Polypeptide variants of fumonisins, additives comprising the polypeptide variants and use of the additives, and methods for cleaving fumonisins

Abstract

This invention relates to polypeptide variants of lysing fusarium toxins by a carboxylesterase having SEQ ID No. 46, each of said polypeptide variants having an amino acid sequence shortened by 47 amino acids at the N-terminus, and said amino acid sequence having at least 70%, preferably 80%, particularly preferably 100% sequence identity with amino acid sequence segment 48-540 of SEQ ID No. 46, i.e., SEQ ID No. 1; and isolated polynucleotides encoding said polypeptide variants; and additives comprising at least one polypeptide variant and optionally at least one adjuvant for lysing fusarium toxins; and the use of said polypeptide variants or additives for hydrolyzing at least one fusarium toxin, and methods for hydrolyzing at least one fusarium toxin.

Description

[0001] This invention relates to polypeptide variants that lyse Fusarium toxin, additives containing said polypeptide variants, and the use of said polypeptide variants and / or said additives, as well as methods for lysing Fusarium toxin by means of said polypeptide variants and / or said additives containing said polypeptide variants.

[0002] Mycotoxins are frequently found in agricultural plant products and cause serious economic damage depending on the type and concentration of the mycotoxin, particularly in food or feed prepared from agricultural products, and in animals and humans fed with such food or feed, where the damage is extremely diverse. Many methods have been developed to render mycotoxins harmless, that is, to detoxify or degrade them, in order to minimize the damage caused by mycotoxins in the fields of animal and human nutrition, animal husbandry, feed and food processing, etc.

[0003] A prominent group of fungal toxins is the fusarin class, where the terms "fusarin" or "fusarin class" are equivalent and each refers to at least one or all of the fusarin produced by species of the genus *Fusarium*, as well as their derivatives and degradation products, but particularly to fusarin A1-2 (FA1-2), fusarin B1-4 (FB1-4), fusarin C1, 2, 4 (FC1, FC2, FC4), and HFC1, and also to partially hydrolyzed fusarin FA1-2, FB1-4, FC1-2, FC4, and HFC1. Partially hydrolyzed fusarin has only one tricarboxylic acid residue, while FA1-2, FB1-4, FC1-2, FC4, and HFC1 have two tricarboxylic acid residues. Furthermore, structurally similar toxins from *Alternaria alternata lycopersici* (AAL) are also included in the Fusarium toxin group, which is further subdivided into AAL-TA1 (CAS No. 79367-52-5), AAL-TA2 (CAS No. 79367-51-4), AAL-TB1 (CAS No. 176590-32-2), and AAL-TB2 (CAS No. 176705-51-4). FA1-2, FB1-4, FC1-2, FC4, and HFC1 have the following structural formulas:

[0004]

[0005]

[0006] FB1 is the most frequently occurring toxin from the Fusarium toxin group; however, many derivatives and related molecules are known to have also shown toxic effects in humans and animals. Diseases caused by the ingestion of fungal toxins in humans or animals are termed fungal toxin poisoning, and in the case of Fusarium toxins, it is also called Fusarium toxin-fungal poisoning. Fusarium toxins are known to inhibit sphingolipid metabolism through their interaction with ceramide synthase. Sphingolipids are not only components of the cell membrane but also play important roles as signaling or messenger molecules in many fundamental cellular processes, such as cell growth, cell migration, and cell junctions, in inflammatory processes, or intracellular transport programs. Due to their inhibition of sphingolipid metabolism, Fusarium toxins are considered responsible for their toxic effects in a wide variety of animal species and in humans. Thus, Fusarium toxins have been shown to produce carcinogenic effects in rodents in an immunosuppressive manner, and epidemiological data have linked them to esophageal cancer and neural tube defects in humans. In various animal species, such as pigs, they are considered responsible for the typical pulmonary edema caused by poisoning. Examples of Fusarium fungal poisoning include neurotoxic diseases such as leukomalacia in horses or pulmonary edema in pigs caused by Fusarium moniliforme poisoning. Given the near-ubiquitous presence of Fusarium toxin contamination on various grains, particularly corn, nuts, and vegetables, their strong negative effects on human and animal health cannot be ignored.

[0007] The microbial degradation of Fusarium moniliforme has been described in EP-A 1 860 954, which uses microorganisms to detoxify Fusarium moniliforme and its derivatives by adding detoxifying bacteria or yeast selected from precisely defined strains for detoxifying Fusarium moniliforme to the feed.

[0008] The catabolic pathways for the biodegradation of fusarium moniliforme and the genes and enzymes responsible for them have also been described. Thus, for example, EP-A 0 988 383 describes compositions and methods for detoxifying fusarium moniliforme, wherein the enzymes used to degrade fusarium moniliforme are first produced in a transgenic plant, wherein the detoxification of fusarium moniliforme is achieved by means of an amino oxidase, which requires molecular oxygen for its enzymatic activity.

[0009] Furthermore, WO 2004 / 085624 describes aminotransferases, deaminases, and aminomutases, as well as methods for enzymatically detoxifying amination toxins (e.g., Fusarium moniliforme). Polypeptides with deaminase activity are used herein for detoxification.

[0010] The products or methods described above have disadvantages, namely, that molecular oxygen and optional cofactors are required for the detoxification of fungal toxins, and in particular, the amino oxidases described above do not show any effect under anaerobic reaction conditions.

[0011] EP-A 2 326 713 relates to additives and methods for preparing said additives, which enable successful degradation of Fusarium moniliforme in an oxygen-independent and cofactor-free enzymatic reaction. However, the carboxylesterase described therein, which is crucial for detoxification, has low temperature stability, making the additive or the carboxylesterase of SEQ ID No. 46 unsuitable for use at high temperatures.

[0012] In the food and feed industries, heat treatment for the preparation of hygienic products (in which microbial load is reduced) is of great significance. In particular, feed pelleting is widely popular and a standardized process for numerous reasons (e.g., to improve flowability, to reduce dust generation, to reduce microbial load, especially Salmonella load). During pelleting, the article is typically wetted with hot steam, heated, and then extruded under pressure through a die. Using peptides or enzymes as additives to the food or feed to be pelleted is a technical challenge because enzymes or peptides are generally sensitive to high temperatures. Heat treatment of enzymes or peptides can lead to a decrease in their specific activity and / or irreversible denaturation. One possibility to resist this is protein encapsulation or coating, such as that described in WO 92 / 12645. This successfully protects the protein from the effects of heat; however, this practice carries the risk that the protein may not be released quickly enough in the oral-gastric-intestinal tract, and therefore its effects may not be exerted quickly enough or at all. To date, known peptides for detoxifying Fusarium toxins cannot be added to pelleted feed or food without prior encapsulation or coating due to their low temperature stability.

[0013] Detoxification of Fusarium toxin at high temperatures is an important technical process in the production of, for example, corn products such as porridge, popcorn, cornflakes, cornbread, or tortillas, as well as starch liquefaction, saccharification, or fermentation processes (e.g., pulping or fermentation, particularly in bioethanol production). It is crucial to ensure that the food or feed prepared through these processes does not contain harmful amounts of Fusarium toxin. Polypeptides known to date cannot be used in these processes due to their extremely low or nonexistent activity at their respective process temperatures.

[0014] Therefore, there is a need for enzymes or peptides for the specific, safe and reliable lysis of Fusarium toxins (particularly for the detoxification of Fusarium toxins), wherein the enzymatic reaction requires neither oxygen nor cofactors, and the enzymes or peptides also have sufficient temperature stability and sufficient temperature activity so that they can be used in technical processes at high temperatures.

[0015] The present invention aims to provide a polypeptide variant of the cleavage of fusarium toxin by the carboxylesterase of SEQ ID No. 46 for use, which enables successful cleavage of at least one fusarium toxin into non-toxic or low-toxic products in the absence of oxygen and cofactors, wherein the polypeptide variant has improved temperature stability or improved temperature activity compared to the fusarium toxin carboxylesterase of SEQ ID No. 46.

[0016] To address this objective, the present invention is characterized primarily in that each of the polypeptide variants has an amino acid sequence shortened by 47 amino acids at the N-terminus, wherein said amino acid sequence has at least 70%, preferably 80%, and particularly preferably 100% sequence identity with amino acid sequence segment 48-540 of SEQ ID No. 46, i.e., SEQ ID No. 1. It has been surprisingly shown that the amino acid sequence shortened by 47 amino acids compared to SEQ ID No. 46 is not only significantly more active than that sequence, but also exhibits improved temperature stability.

[0017] As in a further modification of the invention, a polypeptide variant of SEQ ID No. 1 is formed, particularly a polypeptide variant having an amino acid sequence having at least 70% sequence identity with SEQ ID No. 1 and having amino acid substitutions at at least one position selected from the group consisting of: 10, 33, 66, 107, 140, 144, 149, 151, 157, 199, 266, 267, 270, 272, 275, 280, 284, 286, 293, 302, 312, 329, 332. The following peptide variants, 360, 363, 364, 365, 367, 371, 372, 377, 389, 391, 394, 418, 419, 424, 427, 429, 430, 436, 440, 443, 447, 453, 455, 456, 457, 462, 463, 464, 465, 469, 473, 478, 487, and 490, were obtained, exhibiting at least a 4% improvement in temperature stability compared to the Fusarium toxin carboxylesterase having SEQ ID No. 1. By using such peptide variants with properties capable of cleaving Fusarium toxin, detoxification of Fusarium toxin can be successfully achieved, for example, during technical processes at high temperatures. This is made particularly possible by the improved temperature activity, in addition to enhanced temperature stability. In particular, this ensures that the enzymatic activity of the peptide variant remains intact even under high temperature loads (such as during transport in a container).

