Glucose oxidase variants

Abstract

The present disclosure relates to a glucose oxidase variant derived from the amino acid sequence of SEQ ID NO: 1. The glucose oxidase variant comprises an amino acid substitution at any one of position 159, 411, 443, 468 and / or 491 and optionally at any one of position 92, 433, 440 and / or 503. The glucose oxidase variants exhibit enzymatic activity at both room temperature and elevated temperature.

Description

[0001] Cross-citation of relevant applications and literature

[0002] This patent application claims priority to U.S. Provisional Patent Application 63 / 582,640, filed September 14, 2023, the entire contents of which are incorporated herein by reference. This patent application also includes a sequence list, filed electronically, which is also incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to glucose oxidase variants that exhibit activity at elevated temperatures while maintaining activity at room temperature. Background Technology

[0004] Glucose oxidase is a flavin adenine dinucleotide (FAD)-dependent enzyme that oxidizes β-D-glucose to D-gluconic acid-ω-lactone and hydrogen peroxide in the presence of molecular oxygen. It is used as an oxidant in industries including pharmaceuticals, medicine, textiles, and food. In baking applications, glucose oxidase, through its in-situ release of hydrogen peroxide, promotes the formation of an ordered gluten network in bread dough, thereby improving its processing properties, bread volume, and crumb uniformity.

[0005] In terms of catalysis, glucose oxidase is known for its rapid and highly specific mechanism of action (approximately 10). 6 M -1 ·s -1 This enzyme is considered near-ideal. Thermodynamically, it is susceptible to changes in conditions such as temperature, pH, or ionic strength. In biotechnology and other industrial applications, glucose oxidases that retain their full catalytic activity while also possessing higher thermodynamic stability are needed. Summary of the Invention

[0006] This disclosure provides glucose oxidase variants having enzymatic activities different from those of the parent (wild-type) glucose oxidase.

[0007] According to a first aspect, this disclosure provides a glucose oxidase variant that: (i) has at least 90% identity with the amino acid sequence of SEQ ID NO: 1, and (ii) contains an amino acid substitution at any of positions 159, 411, 443, 468, and / or 491. In some embodiments, the glucose oxidase variant may contain an amino acid substitution at position 159. In additional embodiments, the amino acid substitution at position 159 may be A159F, A159L, A159K, A159R, A159Y, A159T, A159V, or A159S. In some embodiments, the glucose oxidase variant may contain an amino acid substitution at position 411. In additional embodiments, the amino acid substitution at position 411 may be T411V, T411S, T411A, T411Q, T411E, or T411K. In some embodiments, the glucose oxidase variant may contain an amino acid substitution at position 443. In additional embodiments, the amino acid substitution at position 443 may be A443I, A443L, A443F, A443M, A443Y, or A443V. In some embodiments, the glucose oxidase variant may contain an amino acid substitution at position 468. In additional embodiments, the amino acid substitution at position 468 may be H468R, H468A, H468K, H468G, or H468S. In some embodiments, the glucose oxidase variant may contain an amino acid substitution at position 491. In additional embodiments, the amino acid substitution at position 491 may be Q491K, Q491R, or Q491E. In another embodiment, the glucose oxidase variant may also contain one or more additional amino acid substitutions at any of positions 92, 433, 440, and / or 503. In some embodiments, the glucose oxidase variant may contain an amino acid substitution at position 92. In additional embodiments, the amino acid substitution at position 92 may be D92E, D92Q, D92A, D92K, D92R, D92S, or D92Y. In some embodiments, the glucose oxidase variant may contain an amino acid substitution at position 433. In additional embodiments, the amino acid substitution at position 433 may be S433A, S433V, S433L, S433G, S433F, S433Y, or S433I. In some embodiments, the glucose oxidase variant may contain an amino acid substitution at position 440. In additional embodiments, the amino acid substitution at position 440 may be A440G, A440E, A440D, A440S, A440F, or A440K. In some embodiments, the glucose oxidase variant may contain an amino acid substitution at position 503.In an additional embodiment, the amino acid substitution at position 503 may be 503K, Q503A, Q503R, Q503S, or Q503E.

