCTGGCAAGTTCTGGGT GGACTCTTTCCCCTCTCTGAAGTACTTGCC TGCCTGGTTCCCGGGGGCGGTCTTCAAGC GTAAAGCGAAAGTCTGGAGGGAAGCGGC GGATCATATGGTCGATATGCCGTACGAAA CAATGAGAAAACTGGCACCCCAGGGACT CACCCGGCCGTCGTATGCTTCAGCGAGGC TTCAGGCAATGGACTTGAATGGTGATCTA GAGCACCAGGAGCATGTAATTAAGAATA CTGCTGCTGAGGTCAATGTGGGCGGCGGT GACACCACGGTCAGTGCAATGTCCGCGTT TATTTTGGCCATGGTCAAATACCCCGAGG TTCAAAGGAAGGTCCAGGCCGAGCTTGAT GCTTTGACCAACAATGGGCAGATACCAGA CTATGATGAGGAGGACGATTCCTTGCCAT ATTTGACAGCCTGCATCAAGGAGCTCTTC CGATGGAACCAAATTGCCCCACTTGCCAT CCCACACAAGCTGATGAAGGATGATGTCT ATAGGGGATACCTTATCCCCAAGAACACG CTGGTGTTTGCCAATACCTGGGCTGTTCTC AATGACCCCGAAGTCTATCCAGATCCTTC TGTGTTCCGCCCGGAAAGATACCTCGGCC CCGATGGTAAACCCGACAACACTGTTCGC GATCCTAGAAAGGCTGCCTTCGGCTACGG TCGTCGTAACTGTCCGGGAATCCATCTGG CACAATCGACAGTTTGGATTGCTGGTGCT ACGCTCCTGAGTGCCI TCAACAI TGAGCG TCCAGTCGACCAGAACGGCAAGCCGATCG ACATACCCGCGGACTTTACCACAGGCTTTTTCCGCCACCCTGTACCCTTCCAGTGTCGC TTTGTTCCGAGAACTGAGCAAGTCTCGCA GAGTGTGAGCGGCCC AHydroxytryptamine kinase ATGCATATCCGCAACCCCTACCGGACGCC AA TCGACTACCAGGCG ITATCGGAAGCCT(PsiK)TCCCACCGCTGAAGCCCTTTGTGTCCGTC AATGCTGATGGCACTTCGAGTGTCGACCT GACCATCCCTGAAGCGCAAAGAGCTTTCA CAGCTGCGCTGTTGCACCGGGACTTCGGC CTCACCATGACTATCCCCGAAGACAGATT ATG TCC TACGGTGCCCAACCGACI CAACT ATGTCCTCTGGATTGAGGATATTTTCAACT ACACCAACAAGACCCTCGGTCTGTCTGAT GACCGGCCCATCAAGGGCGTGGATATCGG AACCGGTGCTTCTGCTATCTACCCCATGCTTGCCTGCGCGCGCTTCAAGGCCTGGAGCAWSGR Docket No. 66180-701.601SEQ ID NO. Enzyme Sequence TGGTGGGCACGGAAGTTGAGAGGAAATG TATTGACACCGCACGTTTGAATGTGGTCG CCAACAACCTTCAAGATCGATTGTCCATC CTGGAGACTAGCATTGATGGTCCAATCCT CGTTCCGATCTTCGAGGCAACGGAGGAAT ACGAATATGAGTTTACAATGTGCAATCCT CCTTTCTACGATGGAGCTGCCGACATGCA GACGTCCGATGCAGCCAAGGGATTTGGCT TTGGTGTTGGCGCGCCGCACTCCGGAACTGTAATAGAGATGAGCACAGAGGGGGGG AGAGTGCCTTTGTAGCTCAGATGGTCCGT GAATCGCTAAAACTTCGTACCCGCTGCCG ATGGTATACTTCCAATCTTGGGAAATTGA AGAGCTTGAAGGAGATTGTCGGTCTACTC AAGGAACTGGAAATATCGAATTACGCCAT CAACGAGTATGTGCAAGGATCAACAAGG CGCTATGCAGTTGCATGGTCCTTCACCGA CATTCAGCTACCAGAGGAGCTGAGTCGGC CTTCAAATCCGGAGCTCTCATCTCTCTTC3 Psilocybin synthase (PsiM) ATGGCGTTTGATCTGAAGACGGAGGATGG TCTCATCACCTACCTCACTAAGCATCTGA GCCTCGATGTCGACACTTCGGGGGTAAAG CGGCTCTCGGGGGGCTTCGTTAATGTCAC CTGGCGAATCAAACTCAACGCTCCATACC AAGGCCATACGAGCATAATTCTAAAACAT GCTCAGCCTCATATGTCTACCGACGAAGA TTTTAAAATTGGCGTGGAGCGCAGTGTCT ATGAGTATCAGGCCATCAAGCTGATGATG GCCAATCGGGAAGTTTTGGGAGGTGTGGA CGGAATTGTCTCTGTGCCGGAAGGGCTGA ACTACGATTTGGAGAACAATGCACTTATC ATGCAGGACGTGGGCAAGATGAAGACCC TACTGGACTATGTAACTGCCAAACCTCCCTTGGCGACGGATATCGCGAGGCTCGTGGG GACCGAGATAGGAGGTTTCGTCGCTAGGT TGCACAACATTGGCCGTGAAAGACGCGAC GACC CGGAGTTC AAGTTCT TCAGCGGTAA TATTGTTGGTCGTACGACTTCTGACCAGTT GTACCAGACCATTATCCCAAATGCGGCAA AGTATGGCGTGGATGACCCTCTCCTACCG ACCGTCGTGAAGGATCTCGTTGATGATGT AATGCACTCAGAGGAGACAC TGGTGATG GCAGACCTTTGGTCGGGGAATATCTTACT ACAACTGGAAGAGGGTAACCCCTCCAAA CTGCAGAAGATCTACATCTTGGACTGGGA GCTGTGTAAATACGGCCCCGCCTCCCTTG ATCTTGGGTACTTTTTGGGCGACTGCTACCTTATATCGCGGTTCCAGGATGAGCAGGTT GGAACAACCATGAGACAAGCCTACCTGC AATCATATGCACGCACCTCCAAGCACTCC ATCAACTATGCCAAGGTTACTGCTGGTAT TGCTGCCCACATCGTCATGTGGACAGACT TC ATGCAATGGGGAAGCGAGGAAGAACGC ATTAACTTTGTC AAGAAGGGCGTCGCTGWSGR Docket No. 66180-701.601SEQ ID NO. Enzyme Sequence CTTTCCACGATGCACGAGGAAACAACGAC AATGGCGAAATCACAAGTACTCTGCTCAA AGAGAGTTCCACAGCG4 Tryptamine 5-hydroxylase ATGGAGCTGACGATGGCTTCTACAATGAG TCTAGCACTGCTCGTTCTGTCAGCAGCAT(T5H)ATGTCCTTGTGGCCTTACGACGATCGAGG AG TAGCAGCAGCAAACCGAGACGGCTTC CGCCCTCCCCTCCCGGCTGGCCCGTCATC GGCCATCTCCATTTGATGTCTGGCATGCCT CACCACGCGTTAGCGGAGCTGGCGCGCAC CATGAGAGCACCTTTGTTCCGCATGCGTC TGGGCTCCGTGCCAGCAGTTGTCATTTCC AAACCAGACTTGGCGCGGGCGGCGTTGAC GACAAATGATGCTGCCTTGGCATCACGCC CCCACCTCCTGTCCGGTCAATTCCTCTCGT TCGGGTGTTCCGATGTTACGTTCGCTCCG GCTGGGCCATATCACCGGATGGCCAGGAG AGTGGTGGTAAGCGAGTTGCTTTCTGCGC GACGCGTTGCTACCTACGGGGCGGTGCGT GTTAAGGAATTGCGTCGCCTCCTGGCTCA TCTGACCAAGAACACTTCGCCAGCCAAGC CTGTCGACCTCTCGGAGTGCTTCCTCAATC TAGCAAACGACGTGCTATGTCGGGTAGCC TTTGGTCGGCGGTTTCCGC ATGGCGAAGG TGATAAGTTTGGGAGCTGTGCTCGCCGAGG CTCAGGATCTGTTTGCCGGCTTCACCATA GGCGACTTCTTCCCCGAGCTTGAGCCTGT CGCTTCAACAGTCACTGGACTCAGACGCC GGTTGAAGAAGTGCTTGGCGGATCTCCGT GAGGCCTGTGACGTAATCGTCGATGAACACACTATCGGGAAATCGCCAGCGTATCCCCG GTGACCGAGACGAGGACTTTGTGGATGTT TTGCTCCGAGTGCAGAAGTCACCGGATCT