[0018] The term "carboxylesterase" encompasses all such enzymes, polypeptides, or polypeptide variants capable of cleaving carboxylic ester compounds into corresponding alcohol and carboxylic acid compounds with the aid of water. The term "fusarium toxin carboxylesterase" encompasses all such enzymes, polypeptides, or polypeptide variants capable of hydrolyzing at least one f. spore toxin by hydrolyzing at least one propanetricarboxylic acid (propane-1,2,3-tricarboxylic acid) therefrom. The "characteristics of f. spore cleavage" described herein refer to the ability to hydrolyze at least one propanetricarboxylic acid residue from at least one f. spore toxin (particularly FA1-2, FB1-4, FC1-2, FC4, HFC1, AAL-TA1-2, and AAL-TB1-2 or their derivatives or degradation products).

[0019] The terms used below are derived from technical terms and are always used in their conventional sense unless otherwise specified. Thus, the term "polynucleotide" refers to every type of genetic material of all lengths and sequences, such as single-stranded and double-stranded DNA and RNA molecules, including regulatory elements, structural elements, gene clusters, plasmids, whole genomes, and their fragments. The name "polypeptide" includes proteins, such as enzymes and antibodies, as well as polypeptides with up to 500 amino acids, such as peptide inhibitors, protein domains, and short polypeptides with small sequence lengths, such as fewer than 10 amino acids, such as receptors, ligands, peptide hormones, tags, etc. The name "position in a polynucleotide or polypeptide" refers to a single specific base or amino acid in the sequence of said polynucleotide or polypeptide. Amino acid names are abbreviated to single-letter or three-letter codes familiar to those skilled in the art.

[0020] The term "unit" or "U" refers to a measure of the catalytic activity of an enzyme, polypeptide, or polypeptide variant, and is defined as the number of micromoles (μmol) of substrate (in this case, Fusarium moniliforme B1) that are converted or cleaved within one minute under defined conditions. For example, if at least one tricarboxylic acid residue is cleaved from 60 μmol of FB1 within 15 minutes, this corresponds to 4 units of catalytic activity. For FB1 cleavage, the reaction conditions are defined as follows: the conversion reaction is carried out for 30 minutes at 30°C in 20 mM Tris-HCl buffer (pH 8.0) containing 0.1 mg / ml bovine serum albumin. The substrate concentration in the reaction is 100 μM FB1.

[0021] The enzyme concentration of an enzyme solution, peptide solution, or peptide variant solution, given in "units / mL solution", is defined as the "catalytic activity", "catalytic enzyme activity", or "activity" of the enzyme solution, peptide solution, or peptide variant solution.

[0022] The term "specific activity" is defined as the catalytic activity per milligram of an enzyme, polypeptide, or polypeptide variant, and is calculated from the ratio of the catalytic activity of the enzyme solution to the mass concentration (mass / volume unit) of the enzyme in that solution. For example, if an enzyme solution has a catalytic activity of 50 U / ml and a mass concentration of 1 mg / ml, then the specific activity is 50 U / mg.

[0023] The term "temperature stability" refers to the property of an enzyme, peptide, or peptide variant to retain its catalytic activity after a time-limited exposure to high temperatures (pre-incubation). Temperature stability is determined by measuring and comparing the activity of an enzyme solution, peptide solution, or peptide variant solution under identical and defined conditions for 5 minutes of heat treatment with and without heat treatment. Therefore, temperature stability is a measure of an enzyme's resistance to time-limited thermal effects. The temperature at which a heat-treated enzyme retains 50% of its remaining activity compared to a 100% untreated control is a measure of temperature stability and is abbreviated as T(50%). For example, if an enzyme solution without pre-incubation has an activity of 50 U / ml and after pre-incubation at 50°C for 5 minutes has an activity of 25 U / ml, then the enzyme is temperature stable at 50°C, or in other words, the enzyme is temperature stable up to 50°C. The increase in T (50%) of the peptide variant relative to the parent peptide of SEQ ID No. 1 is defined as a measure of improved temperature stability and can be given relatively as a percentage value or absolutely in degrees Celsius.

[0024] The term "temperature activity" defines a temperature at which the enzyme, polypeptide, or polypeptide variant exhibits the highest activity, wherein catalytic activity is measured over a period of 30 minutes.

[0025] The term "peptide variant" or "variant" specifically refers to a polypeptide sequence having at least one amino acid substitution compared to SEQ ID No. 46, wherein the enzymatic function, i.e., the property of cleaving Fusarium toxin, is still retained. Furthermore, a "peptide variant" may also have amino acid insertions or deletions relative to the polypeptide sequence of SEQ ID No. 46, particularly sequences that are lengthened or shortened at the C-terminus or N-terminus. If the enzymatic reaction mechanism remains unchanged, then the enzymatic function is substantially preserved, i.e., Fusarium toxin is hydrolyzed at the same site and the specific activity of the variant relative to the original parent polypeptide of SEQ ID No. 46 is at least 10%, preferably at least 50%, more preferably at least 90%, however particularly greater than >100%.

[0026] Amino acid substitutions at specific positions are described using the following nomenclature: original amino acid; position; new amino acid. For example, if proline at position 134 is replaced by glycine, this is indicated as Pro134Gly or P134G. Multiple mutations are separated by plus signs or forward slashes. For example, if proline at position 134 is replaced by glycine and arginine at position 136 is replaced by lysine, this is indicated as Pro134Gly+Arg136Lys or Pro134Gly / Arg136Lys or P134G+R136K or P134G / R136K. If an amino acid at a position is replaced by two or more alternative amino acids, the alternative amino acids are separated by commas or forward slashes. For example, if the proline at position 134 is replaced not only by glycine but also by serine, valine, and methionine, then this is indicated by Pro134Gly,Ser,Val,Met or Pro134Gly / Ser / Val / Met or P134G,S,V,M or P134G / S / V / M. If the amino acid substitution or replacement at a specific position is not defined in detail, then this is interpreted as meaning that these amino acids can be substituted by all other amino acids. For example, if the mutation of proline at position 134 is not defined in detail, then that proline can be substituted by one of the following amino acids: A, R, N, D, C, Q, E, G, H, I, L, K, M, F, S, T, W, Y, or V.

[0027] The term "sequence identity" refers to the percentage of sequence identity. For amino acid and nucleotide sequences, sequence identity can be determined visually, but is preferably calculated using a computer program. The amino acid sequence having SEQ ID No. 1 is defined as the reference sequence. Sequence comparisons are also performed within sequence segments, where consecutive sequences of the reference sequence are understood as segments. For nucleotide sequences, the length of the sequence segment is typically 18 to 600 nucleotides, preferably 45 to 200 nucleotides, more preferably 100 to 150 nucleotides. For peptide sequences, the length of the sequence segment is typically 3 to 200 amino acids, more preferably 15 to 65 amino acids, and most preferably 30 to 50 amino acids. Numerous commercially available or freely available bioinformatics programs exist that can be invoked for homology determination and are continuously being developed. Examples of such programs include the GCG Wisconsin Bestfit software package (Devereux et al., 1984), BLAST (Altschul et al., 1990), or BLAST 2 (Tatusova and Madden, 1999). Due to the different configuration possibilities of these algorithms, they may yield different results with the same input sequence. Therefore, it is necessary to define the search algorithm and the associated settings. In this case, sequence identity is determined using the NCBI BLAST (Basic Local Alignment Search Tool) program, specifically BLASTP for peptides and BLASTN for polynucleotides, which is available on the homepage of the National Center for Biotechnology Information (NCBI; http: / / www.ncbi.nlm.nih.gov / ). Therefore, it is possible to compare two or more sequences according to the algorithm of Altschul et al., 1997 (NucleicAcids Res., 25:3389-3402). Here, the version of the program from August 12, 2014 is used.As part of the program setup, consider the basic settings, specifically for amino acid sequence comparison: "max target sequence" = 100; "expected threshold" = 10; "word size" = 3; "matrix" = BLOSOM62; "gap costs" = "Existence: 11; Extension: 1"; "computational adjustment" = "Conditional compositional score matrix adjustment"; and for nucleotide sequence comparison: word size: 11; expected value: 10; gap costs: existence = 5, extension = 2; filter = low complexity activated; match / mismatch scores: 2, -3; filter string: L; m.