[0008] According to a second aspect, this disclosure provides a heterologous nucleic acid molecule comprising an open reading frame encoding an open reading frame encoding a glucose oxidase variant described herein. In one embodiment, the heterologous nucleic acid molecule further comprises at least one promoter operatively associated with the open reading frame.

[0009] According to a third aspect, this disclosure provides a vector comprising the heterologous nucleic acid molecule described herein.

[0010] According to the fourth aspect, this disclosure provides an expression cassette containing the heterologous nucleic acid molecule described herein.

[0011] According to a fifth aspect, this disclosure provides a recombinant microbial host cell expressing the glucose oxidase variant described herein. In one embodiment, the recombinant microbial host cell comprises the heterologous nucleic acid molecule described herein, the vector described herein, or the expression cassette described herein. In another embodiment, the recombinant microbial host cell is yeast. In a further embodiment, the recombinant microbial host cell is derived from the genus *Saccharomyces* (Yeast). Saccharomyces ) strain. In another embodiment, the recombinant microbial host cell is derived from Saccharomyces cerevisiae (Saccharomyces cerevisiae). Saccharomyces cerevisiae In another embodiment, the recombinant microorganism is derived from the genus *Komagata* (…). Komagataella In another embodiment, the recombinant microbial host cell is derived from *Phaeodactylum fafesumi* (a type of yeast). Komagataella phaffii ).

[0012] According to a sixth aspect, this disclosure provides a method for preparing the glucose oxidase variant described herein. The method includes expressing the heterologous nucleic acid molecule, the vector, or the expression cassette described herein in a recombinant microbial host cell. In one embodiment, the glucose oxidase variant is an intracellular polypeptide or a secreted polypeptide. In another embodiment, the secreted polypeptide is in free form or bound to the surface of the recombinant microbial host cell. In yet another embodiment, the polypeptide bound to the surface of the recombinant yeast host cell is a tethering polypeptide. In one embodiment, the method further includes (ii) substantially separating the glucose oxidase variant from the recombinant microbial host cell after step (i). In yet another embodiment, the method further includes drying the glucose oxidase variant after step (i) or (ii).

[0013] According to a seventh aspect, this disclosure provides a composition comprising a glucose oxidase variant described herein, and a carrier. In one embodiment, the glucose oxidase variant is obtainable by the methods described herein, or obtained by the methods described herein. In other embodiments, the composition further comprises another enzyme.

[0014] According to an eighth aspect, this disclosure provides a method for preparing dough or a baked product prepared from the dough, the method comprising adding an effective amount of the glucose oxidase variant described herein, optionally in combination with a fermenting yeast, to the dough. In one embodiment, the method further comprises proofing the dough before, during, and / or after the addition. In another embodiment, the method further comprises baking the dough after the addition. In a further embodiment, the method is used to increase the softness and / or elasticity of the baked product. In additional embodiments, the method is used to increase the strength of the dough, and in other embodiments, it can be used to at least partially reduce the amount of chemical dough enhancers in the dough. Attached Figure Description

[0015] Therefore, the nature of the invention has been generally described, and preferred embodiments of the invention will now be illustrated by way of the accompanying drawings, wherein: Figure 1 The relative glucose oxidase activities of enzyme variants expressed in *Saccharomyces cerevisiae* after incubation at 25°C (solid bars) or 65°C (striped bars) for ten minutes are provided. The 25°C activity is reported as a percentage of wild-type activity. The 65°C activity is reported as a percentage of the baseline activity level at 25°C for each variant. Each data point is the average of two technical replicates. The assay was performed twice.

[0016] Figure 2 Absolute glucose oxidase activity (absorbance measured at 510 nm) of the enzyme variant expressed in *Saccharomyces cerevisiae* at 25 °C is provided. Each data point is the average of three technical replicates. The assay was performed twice. Error bars represent the standard deviation of the mean.