GGAGGTTCCACTCACTGATGACAACCTGA AAGCCCTAGTGCTTGACATGTTTGTCGCC GGGACCGATACCACTTTGCCACGCTCGA ATGGGTAATGACCGAACTCGTCCGCCATC CGCGCATTCTAAAAAAGGCCCAGGAGGA AGTAAGACGTGTGGTGGGAGACAGTGGA CGGGTCGAGGAATCCCATCTTGGAGAGTT ACACTACATGCGCGCCATCATCAAAGAGA CCI TCCGACTGCATCCTGCTGTrCCCTTGC TCGTCCCTCGCGAGTCTGTTGCGCCTTGCA CACTCGGGGGTTATGATATTCCTGCTAGG ACAAGGGTCTTCATCAACACGTTCGCCAT GGGCCGAGATCCAGA A ATCTGGGAC AAT CCGCTGGAGTACAGCCCCGAAAGGTTCGAATCTGCAGGAGGCGGTGGAGAGATTGATC TGAAGGACCCCGACTACAAGCTGCTTCCG TTCGGTGGTGGGAGAAGGGGCTGCCCAG GCTACACCTTTGCGCTGGCTACAGTGCAA GTCTCCCTCGCTTCTCTCCTGTACCACTTT GAGTGGGCCCTTCCCGCTGGAGTAAGGGCAGAGGA TGTCAACCTGGATGAGACT ITCGWSGR Docket No. 66180-701.601SEQ ID NO. Enzyme Sequence GTCTTGCCACGCGTAAAAAGGAACCACTG TTCGTCGCAGTTCGCAAGTCAGACGCCTA TGAATTCAAGGGCGAAGAGCTTAGCGAA GIT5 Acetylserotonin ATGGGCTCCTCTGAGGACCAGGCATATCG TCTCCTTA ATG A CT ATGCCA A CGGATTCAmethyltransferaseTGGTGTCCCAGGTGCTTTTTGCGGCTTGTG(ASM!) AGCTTGGCGTCTTTGACCTGTTGGCAGAA GCCCCAGGGCCGTTGGACGTTGCTGCAGT AGCTGCGGGTGTTCGCGCGAGCGCCCACG GGACGGAGCTGCTCCTGGATATATGCGTA TCACTGAAGCTGCTGAAGGTGGAAACACG GGGCGGTAAAGCCTTC TACCGCAACACCG AACTGAGCTCAGATTATCTGACAACTGTC AGCCCGACTAGTCAATGTAGCATGCTCAA GTACATGGGACGCACGTCCTACCGGTGCT GGGGTCACCTTGCCGATGCTGTTCGCGAA GGTAGGAACCAGTACI TGGAGACCTTCGG TGTACCTGCCGAGGAACTGTTCACCGCTA TTTACCGATCTGAAGGCGAAAGGTTGCAA TTCATGCAGGCTTTGCAGGAGGTCTGGTC GGTCAATGGCAGAAGCGTCCTGACAGCAT TTGATCTATCAGTGTTTCCTCTCATGTGTGATCTGGGAGGCACCTGGATCAAGCTGGAG ACGATCATCTTAAGTAAATTATCTCAGGG CCAAAAGACGAAGCATCGTGTTTTTCTCCC TCATTGGAGGAGCCGGGGCTCTTGCCAAG GAGTGCATGTCGCTATATCCCGGCTGCAA GATCACTGTGTTCGATATCCCCGAAGTCG TGTGGACTGCGAAGCAGCACTTTTCCTTC CAAGAAGAGGAGCAAATCGACTTTCAAG AGGGGGACTTCTTCAAAGATCCGCTCCCC GAGGCGGACCTCTACATACTAGCACGCGT CCTCCACGACTGGGCTGACGGGAAGTGTA GTCATCTCCTAGAACGGATTTATCATACC TGCAAACCTGGTGGAGGGATCCTCGTCATTGAGTCGTTGCTCGATGAGGATAGACGAG GACCACTTCTGACCCAGCTGTATTCGCTC AACATGTTGGTTCAAACCGAGGGCCAGGA ACGAACTCCCACACATTACCACATGCTGT TGTCTTCCGCGGGCTTTCGTGATTTCCAGT TCAAGAAGAC AGGTGCC A TCTACGACGCC ATTCTTGCACGGAAA6 5 -hydroxy-indolethylamine- ATGGAAGGCAAGGTCTACATCGGCGGCG AAGACTATGAGAAAGAATTCACTCCTAAGjV-methyltran sferaseGACTACCTCACCACCTACTACAGCTTCCA(50H-INMT) CTCCGGGCCGGTAGCCGAGCAGGAGATTG TCAAGTTCAGCTTGCAGAACCTCTATCAA ACCTTCTCCACCGGCGGTGTTGGAGGGGA TGITITAA ITGATAI AGGGTC AGGGCCAA CTA TCTACCAACTCCI CAGCGCC TGTGAG GTGTTTCGCGAGATCATTGTTACGGATTA TACCCCCCAGAATCTTCAAGAACTGCAGAAGTGGCTGAAGAAGGAGCCGGGTGCATAWSGR Docket No. 66180-701.601SEQ ID NO. Enzyme Sequence CGACTGGTCGAGTATTGTGCAGCATGCTTGTGAATTGGAGGGTGATCGTTCGAGATGGCAGGAAAAAGAGGCGAAATTAAGGCGAACGGTGACACGGGTGCTTCGCTGCGATGTG ACCAAGACACCTCCACTAGGAAGTGCACA AGTCCCACTGGCGGACTGTGTCCTGACAT TTCTGGCCATGGAGTGTGCCTGTCCCGAC ATCGACACTTATCGTGCTGCGCTACGAAG GTTGGCTGGTCTTCTCAAGCCCGGCGGCC ACTTGGTAACGCTAGTTACTCTGCGCTTCC AGCACTACATGGTCGGACCGAAAAAGTTT TCTGGAGTTTATCTGGAGAAGGAAGTGGT GGAGAAGGCCATCCAAGATGCTGGATGC CAGGTCCTTAAATGCAACTGCGTCTCGCT CTCTTATTCCGAAGCCTACTGCTCCCATGA TGGTCTC TGCT TCGTCG TAGCGCGGAAGG GCCCTTCAGCA17 Rhinella marina ATGGAGAACTC Al ACTCTGC AC AGATGTA CATTGAIGAATTTGATCCTGTACACTACTindolethylamine N- ACCAGACATACTATTCTTCGGGGAAAGGAmethyltransferase GGTATCGCTAGAGAATGGACAGACTTTGC CTTACAGAATCTGCATGAAACATTTGGTC(RmINMT)CAGGAGGTGTGAAAGGAGACATACTAAT TGACTTTGGAGCTGGACCCACAATTATC AACTGCTCTCTGCTTGTGAAGTGTTCAAC AGCATTATAACCTCTGATTTCTTGAGCA AAACCGAGAGCAATTGGAAAAATGGCTG AGAAAGGACCCAGATGCCTTAGACTGGTC TCATTTTACCAAATATGTGTGTGAACTGG AAGGTAACAGAGATAACTGGGAAAAAAA GGAAGAAACGCTGAGGAGAAAAGTAACC AAAGTGTTGAAGTGTGACGCTCTTGCGGA GAAGCCATTTGACGACGTGCCTATGCCAG AAGCCGACTGTCTGATTAGCTGCCTCTGC TTAGAAAATCCTTGTCAAGACCAAGAAGC TTATATC AA TATATTGAAAAAGC I’TAAGG AGCTACTTAAACCCGGTGGTCACATTATA ATTCAGAGTATTCTTAATTGTTCATACTAC CATATTGGTAACAGCTGTTTTTCCCATCTG TCCTTATCTAAGGATGACGTGGAAAAATC ATTTAAAGAGGCCGGGTATGAAATTGTTA AATTAAAGGTGCTGCCACGATCTGTAATG TCAGAAATGGAGATCAGTGATTCTAATGG CTATTACTTTATCCATGCTCGTAAACCACA GAAAGAGTAA40 Psilocybe cubensis ATGATCGCCGTTCTGTTTTTCTTTGTCATC GCAGGCTGCATCTACTACATTGTGTCTCGtryptamine 4- GAGGGTGCGCCGCTCCCGATTGCCCCCGGmonooxygenase (PsiH) GACCCCCAGGTATCCCCATTCCATTTATA GGCAACATGTTTGACATGCCGGAGGAAAcoding sequenceGCCCATGGC I’CACC T1 CCTTCAGTGGGGC (optimized for CGCGACTACAACACCGACATCCTGTATGT