[0028] According to a further modification of the invention, a particularly large improvement in temperature stability is achieved by performing the following amino acid substitutions: amino acid substitutions at positions 10 and 456 are selected from Q, E, N, H, K, and R; amino acid substitutions at positions 33, 107, 293, and 332 are selected from E, Q, D, K, R, and N; amino acid substitutions at positions 66, 463, and 478 are selected from D, E, K, N, Q, and R; amino acid substitutions at positions 140 and 490 are selected from P, A, S, and N; amino acid substitutions at positions 144 and 367 are selected from I, L, M, and V; and amino acid substitutions at positions 149, 270, 312, 329, and 372 are selected from P, A, S, and N. The amino acid substitutions are selected from F, Y, W, and H; the amino acid substitutions at positions 151 and 453 are selected from D, E, K, and R; the amino acid substitutions at positions 157 and 462 are selected from F, H, W, and Y; the amino acid substitutions at positions 199, 302, 365, and 464 are selected from I, L, M, and V; the amino acid substitutions at positions 266 and 455 are selected from A, S, and T; the amino acid substitutions at positions 267, 394, and 429 are selected from A, N, P, and S; the amino acid substitution at position 272 is selected from H, N, Q, and S; the amino acid substitution at position 275 is selected from A, D, E, G, K, N, Q, R, and S; and the amino acid substitution at position 280... The amino acid substitutions are selected from A, D, E, K, N, P, Q, R, and S; the amino acid substitution at position 284 is selected from A, N, P, S, T, and V; the amino acid substitution at position 286 is selected from A, D, E, K, N, P, R, and S; the amino acid substitutions at positions 360, 377, 391, 419, and 427 are selected from A, I, L, S, T, and V; the amino acid substitutions at positions 363, 443, and 457 are selected from A, S, T, and V; the amino acid substitution at position 364 is selected from H, I, L, M, N, Q, S, and V; the amino acid substitution at position 371 is selected from A, I, L, M, S, T, and V; and the amino acid substitution at position 389... The amino acid substitutions are selected from I, L, M, and V; the amino acid substitutions at positions 418, 430, 447, and 473 are selected from A, G, and S; the amino acid substitution at position 424 is selected from A, D, E, G, K, R, and S; the amino acid substitution at position 436 is selected from A, G, S, and T; the amino acid substitution at position 440 is selected from A, G, S, and T; the amino acid substitution at position 465 is selected from A, G, H, N, Q, S, and T; the amino acid substitution at position 469 is selected from D, E, K, and R; and / or the amino acid substitution at position 487 is selected from N, D, Q, H, and S, wherein the amino acids originally present at the above sites are replaced in any way.

[0029] According to a preferred further modification of the present invention, the amino acid substitution is selected from the group consisting of: 10Q, 33E, 66D, 107E, 140P, 144M, 149F, 151R, 157Y, 199I, 266S, 267P, 270F, 272H, 275E, 275A, 280D, 280P, 284T, 284P, 286P, 286R, 293E, 302I, 312F, 329F, 332E, 360V, 363T, 364H, 36 4L, 365I, 367H, 371V, 371M, 372F, 377V, 389L, 391V, 394P, 418A, 419V, 424A, 424K, 427V, 429P, 430A, 436A, 436S, 4 40G, 440S, 443T, 447A, 453R, 455S, 456Q, 457T, 462Y, 463D, 464I, 465H, 465S, ​​465G, 469K, 473A, 478D, 487N and 490P. By having at least one such substitution, the peptide variant can more specifically improve temperature stability or temperature activity, wherein other enzyme parameters (e.g., specific activity, pH-stability, or pH-activity) can also be improved, provided that it has at least the value of the Fusarium toxin carboxylesterase with SEQ ID No. 1.

[0030] According to a further modification of the invention, the polypeptide variant has an amino acid substitution at at least one position selected from the group consisting of 66, 199, 302, 377, 394, 424, 430, and 463, and has at least 6% improved temperature stability compared to the Fusarium toxin carboxylesterase having SEQ ID No. 1. With such a polypeptide variant, it is possible to cleave Fusarium toxin during high-temperature technical processes such as the production of batter products and other corn products (e.g., corn porridge, popcorn, cornflakes, cornbread, or tortillas), as well as starch liquefaction, saccharification, or fermentation processes (e.g., pulping or fermentation processes, particularly in the preparation of bioethanol).

[0031] According to a preferred further modification of the invention, the amino acid substitution is selected from the group consisting of: 66D, 199I, 302I, 377V, 394P, 424A, 430A, and 463D. By means of such substitution, the temperature stability and temperature activity of the polypeptide variant can be improved by at least 3°C ​​relative to the Fusarium carboxylesterase of SEQ ID No. 1.

[0032] According to a further modification of the invention, the polypeptide variant has amino acid substitutions at at least two, particularly three, positions selected from the group consisting of: 10, 33, 66, 107, 140, 144, 149, 151, 157, 199, 266, 267, 270, 272, 275, 280, 284, 286, 293, 302, 312, 329. Examples of the enzymes are 332, 360, 363, 364, 365, 367, 371, 372, 377, 389, 391, 394, 418, 419, 424, 427, 429, 430, 436, 440, 443, 447, 453, 455, 456, 457, 462, 463, 464, 465, 469, 473, 478, 487, and 490, and they exhibit at least 15% improved temperature stability compared to the Fusarium carboxylesterase of SEQ ID No. 1.

[0033] According to a preferred further modification of the present invention, the amino acid substitution is selected from the group consisting of: 10Q, 66D, 144M, 151R, 199I, 266S, 267P, 272H, 275E, 275A, 280D, 284T, 286P, 286R, 293E, 302I, 360V, 363T, 364H, 364L, 365I, 367H, 371V, 371M, 372F. The sequences 377V, 389L, 391V, 394P, 418A, 419V, 424A, 424K, 427V, 429P, 430A, 436A, 436S, 440G, 440S, 443T, 447A, 453R, 455S, 456Q, 457T, 462Y, 463D, 464I, 465H, 465S, ​​465G, 469K, 473A, 478D, 487N, and 490P, have surprisingly shown a positive effect on temperature stability through the substitution of multiple amino acids, with temperature stability improved by more than 7°C by inserting at least three amino acids different from those originally present in the sequence. Such an improvement is sufficient, for example, to use the enzyme during pulping pauses at approximately 55°C in bioethanol production or during feed pelleting at a moderate temperature of approximately 65 to 70°C.

[0034] According to a further modification of the present invention, the amino acid sequence of the polypeptide variant comprises a combination of multiple amino acid substitutions, wherein the positional combinations are selected from the group consisting of: 66 / 199 / 302 / 394 / 424 / 430, 66 / 199 / 302 / 377 / 394 / 424 / 430, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 463, 66 / 144 / 199 / 302 / 360 / 372 / 377 / 394 / 424 / 430 / 443 / 463, 199 / 302 / 377 / 394 / 424 / 430 / 463, 66 / 199 / 302 / 377 / 394, 66 / 199 / 302 / 364 / 377 / 394 / 424 / 430 / 463, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 463 / 465, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 440 / 463, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 447 / 463, 66 / 199 / 302 / 377 / 394 / 418 / 424 / 430 / 463, 66 / 199 / 302 / 377 / 394 / 424 / 436 / 430 / 463, 66 / 199 / 302 / 364 / 377 / 394 / 424 / 430 / 463, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 463 / 490, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 463 / 469, 66 / 199 / 302 / 377 / 389 / 394 / 424 / 430 / 463, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 463 / 465, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 463 / 464, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 463 / 465, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 440 / 463, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 457 / 463, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 436 / 463, 66 / 199 / 302 / 363 / 371 / 377 / 394 / 424 / 430 / 463, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 447 / 453 / 463, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 456 / 462 / 463, 66 / 199 / 302 / 377 / 394 / 419 / 424 / 427 / 430 / 463,66 / 199 / 302 / 365 / 377 / 394 / 424 / 430 / 463 / 487 and 66 / 199 / 302 / 371 / 377 / 394 / 424 / 430 / 463 / 487. The peptide variants thus substituted exhibit at least 25% improved temperature stability compared to the Fusarium carboxylesterase of SEQ ID No. 1. Through such a combination of substitutions, it is possible not only to improve the temperature stability of the peptide variants but also to improve their temperature activity.

[0035] According to a preferred further modification of the invention, the amino acid sequence of the polypeptide variant is selected from the group consisting of SEQ ID Nos. 2 to 29. Such polypeptide variants have improved temperature stability by at least 11°C, preferably at least 13°C, and more preferably at least 15°C compared to the enzyme in SEQ ID No. 1, thereby preserving the activity of the respective polypeptide and thus the detoxification of Fusarium toxin during or after technical processes with high temperature loads (e.g., pulping pauses at 65°C in bioethanol preparation, or granulation at temperatures of approximately 75-80°C).