[0017] Figure 3 Temperature activity curves of enzyme variants expressed in *Saccharomyces cerevisiae* are provided. Results are shown for wild-type or WT (black squares, dashed trend line ■); GOx variant v15 (grey diamonds, solid gray trend line). v16 (gray cross squares, solid light gray trend line □); v24 (gray circles, long dashed gray trend line ○); and v26 (gray triangles, densely packed gray trend lines). ).

[0018] Figure 4The relative glucose oxidase activities of enzyme variants expressed in *Phaeodactylum phragmites* after incubation at 25°C (solid bars) or 65°C (striped bars) for ten minutes are provided. The 25°C activity is reported as a percentage of wild-type activity. The 65°C activity is reported as a percentage of the baseline activity level at 25°C for each variant. Each data point is the average of two technical replicates. The assay was performed twice.

[0019] Figure 5 The absolute glucose oxidase activity of the enzyme variant expressed in *Phaeodactylum phragmites* at 25 °C is provided. Each data point is the average of three technical replicates. The assay was performed twice. Error bars represent the standard deviation of the mean.

[0020] Figure 6 Temperature activity profiles of enzyme variants expressed in *Phaeodactylum phragmus* are provided. Results are shown for wild-type or WT (black squares, dashed trend line ■); GOx variant v29 (grey rhombuses, solid gray trend line). v16 (gray cross squares, solid light gray trend line □); v24 (gray circles, long dashed gray trend line ○); and v26 (gray triangles, densely packed gray trend lines). ).

[0021] Figure 7 Baking application tests comparing wild-type (WT) glucose oxidase with GOx variants v24 and v26 expressed in *Saccharomyces phagnum* are presented. The solid bars on the left and the striped bars on the right depict data from two independent baking tests. Glucose oxidase was added to the dough as a spray-dried sample of the enzyme produced in a bioreactor. The enzyme dosage is expressed in glucose oxidase units per kilogram of flour (GODU) below each bar. No enzyme was added to the control dough. The volume of the final bread is plotted. Detailed Implementation

[0022] This disclosure provides polypeptides with glucose oxidase activity, which belong to Enzyme Committee number 1.1.3.4. These polypeptides are derived from Aspergillus niger (… Aspergillus nigerNaturally occurring glucose oxidases from Aspergillus niger, with GenBank accession number P13006 or Uniprot accession number P13006.1 (corresponding to the amino acid sequence of SEQ ID NO: 1), may be referred to as parental glucose oxidases or wild-type (WT) glucose oxidases. In the context of this disclosure, a polypeptide is considered “derived from naturally occurring glucose oxidases from Aspergillus niger” when it can be obtained by modifying (adding, deleting, and / or substituting) at least one amino acid residue present in the amino acid sequence of SEQ ID NO: 1. In the context of this disclosure, polypeptides derived from naturally occurring glucose oxidases from Aspergillus niger may be referred to as glucose oxidase variants.

[0023] In some embodiments, the glucose oxidase variant exhibits at least 70% identity with the amino acid sequence of SEQ ID NO: 1. As is known in the art, the term "% identity" refers to the relationship between two or more polypeptide sequences determined by comparing sequences. The level of identity can be routinely determined using known computer programs. Identity can be readily calculated using known methods, including but not limited to those described in the following literature: Computational Molecular Biology (Lesk, AM, ed.) Oxford University Press, NY (1988); Biocomputing: Informatics and Genome Projects (Smith, DW, ed.) Academic Press, NY (1993); Computer Analysis of Sequence Data, Part I (Griffin, AM, and Griffin, HG, eds.) Humana Press, NJ (1994); Sequence Analysis in Molecular Biology (von Heinje, G., ed.) Academic Press (1987); and Sequence Analysis Primer (Gribskov, M. and Devereux, J., eds.) Stockton Press, NY (1991). Preferred methods for determining identity are designed to provide the best match between test sequences. Methods for determining identity and similarity are incorporated into publicly available computer programs. Sequence alignment and percentage identity calculations can be performed using the LASERGENE bioinformatics computing suite (DNASTAR Inc., Madison, Wis.) or the Megalign program of Geneious Prime. Multiple alignments of the sequences disclosed herein were performed using the Clustal Omega alignment method, which employs an algorithm based on a Hidden Markov Model with default parameters (including cluster size = 100).