CGACGCGGGAGGTACTGAGATGGTCATTCAspergillus niger)TCAACACTCTAGAGACCATCACTGACCTTWSGR Docket No. 66180-701.601SEQ ID NO. Enzyme Sequence CTGGAGAAACGTGGGTCGATCTATTCCGG CCGTCTTGAATCGACCATGGTCAACGAGT TGATGGGCTGGGAGTTCGATTTAGGGTTCATCACCCTATGGCGATCGGTGGAGAGAGG AGCGGCGCATGTTCGCTAAGGAATTCTCC GAGAAGGGGATCAAGCAATTCCGACATG CACAGGTCAAGGCAGCGCATCAGTTGGTA CAGCAGCTGACGAAGACGCCAGACAGGT GGGCTCAGCACATAAGGCACCAGATTGCG GCCATGAGTTTGGATATAGGTTACGGAAT TGATCTAGCCGAAGACGACCCCTGGCTGG AGGCCACTCATCTGGCGAATGAGGGACTC GCAATTGCTTCTGTGCCTGGGAAATTCTG GGTCGACTCCTTCCCTTCCCTTAAATACCT CCCCGCATGGTTCCCCGGCGCGGTTTTCA AGCGGAAGGCCAAGGTCTGGCGTGAAGC TGCTGATCACATGGTGGATATGCCGTACG AGACGATGCGAAAACTAGCACCACAAGG CCTGACAAGACCAAGCTATGCCAGTGCTC GACTCCAAGCGATGGATTTGAATGGAGAT CTTGAACACCAAGAGCATGTCATCAAGAA CACCGCCGCAGAGGTGAATGTTGG TGGTG GGGATACCACTGTGTCGGCTATGAGCGCT TTTATCCTCGCAATGGTTAAATATCCCGA GGTCCAACGAAAGGTTCAAGCCGAACTCG ACGCTTTGACGAACAACGGTCAGATACCA GACTATGACGAAGAAGACGATTCGCTGCC GI ACC rCACGGCTIGTATCAAAGAGCTCT TTCGCTGGAACCAGATCGCCCCTCTGGCC ATTCCGCACAAGCTGATGAAGGATGATGT GTACCGTGGATATTTGATTCCCAAGAATA CGCTTGTGTTTGCCAACACATGGGCCGTG CTTAATGACCCTGAAGTGTATCCGGATCC AAGTGTCTTCAGACCTGAACGTTACCTAGG GCCCTGATGGAAAGCCTGACAACACAGTT AGGGATCCCCGCAAAGCAGCCTTTGGCTA CGGTCGTCGCAATTGCCCGGGTATTCATC TTGCCCAAAGCACAGTGTGGATCGCTGGTGCGACTCTCTTGTCAGCGTTCAACATCGA GCGCCCGGTTGATCAGAATGGCAAGCCCA TCGATATTCCTGCGGACTTCACCACCGGG TTCTTCCGGCACCCTGTCCCGTTCCAGTGT CGGTTTGTTCCCAGAACAGAACAAGTCTC TCAGTCTGTATCAGGGCCATAA41 Psilocybe cubensis ATGGCCTTTGATCTCAAAACAGAAGACGG CCTGATTACCTACCTGACAAAACATCTGThydroxytryptamine kinaseCTCTCGATGTCGATACAAGTGGAGTGAAG(PsiK) coding sequence CGTCTATCAGGCGGGTTTGTAAATGTTAC ATGGCGCATCAAATTGAATGCTCCGTACC(optimized for A niger)AAGGGCATACCTCAATAATTCTTAAGCAC GCTCAGCCCCACATGAGCACCGACGAAG ATTTCAAAATAGGTGTCGAAAGGAGTGTC TACGAGTATCAGGCCATC AAGCTCATGATGGCGAATCGGGAAGI CC TCGGTGGTGI GGWSGR Docket No. 66180-701.601SEQ ID NO. Enzyme Sequence ATGGCATTGTCAGCGTGCCGGAGGGTCTC AACTATGATTTAGAGAATAACGCCTTGAT CATGCAAGACGTTGGAAAGATGAAGACC TTGCTAGACTAI GTCACCGCCAAGCCCCC GTTGGCTACAGACATTGCTCGACTAGTAG GGACTGAGATCGGAGGCTTTGTTGCTCGA CTGCACAACATTGGTAGAGAAAGGCGTG ATGACCCTGAATTCAAGTTCTTCTCCGGA AATATAGTGGGTAGAACCACCTCCGATCA ACTCTACCAGACCAI CATCCCCAACGCTG CCAAATATGGGGTGGACGATCCTCTGTTGCCTACCGTTGTGAAGGACCTGGTTGATGATGTGATGCACTCAGAAGAGACGTTGGTTATGGCTGACCTCTGGTCCGGCAACATCCTCCTTCAACTGGAGGAGGGCAATCCAAGCAAGTTGCAGAAGATCTACATCCTGGACTGG GAGCTGTGCAAGTACGGCCCAGCGTCTCT TGATCTTGGGTACTTTCTTGGCGACTGTTA TCTTATTAGTCGCTTCCAGGATGAGCAGG TCGGAACGACGATGCGCCAGGCATACCTC CAATCGTAI GC ACGGACT ICC AAGCATTC CATCAACTACGCGAAGGTC ACI GCCGGCA TCGCAGCACACATCGTCATGTGGACGGAC TTCATGCAGTGGGGTTCGGAGGAAGAACG CATTAACTTCGTCAAGAAAGGGGTGGCAG CCTTCCATGACGCCCGGGGAAACAATGAC AACGGCGAGATTACGTCTACTCTGCTGAA GGAGAGCTCGAC TGCG42 Arabidopsis thaliana ATGTCCTCAGACCAGCTTTCCAAGTTCCT GGACCGCAACAAGATGGAGGACAATAAAacetylserotoninCGCAAGGTGCTTGACGAAGAAGCCAAGGmethyltransferase (ASMT) CCAGCTTGGACATTTGGAAGTACGTCTTC GGCTTTGCAGACATTGCTGCGGCGAAATGcoding sequence (optimized for TGCTATCGACCTCAAGATCCCCGAGGCGAA. niger) TTGAGAACCACCCATCCTCCCAACCAGTG ACGCTAGCTGAACTTAGCAGCGCCGTGTC TGCAAGTCCCAGCCATCTCCGAAGAATCA TGCGCTTCTTGGTGCACCAAGGCATTTC AAGGAGATTCCCACCAAGGATGGCTTGGC CACTGGTTATGTCAACACCCCTCTTTCAA GAAGGTTGATGATTACACGACGCGATGGG AAATCGTTAGCCCCCTTTGTTTCTGTTCGAG ACCACTCCGGAGATGCTGGCTCCCTGGCT GCGTTTGTCAAGTGTTGTTTCGTCGCCTGTCAATGGGTCTACACCACCGCCTTTTGATG CCGTCCACGGAAAAGATGTCTGGTCTTTT GCCCAGGACAACCCCTTCCTCTCCGACAT GA TC AACGAAGCCATGGCTTGTGATGCGC GGAGGGTGGTGCCGAGAGTAGCAGGAGC TTGCCATGGCCTCTTCGACGGAGTGACCA CCATGGTGGATGTAGGGGGTGGAACTGGC GAGACAATGGGCATGTTGGTCAAGGAATT TCCG TGGATCAAGGGCTTCAACTTCGATCTTCCTCATGTTATCGAGGTGGCCGAAGTCWSGR Docket No. 66180-701.601SEQ ID NO. Enzyme Sequence CTGGATGGTGTTGAAAATGTTGAGGGTGA TATGTTCGACTCCATACCAGCATGCGATG CAATCTTCATCAAGTGGGTGCTACACGAC TGGGGTGACAAAGACTGCATCAAAATCCT GAAGAACTGCAAGGAAGCGGTACCTCCG AATATAGGCAAGGTTCTCATTGTCGAAAG TGTCATTGGAGAGAATAAGAAGACGATG ATCGTGGATGAACGGGATGAGAAGCTGG AGCATGTTCGTCTCATGCTCGACATGGTC ATGA TGGCGCACACCTCGACGGGGAAGG AGCGGACTTTAAAAGAATGGGATTTTGTC TTGAAAGAGGCTGGTTTCGCACGATATGA GGTCCGTGATATTGATGATGTGCAGTCTCTGATCATCGCCTACCGCAGCTAASystems for regulation of enzyme expression