[0036] According to a further modification of the invention, each amino acid sequence of the polypeptide variant comprises a combination of multiple amino acid substitutions, wherein the positional combinations are selected from the group consisting of: 66 / 99 / 302 / 364 / 377 / 389 / 394 / 419 / 424 / 427 / 430 / 447 / 463 / 465 / 469, 66 / 199 / 302 / 377 / 389 / 394 / 419 / 424 / 427 / 430 / 447 / 463 / 465 / 469, 66 / 199 / 302 / 363 / 364 / 371 / 377 / 389 / 394 / 419 / 424 / 427 / 430 / 447 / 463 / 464 / 465 / 469, 66 / 199 / 302 / 363 / 371 / 377 / 389 / 394 / 419 / 424 / 427 / 430 / 447 / 463 / 464 / 465 / 469, 66 / 199 / 302 / 364 / 367 / 371 / 377 / 389 / 394 / 418 / 419 / 424 / 427 / 430 / 436 / 440 / 447 / 463 / 464 / 465 / 469 / 490, 66 / 199 / 302 / 367 / 371 / 377 / 389 / 394 / 418 / 419 / 424 / 427 / 430 / 436 / 440 / 447 / 463 / 464 / 465 / 469 / 490, 66 / 199 / 302 / 363 / 367 / 371 / 377 / 394 / 424 / 430 / 463 / 490, 66 / 199 / 302 / 377 / 394 / 418 / 419 / 424 / 427 / 430 / 436 / 440 / 447 / 463, 66 / 199 / 302 / 377 / 389 / 394 / 424 / 430 / 457 / 463 / 464 / 465 / 469, 66 / 199 / 302 / 363 / 371 / 377 / 389 / 394 / 419 / 424 / 427 / 430 / 440 / 447 / 457 / 463 / 464 / 469 / 490, 66 / 199 / 302 / 377 / 394 / 424 / 430 / 463 / 447 / 490 / 469 / 465、66 / 199 / 302 / 377 / 394 / 424 / 430 / 463 / 490 / 469 / 465 / 419 / 427 / 371 / 487、66 / 199 / 302 / 371 / 377 / 394 / 419 / 424 / 427 / 430 / 447 / 453 / 463 / 465 / 469 / 487 / 490, 66 / 199 / 302 / 367 / 371 / 377 / 389 / 394 / 418 / 419 / 424 / 427 / 429 / 430 / 436 / 440 / 447 / 457 / 463 / 464 / 465 / 469 / 490,Peptide variants 66 / 199 / 302 / 371 / 377 / 389 / 394 / 419 / 424 / 427 / 430 / 436 / 447 / 453 / 456 / 462 / 463 / 465 / 469 / 490 / 487 and 66 / 199 / 302 / 367 / 371 / 377 / 389 / 394 / 418 / 419 / 424 / 427 / 429 / 430 / 436 / 440 / 447 / 453 / 456 / 457 / 462 / 463 / 464 / 465 / 469 / 487 / 490. These peptide variants exhibit at least 40% improved temperature stability and increased temperature activity compared to the Fusarium toxin carboxylesterase of SEQ ID No. 1, thus making them usable in many methods requiring higher temperatures.

[0037] According to a preferred further modification of the invention, the amino acid sequence of the polypeptide variant is selected from the group consisting of SEQ ID Nos. 30 to 45. Such polypeptide variants have improved temperature stability compared to the enzyme in SEQ ID No. 1, at least 18°C, preferably at least 22°C, and more preferably at least 27°C, thereby ensuring the activity of the polypeptide and thus the detoxification of Fusarium toxins during or after technical processes with high temperature loads (e.g., granulation at temperatures exceeding 80°C, particularly exceeding 85-90°C). In particular, granulation at high temperatures of approximately 90°C is of great significance in the poultry industry to ensure a sufficient reduction of Salmonella load in the feed.

[0038] The term "conservative mutation" refers to the substitution of an amino acid by another amino acid that is considered conserved by a person skilled in the art (i.e., has similar specific properties), meaning that the properties of the amino acid are preserved. Specific properties of an amino acid include, for example, its size, polarity, hydrophobicity, charge, or pK value. Amino acids can be grouped based on their properties, and these groups can be depicted using a Venn diagram. Amino acids from the same group and preferably from the same subgroup can be substituted for each other. The classification of amino acids into groups and subgroups based on properties such as hydrophobicity, polarity, and size is known from Taylor WR (1986). "Conservative mutation" refers, for example, the substitution of one acidic amino acid for another, one basic amino acid for another, one polar amino acid for another, and so on. In particular, the polypeptide variant may also contain at least one conserved amino acid substitution at at least one position, wherein the conserved amino acid substitution is selected from the group consisting of: G to A, A to G / S, V to I / L / A / T / S, I to V / L / M, L to I / M / V, M to L / I / V, P to A / S / N, F to Y / W / H, Y to F / W / H, W to Y / F / H, R to K / E / D, K to R / E / D, H to Q / N / S, D to N / E / K / R / Q, E to Q / D / K / R / N, S to T / A, T to S / V / A, C to S / T / A, N to D / Q / H / S, and Q to E / N / H / K / R.

[0039] If a substitution at a specific position in a polypeptide variant according to the invention results in, for example, the substitution of a polar amino acid (e.g., Asp) for a hydrophobic amino acid (e.g., Ala), then "conservative mutation" also refers to all mutations at said position that result in the substitution of another hydrophobic amino acid (e.g., glycine, leucine, phenylalanine, valine). Further polypeptide variants containing alternative conserved mutations are also included herein.

[0040] Furthermore, the present invention also aims to provide a polynucleotide encoding a polypeptide variant of the cleavage enzyme of the SEQ ID No. 1 for use, wherein the polypeptide variant enables successful cleavage of at least one fusarium toxin into a non-toxic or low-toxic product in an oxygen-independent and cofactor-free manner, and wherein the polypeptide variant has improved temperature stability compared to the SEQ ID No. 1 fusarium toxin carboxylesterase.

[0041] To address this issue, the present invention is characterized in that the polynucleotide has a nucleotide sequence encoding a polypeptide variant of the cleavage toxin of the toxin carboxylesterase having the amino acid sequence of SEQ ID No. 1, wherein the polypeptide variant has an amino acid sequence having at least 70% sequence identity with the amino acid sequence having SEQ ID No. 1, and the polypeptide variant has an amino acid substitution at at least one position selected from the group consisting of: 10, 33, 66, 107, 140, 144, 149, 151, 157, 199, 266, 267, 270, 272, 275, 280, 284, 286, 293, 302, 312, 329, 332, 360, 363, 364, 365, 367, 371, 372, 377, 389, 391, 394, 418, 419, 424, 427, 429, 430, 436, 440, 443, 447, 453, 455, 456, 457, 462, 463, 464, 465, 469, 473, 478, 487, and 490, however, specifically possess the following substitutions: 10Q, 33E, 66D, 107E, 1 40P, 144M, 149F, 151R, 157Y, 199I, 266S, 267P, 270F, 272H, 275E, 275A, 280D, 280P, 284T, 284P, 28 6P, 286R, 293E, 302I, 312F, 329F, 332E, 360V, 363T, 364H, 364L, 365I, 367H, 371V, 371M, 372F, 377 V, 389L, 391V, 394P, 418A, 419V, 424A, 424K, 427V, 429P, 430A, 436A, 436S, 440G, 440S, 443T, 447A, 453R, 455S, 456Q, 457T, 462Y, 463D, 464I, 465H, 465S, ​​465G, 469K, 473A, 478D, 487N, and 490P, or combinations thereof. Using such isolated polynucleotides, transgenic host cells for producing polypeptide variants according to the invention can be prepared by means of an expression vector.

[0042] The term "expression vector" refers to a DNA construct capable of expressing a gene in vivo or in vitro. Specifically, the term encompasses DNA constructs adapted to transfer a nucleotide sequence encoding the polypeptide into a host cell, thereby integrating the nucleotide sequence into the genome or allowing it to exist freely in extrachromosomal space, and expressing the nucleotide sequence encoding the polypeptide within the cell and optionally extracting the polypeptide from the cell.

[0043] The term "host cell" encompasses all such cells that either contain the nucleotide sequence to be expressed or an expression vector, and are capable of producing the enzyme or polypeptide according to the invention. In particular, the term covers prokaryotic and / or eukaryotic cells, preferably Pichia pastoris, Escherichia coli, Bacillus subtilis, Streptomyces, Hansenula, Trichoderma, Lactobacillus, Aspergillus, plant cells, and / or spores of Bacillus, Trichoderma, or Aspergillus. The name “Pichiapastoris” used here is a synonym for “Komagataella pastoris”, where Pichiapastoris is the older name and Komagataella pastoris is the newer systematic name (Yamada et al., 1995).

[0044] Furthermore, the present invention also aims to provide an additive for cleaving Fusarium toxins for use, said additive comprising at least one polypeptide variant of a Fusarium toxin carboxylesterase having the amino acid sequence of SEQ ID No. 46, wherein the respective polypeptide variant cleaves at least one Fusarium toxin into a non-toxic or low-toxic product in an oxygen-independent and cofactor-free manner and has improved temperature stability compared to the Fusarium toxin carboxylesterase of SEQ ID No. 46.

[0045] To address this task, the present invention is characterized in that the additive for lysing Fusarium toxin comprises at least one polypeptide variant of the Fusarium toxin carboxylesterase according to the invention, and optionally, at least one adjuvant. By adding such an additive to feed contaminated with Fusarium toxin, detoxification of Fusarium toxin can be successfully achieved, which can be measured significantly by a reduction in the ratio of dihydrosphingosine to sphingosine in the plasma and / or kidneys and / or lungs and / or liver of subjects fed with said additive.

[0046] The ratio of dihydrosphingosine to sphingosine in different organs and in animal plasma is a widely accepted and sensitive biomarker for the toxic effects of falciparum toxins (especially FB1). Fusarium toxin-induced sphingolipid metabolism disorders are particularly associated with encephalopathy in horses or pulmonary edema in pigs. The importance of the dihydrosphingosine to sphingosine ratio as a biomarker and its analytical measurement are described in Grenier et al. (Biochem. Pharmaceuticals, Vol. 83, (2012), pp. 1465-1473) and in EFSA Journal (2014, 12(5): 3667).