[0024] The variants disclosed herein exhibit glucose oxidase activity. It is well known in the art how to determine whether a peptide exhibits glucose oxidase activity. For example, in a first step, a peptide suspected of having glucose oxidase activity can be contacted with a substrate known to be acted upon by this enzyme (e.g., β-D-glucose). If the peptide being tested exhibits glucose oxidase activity, it will produce hydrogen peroxide (H₂O₂) and a lactone (e.g., D-gluconic acid-δ-lactone) in the presence of oxygen. In a further step, the presence / amount of released hydrogen peroxide can be determined by using a peroxidase to generate a detectable dye (e.g., quinone imine detectable at 510 nm; or o-anisidine dihydrochloride detectable at 540 nm). In this further step, the detectable dye can be used in conjunction with the peroxidase to determine glucose oxidase activity.

[0025] The variants of this disclosure exhibit glucose oxidase activity at room temperature (e.g., at a temperature between 20°C and 30°C, and in some embodiments, at about 25°C). In the context of this disclosure, a polypeptide “exhibiting glucose oxidase activity at room temperature” means a polypeptide that, when measured under similar assay conditions and at the same temperature, possesses at least 10% of wild-type glucose oxidase activity. In some embodiments, the glucose oxidase variant exhibits at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more of wild-type glucose oxidase activity when measured under similar assay conditions and at the same temperature. In additional embodiments, the glucose oxidase variant exhibits at least 20% or more of wild-type glucose oxidase activity when measured under similar assay conditions and at the same temperature. In further embodiments, the glucose oxidase variant exhibits at least 25% or more of wild-type glucose oxidase activity when measured under similar assay conditions and at the same temperature. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 30% or more of the wild-type glucose oxidase activity. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 35% or more of the wild-type glucose oxidase activity. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 40% or more of the wild-type glucose oxidase activity. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 45% or more of the wild-type glucose oxidase activity. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 50% or more of the wild-type glucose oxidase activity. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 55% or more of the wild-type glucose oxidase activity. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 60% or more of the wild-type glucose oxidase activity. In an additional embodiment, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 65% or more of the wild-type glucose oxidase activity. In an additional embodiment, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 70% or more of the wild-type glucose oxidase activity. In an additional embodiment, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 75% or more of the wild-type glucose oxidase activity.In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 80% or more of the wild-type glucose oxidase activity. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 85% or more of the wild-type glucose oxidase activity. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 90% or more of the wild-type glucose oxidase activity. In additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits at least 95% or more of the wild-type glucose oxidase activity. In some additional embodiments, when measured under similar assay conditions and at the same temperature, the glucose oxidase variant exhibits substantially the same activity as wild-type glucose oxidase (e.g., between 95% and 105%). In still other embodiments, when measured under similar assay conditions and at the same temperature, it exhibits higher activity than wild-type glucose oxidase (e.g., exceeding 100%, 105%, 110%, 115%, 120%, or higher).

[0026] In addition to exhibiting activity at room temperature, the variants of this disclosure also exhibit higher activity than wild-type glucose oxidase at elevated temperatures (e.g., at temperatures equal to or above 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, or 79°C). In some embodiments, this means that the variants of this disclosure exhibit 50% or more of residual activity. The expression "residual activity" refers to the ratio of the activity of the glucose oxidase variant after heat shock treatment to the activity of the glucose oxidase variant that has not been heat-shocked. Heat shock treatment is performed at an elevated temperature (e.g., 65°C) for a defined duration (e.g., 10 minutes). In some embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes). In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 50% or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes). In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 55% or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes). In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 60% or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes). In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 65% or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes). In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 70% or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes). In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 75% or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes). In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 80% or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes). In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 85% or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes). In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 90% or more (e.g., when measured, for example, after heat shock at 65°C for 10 minutes).In some additional embodiments, the residual activity of the glucose oxidase variant may be equal to or greater than 95% or more (e.g., when measured after heat shock at 65°C for 10 minutes, for example).