[0146] Provided herein are systems and methods for regulating the expression (e.g., production) of one or more enzymes (e.g., enzymes that mediate the biosynthesis of one or more tryptamine alkaloids provided herein). In a system or method provided herein, regulating the expression of an enzyme can comprise modulating the production of an enzyme involved in the biosynthesis of tryptamine alkaloids (e.g., an enzyme provided in Table 5). In some embodiments, regulating the expression of an enzyme can comprise conditionally expressing a nucleic acid sequence encoding the enzyme. In certain embodiments, regulating the expression of an enzyme can comprise inducing the production of an enzyme. In certain embodiments, regulating the expression of an enzyme can comprise stopping or inhibiting the production of an enzyme. In certain embodiments, regulating the expression of an enzyme can comprise increasing the production of an enzyme. In certain embodiments, regulating the expression of an enzyme can comprise decreasing the production of an enzyme.

[0147] In some embodiments, regulating the expression of one or more enzymes can comprise regulating the expression of two or more enzymes. In some embodiments, the regulating the expression of two or more enzymes comprises regulating the expression of the two or more enzymes independently. In some embodiments, the regulating the expression of two or more enzymes comprises regulating the expression of the two or more enzymes differently. For example, in some embodiments, regulating the expression of two or more enzymes comprises inducing the expression of a first enzyme and inhibiting the expression of a second enzyme. In some embodiments, the regulating the expression of two or more enzymes comprises regulating the expression of the two or more enzymes in the same way. For example, in some embodiments, regulating the expression of two or more enzymes comprises inducing the expression of a first enzyme and inducing the expression of a second enzyme. In some embodiments, the regulating the expression of two or more enzymes comprises regulating the expression of sets of enzymes differently. For example, in some embodiments, regulating theWSGR Docket No. 66180-701.601expression of two or more enzymes comprises inducing the expression of a first and a second enzyme and inhibiting the expression of a third enzyme.