[0047] According to a further modification of the invention, the additive is formed such that the adjuvant is selected from the group consisting of: inert carriers, vitamins, minerals, plant-derived substances, enzymes, and other components for detoxifying mycotoxins, such as mycotoxin-degrading enzymes, particularly aflatoxin oxidase, ergotamine hydrolase, ergotamine amidase, zearalenone esterase, zearalenone lactone lactonease, zearalenone hydrolase, ochratoxin amidase, fusarium aminotransferase, amino polyol amino oxidase, deoxyfusarium alcohol epoxide hydrolase, deoxyfusarium alcohol dehydrogenase, deoxyfusarium alcohol oxidase, trichothecene dehydrogenase, trichothecene oxidase; microorganisms that degrade mycotoxins; and substances that bind mycotoxins, such as microbial cell walls or inorganic materials such as bentonite. By using such additives, it can be ensured, for example, in feed or food, that the amount of Fusarium toxin optionally contained is safely and reliably lysed, in particular detoxified, to such an extent that no harmful effects exist on the bodies of subjects who have ingested such feed or food.

[0048] Another application of the present invention is in additives that, in addition to containing at least one polypeptide variant according to the invention, contain at least one enzyme, such as an enzyme involved in the degradation of proteins, such as a protease, or an enzyme involved in the metabolism of starch or fiber or fat or glycogen, such as an amylase, cellulase or glucanase, and such as a hydrolase, lipase, mannosidase, oxidase, oxidoreductase, phytase or xylanase.

[0049] Furthermore, the present invention also aims at the use of the additive according to the invention for the lysis of at least one Fusarium toxin in food or feed, particularly granulated, and particularly for use in pig, poultry, cattle, horses, fish, or aquaculture. As food or feed, all foods or feeds suitable for human or animal nutrition (particularly suitable for livestock, sheep, or goats) can be used, particularly dry distillers' grains.

[0050] Furthermore, the present invention also aims to address the use of the additive according to the invention for the lysis of at least one Fusarium toxin during the preparation or processing of food or feed, particularly at a temperature of at least 50°C. Such use of the additive ensures the detoxification of Fusarium toxins, for example, during food technology processes where treatment at high temperatures is important, such as in the processing of corn or grains, in starch liquefaction, in saccharification, or in fermentation processes (e.g., pulping or fermentation processes, particularly in the preparation of bioethanol). This ensures that no significant (particularly health-damaging) amount of Fusarium toxin remains intact in products derived from such methods (e.g., feed pellets, pasta products, porridge, popcorn, cornflakes, cornbread, tortillas, dried distillers' grains, or starch).

[0051] Furthermore, the present invention also aims at the use of at least one polypeptide variant according to the invention or at least one additive according to the invention in the preparation of formulations for the prevention and / or treatment of Fusarium toxin poisoning. Through such use of the polypeptide variant or additive, in the case of prevention, it is possible to maintain the health status of a person or animal substantially at a level corresponding to the absence of oral ingestion of Fusarium toxin or a reduced level of oral ingestion of Fusarium toxin, despite oral ingestion of Fusarium toxin. In the case of treatment of Fusarium toxin poisoning, it is possible to alleviate the symptoms of such diseases and, in particular, significantly improve the ratio of dihydrosphingosine to sphingosine in organs and / or plasma. Furthermore, through such use, it is also possible to improve the productivity of useful animals, particularly feed utilization and weight gain, and reduce mortality.

[0052] Furthermore, the present invention also aims to provide a method for enzymatically cleaving at least one Fusarium toxin for use, wherein the method can hydrolyze at least one Fusarium toxin in an oxygen-independent, specific, safe and reliable manner with a polypeptide into a non-toxic or low-toxic product, wherein the hydrolytic cleavage is carried out either during or after heat treatment.

[0053] To solve this task, the method is performed in such a way that at least one tricarboxylic acid is hydrolyzed from the f. spore using a polypeptide variant according to the invention or an additive according to the invention. Here, the at least one f. spore is mixed with at least one polypeptide variant according to the invention or at least one additive according to the invention, and at least one tricarboxylic acid is hydrolyzed from the at least one f. spore using the at least one polypeptide variant, thereby detoxifying the f. spore, wherein the mixture consisting of the respective polypeptide variant and the f. spore is subjected to a heat treatment at at least 50°C, preferably at least 70°C, and the hydrolytic cleavage is performed either during or after the heat treatment.

[0054] In a preferred further modification of the invention, the method is carried out by mixing the polypeptide variant or the additive with feed or food contaminated with at least one Fusarium toxin and then subjecting it to heat treatment (optionally by a granulation process). This ensures that once the mixture of the polypeptide variant and the Fusarium toxin comes into contact with moisture, the Fusarium toxin contained in the contaminated and optionally granulated feed or food is cleaved. In the case of moist feed or food, such as malt syrup or paste, hydrolysis of the Fusarium toxin occurs in the moist feed or food before oral ingestion. This achieves the goal of minimizing or at least reducing the harmful effects of Fusarium toxin on humans and animals. Here, moisture refers to the presence of water or an aqueous liquid, including, for example, saliva or other liquids present in the digestive tract. The digestive tract is defined as the mouth, pharynx (throat), esophagus, and gastrointestinal tract or their equivalents, although different names may exist in animals or individual components may not be present in the animal's digestive tract.

[0055] In a preferred further modification of the invention, the method is carried out by using the polypeptide variant at a concentration range of 5 U to 500 U, preferably 10 U to 300 U, and more preferably 15 U to 100 U / kg of feed or food. By adding these amounts of the polypeptide variant, it is possible to successfully, depending on the concentration of Fusarium toxin, lyse and thus detoxify the Fusarium toxin in the food or feed (particularly in dry distillers' grains) to such an extent that at least 70%, preferably at least 80%, particularly at least 90% of at least one Fusarium toxin is lysed.

[0056] Unless otherwise explicitly stated, singular names such as “ein,” “eine,” “das,” “die,” or “der” are understood to be exemplary and include many possibilities. For example, if “gene,” “enzyme,” or “cell” is involved, then it is always intended to include the plural.

[0057] The present invention will now be explained in more detail with reference to embodiments.

[0058] peptide variants

[0059] Example 1: Modification, cloning, and expression of polynucleotides encoding polypeptides that lyse Fusarium toxin

[0060] According to the instructions, using the "Quick-change Site-directed Mutagenesis Kits" (Stratagene), amino acid substitutions, insertions, or deletions are performed by PCR through mutation of the nucleotide sequence. Alternatively, complete nucleotide sequences are also synthesized for this purpose (GeneArt). Using standard methods, the nucleotide sequences generated by PCR mutagenesis or purchased from GeneArt are integrated into expression vectors for expression in *E. coli* or *Pichia pastoris*, transformed into *E. coli* or *Pichia pastoris*, and expressed in *E. coli* or *Pichia pastoris* (JMCregg, Pichia Protocols, 2nd edition, ISBN-10:1588294293, 2007; J. Sambrook et al., 2012, Molecular Cloning, A Laboratory Manual, 4th edition, Cold Spring Harbor), where any other suitable host cell can also be considered for this task.

[0061] The term "expression vector" refers to a DNA construct capable of expressing a gene in vivo or in vitro. Specifically, the term encompasses DNA constructs adapted to transfer a nucleotide sequence encoding the polypeptide into a host cell for integration into the genome or free existence in extrachromosomal space, and to express the nucleotide sequence encoding the polypeptide within the cell and optionally extract the polypeptide from the cell. The term "host cell" refers to all such cells that either contain the nucleotide sequence to be expressed or contain an expression vector, and are capable of preparing the enzyme or polypeptide according to the invention. Specifically, the name encompasses prokaryotic and / or eukaryotic cells, preferably Pichia pastoris, Escherichia coli, Bacillus subtilis, Streptomyces, Hansenula, Trichoderma, Lactobacillus, Aspergillus, plant cells, and / or spores of Bacillus, Trichoderma, or Aspergillus. Soluble cell lysates (in the case of Escherichia coli) or culture supernatants (in the case of Pichia pastoris) are considered for determining the catalytic properties of the said polypeptide variants.

[0062] Example 2: Determination of catalytic activity and specific activity of peptides that degrade Fusarium toxin

[0063] The gene encoding a polypeptide variant that degrades Fusarium toxin was cloned into *E. coli* using standard methods, expressed intracellularly, and subsequently lysed by sonication and centrifugation. The clear supernatant was diluted (approximately 10 μL) with 20 mM Tris-HCl buffer (pH 8.0) containing 0.1 mg / ml bovine serum albumin. -3 Up to 10 -5 And so it is used in FB1 degradation batches, thereby degrading 10% to 90% of the amount of FB1 contained in the degradation batch through the peptide.

[0064] To determine the catalytic enzyme activity, an experiment was conducted to hydrolyze Fusarium moniliforme B1 (FB1). The test batch was incubated for 30 minutes at 30°C in 20 mM Tris-HCl buffer (pH 8.0) containing 0.1 mg / ml bovine serum albumin. The batch also contained a substrate concentration of 100 μM FB1 (BiopureReferenzsubstanzen GmbH Tulln, Austria, BRM 001007) and the peptide to be tested. After 30 minutes of incubation, the batch was heat-inactivated at 99°C for 5 minutes to terminate the reaction.

[0065] To determine the enzymatic activity of feed samples, the polypeptide variant transformed with Fusarium toxin must be extracted from the feed samples prior to the test. For this purpose, 10 g of feed was dissolved in 100 ml of 20 mM Tris-HCl buffer (pH 8.0) containing 0.1 mg / ml bovine serum albumin and shaken at 20°C and 150 rpm for 1 hour. The sample was then centrifuged at 4000 g for 15 minutes, and the clear supernatant was diluted as needed (10...). -2 Up to 10 -3 It is used in FB1 batch materials.