[0027] The glucose oxidase variant disclosed herein can have an inactivation temperature higher than that of wild-type glucose oxidase. Inactivation temperature, also known as T0... 50 Inactivation temperature is the temperature at which an enzyme loses 50% of its activity. The inactivation temperature can be measured, for example, by generating temperature-activity profiles of a glucose oxidase variant and fitting each profile to a sum-of-squares model. In some embodiments, the inactivation temperature of the glucose oxidase variant is at least 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or more higher than that of wild-type glucose oxidase. In some additional embodiments, the inactivation temperature of the glucose oxidase variant is at least 6°C, 7°C, 8°C, 9°C, or more higher than that of wild-type glucose oxidase. In some further embodiments, the inactivation temperature of the glucose oxidase variant is at least 8°C, 9°C, or more higher than that of wild-type glucose oxidase.

[0028] The glucose oxidase variant disclosed herein can have a higher melting temperature than the wild-type glucose oxidase. Melting temperature, also known as T0... m Melting temperature refers to the temperature at which the number of folded and unfolded states of an enzyme is equal (e.g., the midpoint of a protein denaturation curve). Melting temperature can be measured, for example, using differential scanning fluorometry with a fluorescent dye. In some embodiments, the melting temperature of the glucose oxidase variant is at least 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, or 9°C higher than the melting temperature of wild-type glucose oxidase. In some additional embodiments, the melting temperature of the glucose oxidase variant is at least 4°C, 5°C, 6°C, 7°C, 8°C, or 9°C higher than the melting temperature of wild-type glucose oxidase. In some further embodiments, the melting temperature of the glucose oxidase variant is at least 7°C, 8°C, or 9°C higher than the melting temperature of wild-type glucose oxidase.

[0029] The glucose oxidase variant of this disclosure may exhibit improved stability compared to wild-type glucose oxidase during storage (at specific temperatures). Stability during storage can be assessed using methods known in the art. For example, activity before and after storage can be determined to calculate the activity loss during storage. Storage can be performed at room temperature (between about 20°C and 30°C), at low temperatures (between about 0°C and 20°C), at frozen temperatures (below 0°C), or at elevated temperatures (e.g., above 30°C). In some embodiments, the stability of the glucose oxidase variant and the wild-type enzyme is determined at elevated temperatures (between about 35°C and 55°C, and in some embodiments, at about 45°C). The stability of the glucose oxidase variant and the wild-type enzyme is determined after specific storage time periods (hours, days, months). In some embodiments, the stability of the glucose oxidase variant and the wild-type enzyme is determined after storage periods of 1 week, 2 weeks, 3 weeks, and / or 4 weeks. After one week of incubation at 45°C, some glucose oxidases will exhibit an activity loss of less than about 15% of the initial activity of samples incubated on day 0 and kept frozen (and in some additional embodiments, the activity loss is equal to or less than about 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, or 6%). After two weeks of incubation at 45°C, some glucose oxidases will exhibit an activity loss of less than about 18% of the initial activity of samples incubated on day 0 and kept frozen (and in some additional embodiments, the activity loss is equal to or less than about 17%, 16%, 15%, or 14%). After three weeks of incubation at 45°C, some glucose oxidases will exhibit an activity loss of less than about 26% of the initial activity of samples incubated on day 0 and kept frozen (and in some additional embodiments, the activity loss is equal to or less than about 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, or 15%). After four weeks of incubation at 45°C, some glucose oxidases will show an activity loss of less than 31% of the initial activity of samples incubated for 0 days and kept frozen (and in some additional embodiments, the activity loss is equal to or less than about 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23% or 22%).