[0148] Provided herein are vectors comprising a system for regulating the expression of one or more enzymes (e.g., an enzyme disclosed herein). A system for regulating the expression of one or more enzymes can comprise a nucleic acid sequence (e.g., a nucleic acid sequence encoding an inducible promoter or a repressible promoter). A system for regulating the expression of one or more enzymes can comprise a plurality of nucleic acid sequences (e.g., a sequence encoding a transcription factor and a sequence encoding a response element). In some embodiments, a vector comprising a system for regulating the expression of one or more enzymes comprises a nucleic acid sequence of a regulation system comprising a plurality of different nucleic acid sequences. For example, a first vector can comprise a nucleic acid sequence encoding a response element of a regulation system and a second vector can comprise a nucleic acid sequence encoding a transcription factor of a regulation system. Tetracycline-controlled transcriptional activation system

[0149] In some embodiments, a system for regulating the expression (e.g., production) of an enzyme comprises a tetracycline-controlled transcriptional activation system. A tetracycline-controlled transcriptional activation system can comprise a second-generation tetracycline-controlled transcriptional activation system. A tetracycline-controlled transcriptional activation system can comprise a method of reversibly turning on the expression of a gene in the presence of the antibiotic tetracycline or one of its derivatives (Tet-ON system ).

[0150] In some embodiments, a system for regulating the expression (e.g., production) of an enzyme comprises a tetracycline-controlled transcriptional inhibition system. A tetracycline-controlled transcriptional inhibition system can comprise a method of reversibly turning off the expression of a gene in the presence of tetracycline or one of its deri vatives (Tet-OFF system).

[0151] In certain embodiments, a tetracycline controlled transcriptional system can comprise a Tet- ON system and a Tet-OFF system.

[0152] In certain embodiments, a derivative of tetracycline can comprise doxycycline.

[0153] A Tet-ON system can comprise a reverse tetracycline transactivator (rtTA) protein. In some embodiments, an rtTA can bind to a nucleic acid (e.g., DNA) at a TetO operator sequence only if the rtTA is bound to a tetracycline (e.g., doxycycline). A rtTA protein can comprise a fusion of a tetracycline repressor (TetR) protein with activation domain of a different protein (e.g., a VP 16 protein). A Tet-ON systems can comprise a tetracycline response element (TRE), comprising a plurality of TetO operator sequences and a minimal promoter (e.g., a CMV promoter). In certain embodiments, the rtTA binds to a TRE and induce expression (e.g., production) of an enzyme provided herein only in the presence of a tetracycline (e.g., doxycycline).WSGR Docket No. 66180-701.601

[0154] A Tet-ON system can comprise a reverse tetracycline transactivator (rtTA) protein. In some embodiments, an rtTA can bind to a nucleic acid (e.g., DNA) at a TetO operator sequence only if the rtTA is bound to a tetracycline (e.g., doxycycline). A Tet-ON systems can comprise a tetracycline response element (TRE), comprising a plurality of TetO operator sequences and a minimal promoter (e.g,, a CMV promoter). In certain embodiments, the rtTA transcription factor only binds to a TRE in the presence of a tetracycline (e.g., doxycycline) and induce expression (e.g., production) of an enzyme provided herein. In certain embodiments, in a Tet-ON system, the production of a protein is be activated in the presence of tetracycline or a derivative thereof. In some embodiments, the expression level from the TRE promoter can be controlled by the concentration of tetracycline of a derivative thereof and by the duration of time the tetracycline or a derivative thereof is present.

[0155] A Tet-OFF system can comprise a tetracycline transactivator (tTA) protein. In some embodiments, an tTA can bind to a nucleic acid (e.g., DNA) at a TetO operator sequence only if the tTA is not bound to a tetracycline (e.g., doxycycline). A tTA transcription factor can comprise a fusion of a tetracycline repressor (TetR) protein with activation domain of a different protein (e.g., a VP16 protein). A Tet-OFF systems can comprise a tetracycline response element (TRE), comprising a plurality of TetO operator sequences and a minimal promoter (e.g., a CMV promoter). In certain embodiments, the tTA is bound to a TRE and induce expression (e.g., production) of an enzyme provided herein only in the absence of a tetracycline (e.g., doxycycline). In certain embodiments, in a Tet-OFF system, the production of a protein is inhibited in the presence of tetracycline or a derivative thereof. In some embodiments, the repression level from the TRE promoter can be controlled by the concentration of tetracycline or a derivative thereof and by the duration of time the tetracycline or a derivative thereof is present.Benzoic acid inducible promoter system

[0156] In some embodiments, a system for regulating the expression (e.g., production) of an enzyme comprises a benzoic acid inducible promoter system. A benzoic acid inducible promoter system can comprise a promoter that is inducible by benzoic acid. In some embodiments, a benzoic acid inducible promoter system can comprise a benzoate-para-hydroxylase (bphA) promoter. A benzoic acid inducible promoter system can be a system that induces the expression of a gene or protein in the presence of benzoic acid. In some embodiments, the production of a protein (e.g., an enzyme provided herein) is induced in the presence of benzoi c acid. Other aromati c compounds with structures similar to benzoic acid (e.g., benzoates) can induce (e.g., activate) the system. In certain embodiments, the production of a protein (e.g., an enzyme provided herein) is induced in the presence of an aromatic compound whose structure is similar to benzoic acid (e.g., a benzoate). The benzoic acid inducible promoter system can be endogenous to Aspergillus niger. In some embodiments, the expression levelWSGR Docket No. 66180-701.601from the bphA promoter can be controlled by the concentration of benzoic acid present and by the duration of time the benzoic acid is present.Sucrose inducible promoter system

[0157] In some embodiments, a system for regulating the expression (e.g., production) of an enzyme comprises a sucrose inducible promoter system. A sucrose inducible promoter system can comprise a promoter that is inducible by a sugar (e.g., sucrose or glucose). In some embodiments, a sucrose inducible promoter system can comprise a beta-fructofuranosidase (sucA) promoter. A sugar inducible promoter system can be a system that induces the expression of a gene or protein in the presence of sucrose. In some embodiments, the production of a protein (e.g., an enzyme provided herein) is induced in the presence of sucrose. Other sugars with structures similar to sucrose (e.g., glucose) can induce (e.g., activate) the system. In certain embodiments, the production of a protein (e.g., an enzyme provided herein) is induced in the presence of a sugar whose structure is similar to sucrose (e.g., a sucrose). The sucrose inducible promoter system can be endogenous to Aspergillus niger. In some embodiments, the expression level from the sucA promoter can be controlled by the concentration of sucrose present and by the duration of time the sucrose is present.Thiamine-repressed promoter system

[0158] In some embodiments, a system for regulating the expression (e.g., production) of an enzyme comprises a thiamine-repressed promoter system. A thiamine-repressed promoter system can comprise a promoter that is repressed by the presence of thiamine. In some embodiments, a thiamine-repressed promoter system can comprise a thiamine-regulatable thiamine thiazole synthase (thiA) promoter. In certain embodiments, a thiamine-repressed promoter system can comprise a promoter that is endogenous to Aspergillus oryzae. In some embodiments, the expression level from the thiA promoter can be controll ed by the concentration of thiamine present and by the duration of time the thiamine is present.Other A. niger promoter systems

[0159] A system for regulating the expression of an enzyme can comprise a promoter endogenous to Aspergillus niger. A promoter system that comprises a promoter endogenous to A. niger may induce or repress (e g., inhibit) the production of a protein. In some embodiments, a system for regulating the expression (e.g., production) of an enzyme can comprise a catalase-R (catR) promoter. In some embodiments, a system for regulating the expression (e.g., production) of an enzyme can comprise a 1,3-beta-glucanosyltransferase (gas) promoter. In some embodiments, a system for regulating the expression (e.g., production) of an enzyme can comprise a glucoamylase A (glaA) promoter. In some embodiments, a system for regulating the expression (e.g., production) of an enzyme can comprise a gaaR promoter. In some embodiments, a system for regulating the expression (e.g., production) of anWSGR Docket No. 66180-701.601enzyme can comprise an araR promoter. In some embodiments, a system for regulating the expression (e.g., production) of an enzyme can comprise a rhaR promoter. In some embodiments, promoter endogenous to Aspergillus niger is induced or repressed by hydrogen peroxide (H₂O₂), calcium carbonate (CaCO₃), low pH, glucose, xylose, galacturonic acid, arabinose, or rhamnose. Examples of inducible or repressible promoters endogenous to Aspergillus niger provided herein include, but are not limited to, promoters provided in Table 6.