[0066] Following the method of Heinl et al. (J. of Biotechnology, 2010, 145, pp. 120-129, 2.6.3, “Liquid chromatography-mass spectrometry”), FB1 was quantified using LC-MS (liquid chromatography-mass spectrometry). For this purpose, calibration was performed using FB1 standards, which also contained complete... 13C-labeled internal FB1 standard (Biopure Referenzsubstanzen GmbH Tulln, Austria). Unlike Heinl et al. (2010), only the degradation of FB1 was measured to determine the catalytic enzyme activity of the peptide solution used. The catalytic enzyme activity of the peptide solution used is given in "units / ml", where one "unit" is defined as the reduction of 1 μmol FB1 / min under the above reaction conditions in this experiment.

[0067] To determine specific activity, enzyme concentration is measured using quantitative Western blotting or ELISA. Specific enzyme activity is calculated by correlating activity (units) with the amount of enzyme used and is given in "units / mg".

[0068] Example 3: Temperature stability of peptides that degrade Fusarium toxin

[0069] As described in Examples 1 and 2, expression and quantification of the peptides that degrade Fusarium toxin were performed. Prior to activity assays, the amount of cell lysate was aliquoted into multiple fractions (approximately 60 μL each). Two to ten fractions were subjected to heat treatment for 5 minutes in a commercial PCR cycler (e.g., Eppendorf Mastercycler Gradient), with each fraction incubated at a different temperature. Simultaneously, another fraction of the cell lysate, the 100% control, was incubated on ice. After heat treatment, all samples / test batches were incubated at 10°C for one minute to ensure temperature uniformity. The enzymatic activity of the heat-treated samples and the 100% control was measured as described in Example 2. The residual activity after heat treatment is referred to as residual activity. The temperature at which the residual activity is 50% of the untreated 100% control is abbreviated as T(50%), and this is a measure of the temperature stability of the peptide.

[0070] The increase in T(50%) (given in degrees Celsius) of a peptide variant compared to the peptide having SEQ ID No. 46 or SEQ ID No. 1 is a measure of improved temperature stability. The increase in the T(50%) value can be given in °C, but also as a percentage value relative to the T(50%) value of the parent peptide. The following example will be used for illustration: if the parent enzyme has catalytic activity of 50 U / ml after incubation on ice for 5 minutes and 25 U / ml after incubation at 48 °C for 5 minutes, then the T(50%) is 48 °C. If the peptide variant has a T(50%) of 51 °C, then the relative increase in temperature stability (T(50%)) is 6.25. This is obtained by dividing the difference of 3 °C between the two T(50%) values ​​by the T(50%) value of the parent initiating enzyme at 48 °C and then multiplying by 100.

[0071] To determine temperature stability, specific activity can be considered instead of catalytic activity.

[0072] Temperature stability can also be determined using alternative enzymatic assays, even without measuring the catalytic activity of FB1 conversion. It is important that identical amounts of the heat-treated peptide and a 100% control are used in the batch, provided, for example, by using the same volume of cell lysate.

[0073] To determine temperature stability, the measurement signal from an enzymatic degradation assay (e.g., MS signal, extinction, etc.) can be considered instead of catalytic activity. If the measurement signal is proportional to the enzymatic activity (e.g., the peak area of ​​converted FB1), then the T(50%) value of the peptide is the temperature at which the measurement signal value of the heat-treated peptide has 50% of the measurement signal value of a 100% control of that peptide.

[0074] The temperature stability (T(50%)) of the peptide with SEQ ID No. 46 was measured to be 42 °C, while the temperature stability of the peptide with SEQ ID No. 1 was 45 °C. Therefore, the relative increase in temperature stability achievable by shortening the N-terminal sequence is approximately 7%. Furthermore, the increased enzymatic activity of the peptide with SEQ ID No. 1 compared to the parental peptide with SEQ ID No. 46 was also determined.

[0075] The temperature stability of the peptide having SEQ ID No. 1 can be further improved by targeted substitution of single amino acids. The relative improvement in temperature stability of these peptide variants compared to the parent peptide having SEQ ID No. 1 is presented in Table 1.

[0076] Table 1: Modification of peptide variants and their relative improvement in temperature stability (in percentage) compared to the parent enzyme with SEQ ID No. 1

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] Example 4: Temperature-dependent activity (temperature activity) of a polypeptide degrading a Fusarium toxin

[0085] Before the experiment, purify the polypeptide variant degrading the Fusarium toxin to be tested for its temperature-dependent activity. For this purpose, the polypeptide variant is purified from the fermentation supernatant in a two-step process by means of anion exchange chromatography and subsequent size exclusion chromatography. The polypeptide variant is adjusted to a concentration of 1 mg / ml and used in the reaction batch at a dilution of 10 -5 -10 -6 . As in the experiment described in Example 3, the activity assay is carried out by FB1 hydrolysis and subsequent quantification of FB1 by means of LC-MS, where the experiment is carried out at various different temperatures. Incubation is carried out at temperatures of 10 °C, 20 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C, 60 °C, 65 °C and 70 °C using two heating plates (Eppendorf, ThermoMixer). 30 minutes after the start of the heat treatment, 100 μl of the reaction batch is taken out and heat-inactivated at 99 °C for 5 minutes. Here, the experiment carried out at 30 °C in the heating plate is used as a 100%-control. Exemplary results are listed in Table 2. Table 2: Temperature-dependent activity of a polypeptide degrading a Fusarium toxin. The value of LOQ is below the detection limit (Level of Quantification: <0.15 U / l, in the test batch)

[0086]

[0087]

[0088]

[0089]

[0090]

[0091] Example 5: Determination of the granulation stability of a polypeptide degrading a Fusarium toxin

[0092] Using standard methods, the selected polypeptide variants were cloned into Pichia pastoris, expressed in a bioreactor under controlled aerobic conditions, and secreted extracellularly. The clear supernatant was separated from the biomass, carrier substance (maltodextrin) was incorporated therein, and it was processed into a granulated powder by means of a spray drying device. The polypeptide variants that degrade fusariotoxins present in powder form were each mixed with the piglet feed at the same concentration of 100 U / kg and processed into feed pellets in a controlled process. During the granulation process, the feed was wetted and heated with hot steam in a single batch at precisely defined temperatures (75 - 95 °C, at intervals of 5 °C). After this preparation stage, the actual granulation process was carried out. As described in Example 2, the residual activity of the polypeptide variants that degrade fusariotoxins contained in the granules was determined, where the ungranulated feed with the respective polypeptide variants that degrade fusariotoxins was used as a 100%-control. Thus, the enzyme activity remaining after the granulation process was defined as the residual activity. The values are given in Table 3.

[0093] Table 3: Granulation temperature and residual activity of polypeptides that degrade fusariotoxins. The values of LOQ are below the detection limit (quantification level: <0.15 U / l, in the test batches)

[0094]