[0030] Glucose oxidase variant

[0031] As noted herein, the glucose oxidase variants disclosed herein are derived from naturally occurring glucose oxidase from *Aspergillus niger*, with GenBank accession number P13006 or Uniprot accession number P13006.1 (corresponding to the amino acid sequence of SEQ ID NO: 1). Wild-type glucose oxidase, when naturally expressed in *Aspergillus niger*, is believed to possess a signal sequence that can be cleaved when the enzyme is secreted in mature form. However, the prediction of the exact domain boundaries of the signal sequence is ambiguous, and therefore the amino acid sequence of mature wild-type glucose oxidase may differ. In some embodiments, the signal sequence of wild-type glucose oxidase comprises the first 16 amino acid residues of the amino acid sequence of SEQ ID NO: 1. In such embodiments, the mature (secreted) forms of wild-type glucose oxidase and glucose oxidase variants will comprise amino acid residues from position 17 to position 605 of the amino acid sequence of SEQ ID NO: 1. In some other embodiments, the signal sequences of wild-type and glucose oxidase variants comprise the first 22 amino acid residues of the amino acid sequence of SEQ ID NO: 1. In such embodiments, the mature (secretory) forms of wild-type glucose oxidase and glucose oxidase variants will contain amino acid residues from position 23 to position 605 of the amino acid sequence of SEQ ID NO: 1. In some additional embodiments, the signal sequence of the wild-type and glucose oxidase variants contains the first 24 amino acid residues of the amino acid sequence of SEQ ID NO: 1. In such embodiments, the mature (secretory) forms of wild-type glucose oxidase and glucose oxidase variants will contain amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 1.