[0160] In some embodiments, a system for regulating the expression of an enzyme comprises a promoter, the promoter comprising a member selected from the group consisting of a tetracyclineresponsive element promoter (TRE promoter), a benzoate-para-hydroxylase (bphA) promoter, a beta-fructofuranosidase (sucA) promoter, a thiamine thiazole synthase (thiA) promoter, a glyceraldehyde-3 -phosphate dehydrogenase (gpdA) promoter, a putative ribosomal subunit (Anl6g04690) promoter PfraA), and a tefl promoter (PtefT).

[0161] Table 6. Aspergillus niger promoters for regulation of expressionPromoter Gene product Induction by / repression by bphA B enzoate-para-hy droxy 1 ase Benzoic acid and benzoate calR Catalase Hydrogen peroxide and calcium carbonategas 1,3-beta-glucanosyltransferase Low pH value / pH>5.0 glaA Glucoamylase A Glucose and xylosegaaR Galacturonic acidaraA ArabinoserhaR RhamnosePharmaceutical formulations

[0162] Certain embodiments relate to formulations that include the described tryptamine alkaloid(s), a derivative, fragment, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount (e.g., to treat a disease disclosed herein).

[0163] The formulation may be a “pharmaceutical composition,” a “pharm ceutical preparation,” or a “pharmaceutical formulation.”

[0164] As used herein, the term “pharmaceutical composition” refers to the combination of one or more pharmaceutical agents (e.g., tryptamine alkaloid) with one or more carriers, inert or active, making the formulation especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. A pharmaceutical composition comprises the physical entity that is administered to a subject, and mayWSGR Docket No. 66180-701.601take the form of a solid, semi -solid or liquid dosage form, for example, tablet, capsule, orally- disintegrating tablet, pill, powder, suppository, solution, elixir, syrup, suspension, cream, lozenge, paste, spray, etc. A pharmaceutical composition may comprise a single pharmaceutical formulation (e.g., extended release, immediate release, delayed release, nanoparticulate, etc.), or multiple formulations (e.g., immediate release and delayed release, nanoparticulate and non-nanoparticulate, etc.).

[0165] As used herein, the terms ‘‘pharmaceutical preparation” or “pharmaceutical formulation” refer to at least one, but may be two, three or more, pharmaceutical agent(s) (e.g., a tryptamine alkaloid, e.g., psilocybin, DMT, or serotonin) in combination with one or more additional components that assist in rendering the pharmaceutical agent(s) suitable for achieving the desired effect upon administration to a subject. The pharmaceutical formulation may include one or more additives, for example pharmaceutically acceptable excipients, earners, penetration enhancers, coatings, stabilizers, buffers, acids, bases, or other materials physically associated with the pharmaceutical agent to enhance the administration, release (e.g., timing of release), deliverability, bioavailability, effectiveness, etc. of the dosage form. The formulation may be, for example, a liquid, a suspension, a solid, a nanoparticle, emulsion, micelle, ointment, gel, emulsion, coating, etc. A pharmaceutical formulation may contain a single pharmaceutical agent (e.g., psilocybin, DMT, or serotonin) or multiple pharmaceutical agents (e.g., a plurality of tryptamine alkaloids). A pharmaceutical composition may contain a single pharmaceutical formulation or multiple pharmaceutical formulations. In some embodiments, a pharmaceutical agent (e.g., psilocybin, DMT, or serotonin) is formulated for a particular mode of administration (e.g., oral administration, etc.). A pharmaceutical formulation is sterile, non-pyrogenic and non-toxic to the subject. The terms “pharmaceutical composition” and “pharmaceutical formulation” may be used interchangeably.

[0166] In some embodiments, a pharmaceutical formulation provided herein comprises a tryptamine alkaloid (e.g., a tryptamine alkaloid synthesized by a method or composition provided herein, e.g., a tryptamine alkaloid produced by a vector provided herein). In certain embodiments, a formulation comprises a tryptamine alkaloid (e.g., a tryptamine alkaloid synthesized by a method or composition provided herein, e.g., a tryptamine alkaloid produced by a vector provided herein) that has been substantially purified. In some embodiments, the substantially purified tryptamine alkaloid is substantially free of contaminants. In some embodiments, a substantially purified tryptamine alkaloid comprises 100% tryptamine alkaloid. For example, substantially purified psilocybin can comprise 100% psilocybin. In some embodiments, a substantially purified tryptamine alkaloid comprises 99% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 98% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 97%WSGR Docket No. 66180-701.601tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 96% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 95% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 94% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 93% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 92% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 91% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 90% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 85% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 80% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 75% tryptamine alkaloid. In some embodiments, a substantially purified tryptamine alkaloid comprises 70% tryptamine alkaloid. In certain embodiments, a formulation provided herein comprises two or more tryptamine alkaloids. A formulation can comprise two or more tryptamine alkaloids that are substantially purified. In certain embodiments, a pharmaceutical formulation provided herein comprises tryptamine, AAnethyltryptamine (NMT), N,N-dimethyltryptamine (DMT), N, N, N-trimethyltryptamine (TMT), 4-hydroxy-tryptamine, 4-hydroxy-Amiethyltryptamine (norpsilocin), 4-hydroxy-A(A-dimethyltryptamine (psilocin), 4-phosphoryloxy-tryptamine (norbaeocystin), 4-phosphoryloxy-A^-methyltryptamine (baeocystin), 4-phosphoryloxy-A(A’-dimethyltryptamine (psilocybin), 4-phosphoryloxy-A(A(Ar-trimethyltryptamine (aeruginascin), Ar, A’-dimethyl-5-hydroxytryptamine (bufotenine), 5-hydroxy tryptamine (serotonin, 5-HT), A'-m ethyl serotonin, N, N, N-trimethylserotonin, 5 -meth oxy serotonin (5-MeO-serotonin), 5 -m ethoxy -A-methyltryptamine (5-MeO-NMT), 5-methoxy-A(AA-dimethyltryptamine (5-MeO-DMT), 5-methoxy-A(Ar, A-m ethyltryptamine (5-MeO-TMT), or combinations thereof. In certain embodiments, a pharmaceutical formulation provided herein comprises tryptamine. In certain embodiments, a pharmaceutical formulation provided herein comprises N-methyltryptamine (NMT). In certain embodiments, a pharmaceutical formulation provided herein comprises A^A imethyltryptamine (DMT). In certain embodiments, a pharmaceutical formulation provided herein comprises A(A(A%rimethyltryptamine (TMT). In certain embodiments, a pharmaceutical formulation provided herein comprises 4-hydroxy-tryptamine. In certain embodiments, a pharmaceutical formulation provided herein comprises 4-hydroxy- / V-methyltryptamine (norpsilocin). In certain embodiments, a pharmaceutical formulation provided herein comprises 4-hydroxy-N,N-dimethyltryptamine (psilocin). In certain embodiments, a pharmaceutical formulation provided herein comprises 4-phosphoryloxy-tryptamine (norbaeocystin). In certain embodiments, a pharmaceutical formulation provided herein comprises 4-phosphoryloxy-A-methyltryptamine (baeocystin). In certain embodiments, a pharmaceutical formulation providedWSGR Docket No. 66180-701.601herein comprises 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin). In certain embodiments, a pharmaceutical formulation provided herein comprises 4-phosphoryloxy-A / A / A rimethyltryptamine (aeruginascin). In certain embodiments, a phar aceutical formulation provided herein comprises A’, A / -dimethyl-5-hydroxytryptamine (bufotenine). In certain embodiments, a pharmaceutical formulation provided herein comprises 5 -hydroxy tryptamine (serotonin, 5-HT). In certain embodiments, a pharmaceutical formulation provided herein comprises N-methylserotonin. In certain embodiments, a pharmaceutical formulation provided herein comprises N,N,N-trimethylserotonin. In certain embodiments, a pharmaceutical formulation provided herein comprises 5-methoxyserotonin (5-MeO-serotonin). In certain embodiments, a pharmaceutical formulation provided herein comprises 5-methoxy-A-methyltryptamine (5-MeO-NMT). In certain embodiments, a pharmaceutical formulation provided herein comprises 5-methoxy-ANV-dimethyltryptamine (5-MeO-DMT). In certain embodiments, a pharmaceutical formulation provided herein comprises 5-methoxy-N,N,N-methyltryptamine (5-MeO-TMT).