[0095] Sequence Listing <110> Erber Aktiengesellschaft <120> Polypeptide variants that cleave fusariotoxins, additives comprising said polypeptide variants and uses of said additives, and a method for cleaving fusariotoxins <130> P05368PCT <160> 46 <170> PatentIn version 3.5 <210> 1 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Modified from SEQ ID No. 46 <400> 1 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asn Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Leu Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Leu Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Ala Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Ala Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Glu Gly Gly Ala Gly Ala Ser Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Glu Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 2 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 2 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Ala Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Glu Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 3 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 3 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 。 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Glu Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 4 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> A polypeptide variant of SEQ ID No. 1 <400> 4 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 5 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 5 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Met 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Val Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Phe Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Thr Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 6 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 6 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asn Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 7 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 7 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Glu Gly Gly Ala Gly Ala Ser Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Glu Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 8 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 8 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser His Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 9 <211> 493 <212> PRT <213> Synthetic Sequence <220> <223> A polypeptide variant of SEQ ID No. 1 <400> 9 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35​​​​​​​​​​​​​​​​​Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 His Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 10 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 10 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg �5 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Gly Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 并480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 11 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 11 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Note: There seems to be an error in the original text where "475 并480" is an incorrect expression. I've translated it as "475 and 480" for the purpose of translation while pointing out the possible error.Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 12 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 12 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ala Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 13 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 13 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Ala Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 14 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 14 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Leu Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 15 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 15 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Pro Pro Ser Lys 485 490 <210> 16 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 16 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 17 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 17 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 18 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 18 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Ser Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 19 <211> 493 <212> PRT <213> Synthetic sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 19 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Ile 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 20 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 20[[ID=3l]] Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Gly Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 21 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 21 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ser Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 22 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 22 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Thr His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 23 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 23 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Ser Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 24 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 24 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Thr Gln Phe Asn Asn Gly 355 360 365 Ile Glu Val Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 25 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 25 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Arg Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 26 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 26 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Gln Ser His Trp Pro Arg Tyr Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 27 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 27 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 28 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 28 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Ile Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Asn Ala Cys Gln Pro Ser Lys 485 490 <210> 29 <211> 493 <212> PRT <213> Synthetic sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 29 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Met Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Asn Ala Cys Gln Pro Ser Lys 485 490 <210> 30 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 30 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Leu Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 31 <211> 493 <212> PRT <213> Synthetic sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 31 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 32 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 32 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Thr Leu Phe Asn Asn Gly 355 360 365 Ile Glu Val Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Ile 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 33 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 33 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Thr Gln Phe Asn Asn Gly 355 360 365 Ile Glu Val Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Ile 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 34 <211> 493 <212> PRT <213> Synthetic Sequence <220> <223> A polypeptide variant of SEQ ID No. 1 <400> 34 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Leu Phe Asn His Gly 355 360 365 Ile Glu Val Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ala Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Ala Glu Met Ser Ser Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Ile 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Pro Pro Ser Lys 485 490 <210> 35 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 35 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn His Gly 355 360 365 Ile Glu Val Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ala Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Ala Glu Met Ser Ser Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Ile 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Pro Pro Ser Lys 485 490 <210> 36 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 36 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Thr Gln Phe Asn His Gly 355 360 365 Ile Glu Val Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Pro Pro Ser Lys 485 490 <210> 37 <211> 493 <212> PRT <213> Synthetic Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 37 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ala Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Ala Glu Met Ser Ser Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Arg Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 38 <211> 493 <212> PRT <213> Synthetic sequence <220> <223> A polypeptide variant of SEQ ID No. 1 <400> 38 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Thr His Trp Pro Arg Phe Asp Ile 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 485 490 <210> 39 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 39 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Thr Gln Phe Asn Asn Gly 355 360 365 Ile Glu Val Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ser Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Thr His Trp Pro Arg Phe Asp Ile 450 455 460 Arg Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Pro Pro Ser Lys 485 490 <210> 40 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 40 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Leu Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Met Phe Gly Ser Leu Ala Gly Gly Ala Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Pro Pro Ser Lys 485 490 <210> 41 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 41 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Met Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Asn Ala Cys Pro Pro Ser Lys 485 490 <210> 42 <211> 493 <212> PRT <213> Artificial sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 42 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Met Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Thr Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Arg Gly Thr Lys Ser His Trp Pro Arg Phe Asp Arg 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Asn Ala Cys Pro Pro Ser Lys 485 490 <210> 43 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 43 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn His Gly 355 360 365 Ile Glu Val Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ala Val Phe Gly Ser Leu Ala Gly Gly Val Gly Pro Ala Asp Ile 420 425 430 Lys Leu Ala Ala Glu Met Ser Ser Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Gln Gly Thr Lys Thr His Trp Pro Arg Phe Asp Ile 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Lys Ala Cys Pro Pro Ser Lys 485 490 <210> 44 <211> 493 <212> PRT <213> Synthetic Sequence <220> <223> Polypeptide Variant of SEQ ID No. 1 <400> 44 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly 355 360 365 Ile Glu Met Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ser Val Phe Gly Ser Leu Ala Gly Gly Val Gly Ala Ala Asp Ile 420 425 430 Lys Leu Ala Ala Glu Met Ser Ala Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Arg Gly Thr Gln Ser His Trp Pro Arg Tyr Asp Arg 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Asn Ala Cys Pro Pro Ser Lys 485 490 <210> 45 <211> 493 <212> PRT <213> Artificial Sequence <220> <223> Polypeptide variant of SEQ ID No. 1 <400> 45 Gln Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val 1 5 10 15 Glu Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala 20 25 30 Ala Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg 35 40 45 Ala Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile 50 55 60 Gly Asp Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu 65 70 75 80 Asp Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly 85 90 95 Gly Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly 100 105 110 Ser Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly 115 120 125 Val Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu 130 135 140 Ala His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn 145 150 155 160 Tyr Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn 165 170 175 Ile Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu 180 185 190 Ser Ala Gly Ala Ser Ala Ile Gly Leu Leu Leu Thr Ser Pro Leu Ser 195 200 205 Glu Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg 210 215 220 Pro Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly 225 230 235 240 Ala Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys 245 250 255 Ile Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg 260 265 270 Pro Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val 275 280 285 Asp Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Ile Val Gly 290 295 300 Gly Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys 305 310 315 320 Thr Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu 325 330 335 Ala Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val 340 345 350 Pro Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn His Gly 355 360 365 Ile Glu Val Leu Ser Ala Ala Phe Val Lys Trp Arg Thr Pro Leu Trp 370 375 380 Arg Tyr Arg Phe Leu Gly Ile Pro Gly Pro Gly Arg Arg Pro Ala Thr 385 390 395 400 His Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser 405 410 415 Val Ala Val Phe Gly Ser Leu Ala Gly Gly Val Gly Pro Ala Asp Ile 420 425 430 Lys Leu Ala Ala Glu Met Ser Ser Ala Trp Val Ser Phe Ala Ala His 435 440 445 Gly Val Pro Asp Arg Gly Thr Gln Thr His Trp Pro Arg Tyr Asp Ile 450 455 460 Ser Gly Glu Ile Lys Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly 465 470 475 480 Leu Gly Val Ser Pro Ser Asn Ala Cys Pro Pro Ser Lys 485 490 <210> 46 <211> 540 <212> PRT <213> Sphingopyxis sp. <400> 46 Val Lys Glu His Gln Cys Arg Gly Gly Arg Ala Ser Pro Ala Ala Pro 1 5 10 15 Ala Thr Trp Leu Ala Arg Ile Ser Val Ser Arg Gly Ala Ser Ala Ile 20 25 30 Ala Trp Thr Phe Met Leu Gly Ala Thr Ala Ile Pro Val Ala Ala Gln 35 40 45 Thr Asp Asp Pro Lys Leu Val Arg His Thr Gln Ser Gly Ala Val Glu 50 55 60 Gly Val Glu Gly Asp Val Glu Thr Phe Leu Gly Ile Pro Phe Ala Ala 65 70 75 80 Pro Pro Val Gly Asp Leu Arg Trp Arg Pro Pro Ala Pro Pro Arg Ala 85 90 95 Trp Ala Gly Thr Arg Asp Gly Arg Arg Phe Ala Pro Asp Cys Ile Gly 100 105 110 Asn Glu Arg Leu Arg Glu Gly Ser Arg Ala Ala Gly Thr Ser Glu Asp 115 120 125 Cys Leu Tyr Leu Asn Ile Trp Ser Pro Lys Gln Val Gly Lys Gly Gly 130 135 140 Leu Pro Val Met Ile Trp Val Tyr Gly Gly Gly Phe Ser Gly Gly Ser 145 150 155 160 Gly Ala Val Pro Tyr Tyr Asp Gly Ser Ala Leu Ala Gln Lys Gly Val 165 170 175 Val Val Val Thr Phe Asn Tyr Arg Ala Gly Ile Leu Gly Phe Leu Ala 180 185 190 His Pro Ala Leu Ser Lys Glu Ser Pro Asn Gly Val Ser Gly Asn Tyr 195 200 205 Gly Leu Leu Asp Met Leu Ala Ala Phe Lys Trp Val Gln Asn Asn Ile 210 215 220 Arg Glu Phe Gly Gly Asp Pro Asn Arg Val Thr Val Phe Gly Glu Ser 225 230 235 240 Ala Gly Ala Ser Ala Leu Gly Leu Leu Leu Thr Ser Pro Leu Ser Glu 245 250 255 Ser Ala Phe Asn Gln Ala Ile Leu Gln Ser Pro Gly Leu Ala Arg Pro 260 265 270 Leu Ala Thr Leu Ser Glu Ser Glu Ala Asn Gly Leu Glu Leu Gly Ala 275 280 285 Asp Ile Ser Ala Leu Arg Arg Ala Asp Ala Gly Glu Leu Thr Lys Ile 290 295 300 Ala Gln Ser Arg Ile Pro Met Ser Arg Gln Phe Thr Lys Pro Arg Pro 305 310 315 320 Met Gly Pro Ile Leu Asp Gly Tyr Val Leu Arg Thr Leu Asp Val Asp 325 330 335 Ala Phe Ala Lys Gly Ala Phe Arg Lys Ile Pro Val Leu Val Gly Gly 340 345 350 Asn Ala Asp Glu Gly Arg Ala Phe Thr Asp Arg Leu Pro Val Lys Thr 355 360 365 Val Leu Glu Tyr Arg Ala Tyr Leu Thr Glu Gln Phe Gly Asp Glu Ala 370 375 380 Asp Ala Trp Glu Arg Cys Tyr Pro Ala Asn Ser Asp Ala Asp Val Pro 385 390 395 400 Ala Ala Val Ala Arg Leu Phe Gly Asp Ser Gln Phe Asn Asn Gly Ile 405 410 415 Glu Leu Leu Ser Ala Ala Phe Ala Lys Trp Arg Thr Pro Leu Trp Arg 420 425 430 Tyr Arg Phe Thr Gly Ile Pro Gly Ala Gly Arg Arg Pro Ala Thr His 435 440 445 Gly Asp Glu Ile Pro Tyr Val Phe Ala Asn Leu Gly Pro Ser Ser Val 450 455 460 Ser Met Phe Gly Ser Leu Glu Gly Gly Ala Gly Ala Ser Asp Ile Lys 465 470 475 480 Leu Ala Thr Glu Met Ser Ala Ala Trp Val Ser Phe Ala Val His Gly 485 490 495 Val Pro Asp Gln Gly Thr Lys Ser His Trp Pro Arg Phe Glu Arg Arg 500 505 510 Gly Glu Ile Met Thr Phe Gly Ser Gln Val Gly Ser Gly Glu Gly Leu 515 520 525 Gly Val Ser Pro Ser Lys Ala Cys Gln Pro Ser Lys 530 535 540