[0167] In some embodiments, a formulation provided herein comprises DMT and tryptamine, NMT, TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 90% w / w of DMT, and also comprises tryptamine, NMT, TMT, or combinations thereof. In certain embodiments, a formulation comprises at least about 80% w / w of DMT, and also comprises tryptamine, NMT, or TMT. In certain embodiments, a formulation comprises at least about 70% w / w of DM T, and also comprises tryptamine, NMT, or TMT. In certain embodiments, a formulation comprises at least about 60% w / w of DMT, and also comprises tryptamine, NMT, or TMT. In certain embodiments, a formulation comprises at least about 50% w / w of DMT, and also comprises tryptamine, NMT, or TMT. In certain embodiments, a formulation comprises at least about 40% w / w of DMT, and also comprises tryptamine, NMT, or TMT. In certain embodiments, a formulation comprises at least about 30% w / w of DMT, and also comprises tryptamine, NMT, or TMT. In certain embodiments, a formulation comprises at least about 20% w / w of DMT, and also comprises tryptamine, NMT, or TMT. In certain embodiments, a formulation comprises at least about 10% w / w of DMT, and also comprises tryptamine, NMT, or TMT. In certain embodiments, a formulation comprises at least about 5% w / w of DMT, and also comprises tryptamine, NMT, or TMT. In certain embodiments, a formulation comprises at least about 1% w / w of DMT, and also comprises tryptamine, NMT, or TMT.

[0168] In some embodiments, a formulation provided herein comprises psilocybin and also comprises tryptamine, 4-hydroxy -tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 90% psilocybin w / w, and also comprises tryptamine, 4-hydroxy -tryptamine, norpsilocin, psilocin,WSGR Docket No. 66180-701.601norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 80% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 70% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 60% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 50% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 40% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 30% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 20% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 10% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 5% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof. In certain embodiments, a formulation provided herein comprises at least about 1% psilocybin w / w, and also comprises tryptamine, 4-hydroxy-tryptamine, norpsilocin, psilocin, norbaeocystin, baeocystin, aeruginascin, or combinations thereof.

[0169] In some embodiments, a formulation provided herein comprises bufotenine and also comprises tryptamine, serotonin, rV-methylserotonin, N, N. A-trimethyl serotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 90% bufotenine w / w, and also comprises tryptamine, serotonin, A’-m ethyl serotoni n, A / A’, JV-trimethyl serotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 85% bufotenine w / w, and also comprises tryptamine, serotonin, N-methylserotonin, N,N,N-trimethylserotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 90% bufotenine w / w, and also comprises tryptamine, serotonin, A-WSGR Docket No. 66180-701.601methylserotonin, AAV A-trimethyl serotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 80% bufotenine w / w, and also comprises tryptamine, serotonin, N-methylserotonin, N,N,N-trimethylserotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 70% bufotenine w / w, and also comprises tryptamine, serotonin, JV-m ethyl serotonin, / V. A^A’-trimethylserotonin, or a combination thereof In certain embodiments, a formulation provided herein comprises at least about 60% bufotenine w / w, and also comprises tryptamine, serotonin, A-methyl serotonin, N, N, N-trimethylserotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 50% bufotenine w / w, and also comprises tryptamine, serotonin, N-methylserotonin, AAV A-trimethyl serotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 40% bufotenine w / w, and also comprises tryptamine, serotonin, N-methylserotonin, N,N,N-trimethylserotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 30% bufotenine w / w, and also comprises tryptamine, serotonin, N-methylserotonin, N,N,N-trimethylserotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 20% bufotenine w / w, and also comprises tryptamine, serotonin, A-methyl serotonin, N, N, N-trimethylserotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 10% bufotenine w / w, and also comprises tryptamine, serotonin, N-methylserotonin, AAV A-trimethyl serotonin, or a combination thereof. In certain embodiments, a formulation provided herein comprises at least about 5% bufotenine w / w, and also comprises tryptamine, serotonin, N-methylserotonin, A, A, A-trimethylserotonin, or a combination thereof In certain embodiments, a formulation provided herein comprises at least about 1% bufotenine w / w, and also comprises tryptamine, serotonin, N-methylserotonin, N,N,N-trimethylserotonin, or a combination thereof.

[0170] In some embodiments, a formulation provided herein comprises 5-MeO-DMT and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 90% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 80% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 70% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 60% 5-MeO-DMT w / w and also comprises tryptamine, serotonin,WSGR Docket No. 66180-701.6015-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 50% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 40% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 30% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 20% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 10% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 5% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof. In certain embodiments, a formulation comprises at least about 1% 5-MeO-DMT w / w and also comprises tryptamine, serotonin, 5-MeO-serotonin, 5-MeO-NMT, 5-MeO-DMT, 5-MeO-TMT, or a combination thereof.

[0171] Certain embodiments, relate to formulations that include one or more of the described tryptamine alkaloids, a derivative, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable additive. The additive may be selected from carriers, excipients, disintegrators or disintegrating aids (e.g., a disintegrant), binders, lubricants, colorants (e.g. pigments), flavorants (e.g., flavorings) coating agents, diluents, bases, dissolving agents or solubilizers, isotonic agents, pH regulators, stabilizers, preservatives, propellants, adhesives, glidants, humectants, and other additives known in the art.

[0172] To prevent contaminations, the described formulations could comprise one or more preservatives having antimicrobial activity, like e.g., benzalkonium chloride (shortened in BAK).

[0173] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, for example, a phosphate buffered saline solution, water, emulsions (e.g., for example an oil / water or water / oil emulsions), and various types of wetting agents. The formulations also can include stabilizers and preservatives. Pharmaceutically acceptable carriers include carbohydrates for example trehalose, mannitol, xylitol, sucrose, lactose, and sorbitol. Other ingredients for use in formulations may include DPPC, DOPE, DSPC and DOPC, Natural or synthetic surfactants may be used. PEG may be used. Dextrans, for example cyclodextran, may be used. Bile salts and otherWSGR Docket No. 66180-701.601related enhancers may be used. Cellulose and cellulose derivatives may be used. Amino acids may be used, for example use in a buffer formulation.

[0174] For further examples of carriers, stabilizers and adjuvants see, e.g., Martin, Remington’s Pharmaceutical Sciences, 15thEd., Mack Publ. Co., Easton, Pa.

[1975] ; herein incorporated by reference in its entirety,

[0175] Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers known in the art, is contemplated.

[0176] In certain embodiments, the formulation may include at least one non-ionic surfactant. Examples of non-ionic surfactants include Polysorbate 80, Polysorbate 20, Poloxamer 407, and Tyloxapol.

[0177] The formulation may be in a form suitable for administration to a subject, e.g., solution, pill, ointment, suspension, eye drops, gel, cream, foam, spray, liniment, and powder. As used herein, the term “administration” refers to the act of giving a drug, prodrug, or other agent, or therapeutic treatment (e.g., tryptamine alkaloid and / or formulations thereof described herein) to a subject (e.g., a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs). Exemplary routes of administration to the human body can be through the mouth (oral), eyes (ophthalmic), skin (transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, rectal, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, intravitreally, periocularly, etc.) and the like. Implantable sustained release forms / formulations are also contemplated.

[0178] The compositions and methods provided herein are applicable for human subjects at risk for, suffering from, or diagnosed as having a mood, anxiety, or substance abuse disorder, for example, depression (e.g., treatment-resistant depression or major depression), Major Depressive Disorder (MDD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), alcohol dependence, alcohol use disorder, tobacco dependence, or nicotine dependence. Compositions and methods provided herein are also applicable for human subjects at risk for,...

Claims

WSGR Docket No. 66180-701.601CLAIMS WHAT IS CLAIMED IS:

1. A vector comprising:a. a nucleic acid sequence encoding one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids;b. a promoter; andc. a system for regulating expression of the one or more enzymes.2 The vector of claim 1, wherein the system comprises a first enzyme and a second enzyme.3 The vector of claim 2, wherein the expression of the first enzyme and the second enzyme are regulated independently.4 The vector of any one of claims 1-3, wherein the promoter comprises an inducible promoter.5 The vector of any one of claims 1-3, wherein the promoter comprises a repressible promoter.6 The vector of any one of claims 1-3, wherein the promoter comprises a constitutive promoter.7 The vector of any one of claims 1-6, wherein the one or more enzymes encoded by the nucleic acid comprise a member selected from the group consisting of tryptamine 4-monooxygenase (PsiH), 4-hydroxy tryptamine kinase (PsiK), Rhinella marina indolethylamine N- m ethyltransferase (RmINMT), psilocybin synthase (PsiM), tryptamine 5-hydroxylase (T5H), acetyl serotonin methyltransf erase (ASMT), and 5-hydroxy-indolethylamine-A- methy I tran sferase (5 O H-1NMT).8 The vector of any one of claims 1-7, wherein the one or more tryptamine alkaloids comprise a member selected from the group consisting of tryptamine (1), A-methyltryptamine (NMT) (2), A’, A-dimethyltryptamine (DMT) (3), N,N,N-trimethyltryptamine (TMT) (4), 4-hydroxy- tryptamine (5), 4-hydroxy-A-methyltryptamine (norpsilocin) (6), 4-hydroxy-A, A- dimethyl tryptamine (psilocin) (7), 4-phosphoryloxy-tryptamine (norbaeocystin) (8), 4- phosphoryloxy-A-methyltryptamine (baeocystin) (9), 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) (10), 4-phosphoryloxy-A’, A, A-trimethyltryptamine (aeruginascin) (11), A'. A- dimethyl-5-hydroxytryptamine (bufotenine) (12), 5-hydroxytryptamine (serotonin, 5-HT) (13), N-methylserotonin (14), N,N,N-trimethylserotonin (15), 5-methoxyserotonin (5 -MeO- serotonin)WSGR Docket No. 66180-701.601(16), 5-methoxy-A’-methyltryptamine (5-MeO-NMT) (17), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) (18), and 5-methoxy-A(A’, A,-methyltiy,ptamine (5-MeO-TMT) (19).

9. The vector of any one of claims 1 -8 wherein the one or more tryptamine alkaloids comprise DMT (3) and a member selected from the group consisting of tryptamine (1), NMT (2), and TMT (4).

10. The vector of any one of claims 1-8, wherein the one or more tryptamine alkaloids comprise psilocybin (10) and a member selected from the group consisting of tryptamine (1), 4-hydroxy- tryptamine (5), norpsilocin (6), psilocin (7), norbaeocystin (8), baeocystin (9), and aeruginascin (11).

11. The vector of any one of claims 1-8, wherein the one or more tryptamine alkaloids comprise bufotenine (12) and a member selected from the group consisting of tryptamine (1), serotonin (13), A’-methylserotonin (14), and N,N,N-trimethylserotonin (15).

12. The vector of any one of claims 1-8, wherein the one or more tryptamine alkaloids comprise 5- MeO-DMT (18) and a member selected from the group consisting of tryptamine (1), serotonin (13), 5-MeO-serotonin (16), 5-MeO-NMT (17), 5-MeO-DMT (18), and 5-MeO-TMT (19).

13. The vector of any one of claims 1-12, wherein the promoter comprises a member selected from the group consisting of a tetracycline-responsive element promoter (TRE promoter), a benzoate- para-hydroxylase (bphA) promoter, a beta-fructofuranosidase (sucA) promoter, a thiamine thiazole synthase (thiA) promoter, a glyceraldehyde-3 -phosphate dehydrogenase (gpdA) promoter, a putative ribosomal subunit (Anl6g04690) promoter (PfraA), and a tefl promoter (Ptefl).

14. A system of vectors, the system comprising the vector of claim any one of claims 1-13.

15. A composition comprising two vectors, a first vector and a second vector, wherein the first vector comprises:a. a nucleic acid sequence encoding one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids, andb. a promoter,wherein the first vector and the second vector comprise a system for independently regulating the expression of the one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids.WSGR Docket No. 66180-701.60116. The composition of claim 15, wherein the first vector and the second vector comprise a system for independently regulating the expression of the one or more enzymes that mediate the biosynthesis of the one or more tryptamine alkaloids.

17. The composition of claim 15 or claim 16, wherein the second vector comprises a tetracycline- controlled transcriptional silencer (tTS) transcription factor.

18. The composition of claim 15 or claim 16, wherein the second vector comprises a reverse tetracycline responsive transcriptional activator (rtTA) transcription factor.

19. The composition of any one of claims 15-18, wherein the composition further comprises a third vector.

20. The composition of claim 19, wherein the third vector comprises:a. a second nucleic acid sequence encoding the one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids, and b. a second promoter,wherein the first vector, the second vector, the third vector, or a combination thereof comprise the system for regulating the expression of the one or more enzymes that mediate the biosynthesis of one or more tryptamine alkaloids.

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