Claims

1. A polypeptide variant of SEQ ID No. 46 that cleaves fusarium toxin by its carboxylesterase, characterized in that, Each of the polypeptide variants is composed of an amino acid sequence that is shortened by 47 amino acids at the N-terminus relative to SEQ ID No. 46, wherein the amino acid sequence differs from amino acid sequence segment 48-540 of SEQ ID No. 46 (i.e., SEQ ID No. 1) by any single amino acid substitution or any combination of amino acid substitutions selected from the group consisting of: L199I; L199I / A394P; N66D / L199I; L199I / L302I; L199I / A377V; L199I / E424A; L199I / S430A; L199I / E463D; L199I / L302I / A394P; L199I / L302I / A377V L199I / L302I / E424A; L199I / A377V / A394P; L199I / A394P / A429P; L199I / L302I / L372F; L144M / L199I / L302I; L199I / Q364L / Q490P; L199I / V447A / T45 5S; N66D / L199I / L302I / A394P / E424A / S430A; N66D / L199I / L302I / A377V / A394P / E424A / S430A; N66D / L199I / L302I / A377V / A394P / E424A / S430A / E463 D; N66D / L144M / L199I / L302I / F360V / L372F / A377V / A394P / E424A / S430A / V443T / E463D; L199I / L302I / A377V / A394P / E424A / S430A / E463D; N66D / L199 I / L302I / A377V / A394P; N66D / L199I / L302I / Q364H / A377V / A394P / E424A / S430A / E463D; N66D / L199I / L302I / A377V / A394P / E424A / S430A / E463D / R465 H;N66D / L199I / L302I / A377V / A394P / E424A / S430A / A440G / E463D;N66D / L1 99I / L302I / A377V / A394P / E424A / S430A / V447A / E463D;N66D / L199I / L302I / A377V / A394P / S418A / E424A / S430A / E463D; N66D / L199I / L302I / A377V / A394P / E424A / T436A / S430A / E463D; N66D / L199I / L302I / Q364L / A377V / A394P / E424A / S430A / E463D; N66D / L199I / L302I / A377V / A394P / E424A / S430A / E463D / Q490P; N66D / L199I / L302I / A377V / A394P / E424A / S430A / E463D / M469K;N66D / L199I / L302I / A377V / T389L / A394P / E424A / S430A / E463D; N66D / L199I / L302I / A377V / A394P / E424A / S430A / E463D / R465S; N66D / L199I / L302I / A377V / A394P / E424A / S430A / E463D / R464I; N66D / L199I / L302I / A377V / A394P / E424A / S430A / E463D / R465G; N66D / L199I / L 302I / A377V / A394P / E424A / S430A / A440S / E463D;N66D / L199I / L302 I / A377V / A394P / E424A / S430A / S457T / E463D;N66D / L199I / L302I / A 377V / A394P / E424A / S430A / T436S / E463D;N66D / L199I / L302I / S363 T / L371V / A377V / A394P / E424A / S430A / E463D;N66D / L199I / L302I / A 377V / A394P / E424A / S430A / V447A / Q453R / E463D; N66D / L199I / L302I / A377V / A394P / E424A / S430A / K456Q / F462Y / E463D; N66D / L199I / L302I / A377V / A394P / M419V / E424A / A427V / S430A / E463D; N66D / L199I / L302I / F365I / A377V / A394P / E424A / S430A / E463D / K487N; N66D / L 199I / L302I / L371M / A377V / A394P / E424A / S430A / E463D / K487N; N66D / L199I / L302I / Q364L / A377V / T389L / A394P / M419V / E424A / A427V / S430A / V447A / E463D / R465S / M469K; N66D / L199I / L302I / A377V / T389L / A394P / M419V / E424A / A427V / S430A / V447A / E463D / R465S / M469K;N66D / L199I / L302I / S363T / Q364L / L371V / A377V / T389L / A394P / M419V / E424A / A427V / S430A / V447A / E463D / R464I / R465S / M469K; N66D / L199I / L30 2I / S363T / L371V / A377V / T389L / A394P / M419V / E424A / A427V / S430A / V447A / E463D / R464I / R465S / M469K; N66D / L199I / L302I / Q364L / N367H / L371V / A377V / T389L / A394P / S418A / M419V / E424A / A427V / S430A / T436A / A440S / V447A / E463D / R464I / R465S / M469K / Q490P; N66D / L199I / L302I / N367H / L 371V / A377V / T389L / A394P / S418A / M419V / E424A / A427V / S430A / T436A / A440S / V447A / E463D / R464I / R465S / M469K / Q490P;N66D / L199I / L302I / S36 3T / N367H / L371V / A377V / A394P / E424A / S430A / E463D / Q490P;N66D / L199 I / L302I / A377V / A394P / S418A / M419V / E424A / A427V / S430A / T436A / A440S / V447A / E463D; N66D / L199I / L302I / A377V / T389L / A394P / E424A / S430A / S457T / E463D / R464I / R465S / M469K; N66D / L199I / L302I / S363T / L371V / A3 77V / T389L / A394P / M419V / E424A / A427V / S430A / A440S / V447A / S457T / E463D / R464I / M469K / Q490P; N66D / L199I / L302I / A377V / A394P / E424A / S430 A / V447A / E463D / R465S / M469K / Q490P;N66D / L199I / L302I / L371M / A377V / A394P / M419V / E424A / A427V / S430A / E463D / R465S / M469K / K487N / Q490P;N66D / L199I / L302I / L371M / A377V / A394P / M419V / E424A / A427V / S430A / V447A / Q453R / E463D / R465S / M469K / K487N / Q490P; N66D / L199I / L302I / N367H / L371V / A 377V / T389L / A394P / S418A / M419V / E424A / A427V / A429P / S430A / T436A / A440S / V447A / S457T / E463D / R464I / R465S / M469K / Q490P;N66D / L199I / L302I / L371M / A 377V / T389L / A394P / M419V / E424A / A427V / S430A / T436A / V447A / Q453R / K456Q / F462Y / E463D / R465S / M469K / K487N / Q490P;N66D / L199I / L302I / N367H / L371V / A 377V / T389L / A394P / S418A / M419V / E424A / A427V / A429P / S430A / T436A / A440S / V 447A / Q453R / K456Q / S457T / F462Y / E463D / R464I / R465S / M469K / K487N / Q490P,; The above positions are numbered according to SEQ ID No.

1.

2. An isolated polynucleotide, characterized in that, The polynucleotide comprises a nucleotide sequence encoding a polypeptide variant according to claim 1.

3. An additive for lysing Fusarium toxin, characterized in that, The additive comprises at least one polypeptide variant according to claim 1.

4. The additive according to claim 3, characterized in that, The additive also contains at least one adjuvant.

5. The additive according to claim 4, characterized in that, The adjuvant is selected from the group consisting of: inert carriers, vitamins, minerals, plant-derived substances, enzymes and other components used to detoxify mycotoxins; and microorganisms that degrade mycotoxins; and substances that bind mycotoxins.

6. The additive according to claim 5, characterized in that, The other components used to detoxify fungal toxins are fungal toxin-degrading enzymes.

7. The additive according to claim 6, characterized in that, The fungal toxin degrading enzymes are selected from aflatoxin oxidase, ergotamine hydrolase, ergotamine amidase, zearalenone esterase, zearalenone lactone esterase, zearalenone hydrolase, ochratoxin amidase, fusarium aminotransferase, amino polyol amino oxidase, deoxyfusarium alcohol epoxide hydrolase, deoxyfusarium alcohol dehydrogenase, deoxyfusarium alcohol oxidase, trichothecene dehydrogenase, and trichothecene oxidase.

8. The additive according to claim 5, characterized in that, The substance that binds to fungal toxins is a microbial cell wall or inorganic material.

9. The additive according to claim 8, characterized in that, The inorganic material is bentonite.

10. Use of the additive according to any one of claims 3 to 9 for cleaving at least one Fusarium toxin in food or feed.

11. The use according to claim 10, characterized in that, The food or feed is granulated.

12. The use according to claim 10, characterized in that, The feed is for use in pig, poultry, cattle, horses, fish, or aquaculture.

13. Use of the additive according to any one of claims 3 to 9 for cleaving at least one Fusarium toxin in a method for preparing or processing food or feed.

14. The use according to claim 13, characterized in that, The method is carried out at a temperature of at least 50°C.

15. A method for hydrolyzing at least one Fusarium toxin, characterized in that, The mixture is brought into contact with at least one peptide variant according to claim 1 or at least one additive according to any one of claims 3 to 9, and the mixture of the peptide variant and the fumigatus toxin is subjected to heat treatment at at least 50°C, and either during or after the heat treatment, the mixture is brought into contact with a sufficient amount of moisture for hydrolytic pyrolysis.

16. The method according to claim 15, characterized in that, The polypeptide variant or the additive is mixed with feed or food contaminated with at least one Fusarium toxin.

17. The method according to claim 15, characterized in that, The heat treatment is performed during the granulation process.

18. The method according to any one of claims 15 to 17, characterized in that, The peptide variant was added at a concentration ranging from 5 U to 500 U / kg of feed or food.

19. The method according to claim 18, characterized in that, The peptide variant was added at a concentration ranging from 10 U to 300 U / kg of feed or food.

20. The method according to claim 19, characterized in that, The peptide variant was added at a concentration ranging from 15 U to 100 U / kg of feed or food.

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