[0032] In the context of this disclosure, the numbering of modified amino acid residues in glucose oxidase variants is provided relative to the full-length amino acid sequence of SEQ ID NO: 1, even though glucose oxidase variants (especially their mature / secretory forms) may lack some N-terminal residues that are cleaved upon secretion. For example, as noted herein, some glucose oxidase variants include a substitution at position 159 of the amino acid sequence in SEQ ID NO: 1. In embodiments where the signal sequence has not yet been cleaved (e.g., prior to secretion), this would correspond to position 159 in the glucose oxidase variant. In embodiments where the first 16 amino acid residues are cleaved upon secretion (or in a cell-free production system), this would correspond to position 143 in the mature form of the glucose oxidase variant. In embodiments where the first 22 amino acid residues are cleaved upon secretion (or in a cell-free production system), this would correspond to position 137 in the secretory glucose oxidase variant. In embodiments where the first 24 amino acid residues are cleaved upon secretion (or in a cell-free production system), this would correspond to position 135 in the mature form of the glucose oxidase variant. In another example, as noted herein, some glucose oxidase variants include a substitution at position 411 of the amino acid sequence of SEQ ID NO: 1. In embodiments where the signal sequence has not yet been cleaved (e.g., before secretion), this corresponds to position 411 in the glucose oxidase variant. In embodiments where the first 16 amino acid residues are cleaved during secretion, this corresponds to position 395 in the mature form of the glucose oxidase variant. In embodiments where the first 22 amino acid residues are cleaved during secretion, this corresponds to position 389 in the secretory glucose oxidase variant. In embodiments where the first 24 amino acid residues are cleaved during secretion (or in a cell-free production system), this corresponds to position 387 in the mature form of the glucose oxidase variant. In yet another example, as noted herein, some glucose oxidase variants include a substitution at position 443 of the amino acid sequence of SEQ ID NO: 1. In embodiments where the signal sequence has not yet been cleaved (e.g., before secretion), this corresponds to position 443 in the glucose oxidase variant. In embodiments where the first 16 amino acid residues are cleaved during secretion, this corresponds to position 427 in the mature form of the glucose oxidase variant. In embodiments where the first 22 amino acid residues are cleaved during secretion, this corresponds to position 421 in the secretory glucose oxidase variant. In embodiments where the first 24 amino acid residues are cleaved during secretion (or in a cell-free production system), this corresponds to position 419 in the mature form of the glucose oxidase variant. In yet another example, as noted herein, some glucose oxidase variants include a substitution at position 468 of the amino acid sequence of SEQ ID NO: 1. In embodiments where the signal sequence has not yet been cleaved (e.g., prior to secretion), this corresponds to position 468 in the glucose oxidase variant.In embodiments where the first 16 amino acid residues are cleaved during secretion, this corresponds to position 452 in the mature form of the glucose oxidase variant. In embodiments where the first 22 amino acid residues are cleaved during secretion, this corresponds to position 446 in the secretory glucose oxidase variant. In embodiments where the first 24 amino acid residues are cleaved during secretion (or in a cell-free production system), this corresponds to position 444 in the mature form of the glucose oxidase variant. In another example, as noted herein, some glucose oxidase variants include a substitution at position 491 of the amino acid sequence of SEQ ID NO: 1. In embodiments where the signal sequence has not yet been cleaved (e.g., prior to secretion), this corresponds to position 491 in the glucose oxidase variant. In embodiments where the first 16 amino acid residues are cleaved during secretion, this corresponds to position 475 in the mature form of the glucose oxidase variant. In embodiments where the first 22 amino acid residues are cleaved during secretion, this corresponds to position 469 in the secretory glucose oxidase variant. In embodiments where the first 24 amino acid residues are cleaved during secretion (or in a cell-free production system), this corresponds to position 467 in the mature form of the glucose oxidase variant. In yet another example, as noted herein, some glucose oxidase variants include a substitution at position 92 of the amino acid sequence of SEQ ID NO: 1. In embodiments where the signal sequence has not yet been cleaved (e.g., before secretion), this corresponds to position 92 in the glucose oxidase variant. In embodiments where the first 16 amino acid residues are cleaved during secretion, this corresponds to position 76 in the mature form of the glucose oxidase variant. In embodiments where the first 22 amino acid residues are cleaved during secretion, this corresponds to position 70 in the secretory glucose oxidase variant. In embodiments where the first 24 amino acid residues are cleaved during secretion (or in a cell-free production system), this corresponds to position 68 in the mature form of the glucose oxidase variant. In yet another example, as noted herein, some glucose oxidase variants include a substitution at position 433 of the amino acid sequence of SEQ ID NO: 1. In embodiments where the signal sequence has not yet been cleaved (e.g., before secretion), this corresponds to position 433 in the glucose oxidase variant. In embodiments where the first 16 amino acid residues are cleaved during secretion, this corresponds to position 417 in the mature form of the glucose oxidase variant. In an embodiment where the first 22 amino acid residues are cleaved during secretion, this corresponds to position 411 in the secretory glucose oxidase variant. In an embodiment where the first 24 amino acid residues are cleaved during secretion (or in a cell-free production system), this corresponds to position 409 in the mature form of the glucose oxidase variant. In yet another example, as noted herein, some glucose oxidase variants include a substitution at position 440 of the amino acid sequence of SEQ ID NO: 1.In embodiments where the signal sequence has not yet been cleaved (e.g., prior to secretion), this corresponds to position 440 in the glucose oxidase variant. In embodiments where the first 16 amino acid residues are cleaved during secretion, this corresponds to position 424 in the mature form of the glucose oxidase variant. In embodiments where the first 22 amino acid residues are cleaved during secretion, this corresponds to position 418 in the secretory glucose oxidase variant. In embodiments where the first 24 amino acid residues are cleaved during secretion (or in a cell-free production system), this corresponds to position 416 in the mature form of the glucose oxidase variant. In yet another example, as noted herein, some glucose oxidase variants include a substitution at position 503 of the amino acid sequence of SEQ ID NO: 1. In embodiments where the signal sequence has not yet been cleaved (e.g., prior to secretion), this corresponds to position 503 in the glucose oxidase variant. In embodiments where the first 16 amino acid residues are cleaved during secretion, this corresponds to position 487 in the mature form of the glucose oxidase variant. In embodiments where the first 22 amino acid residues are cleaved during secretion, this corresponds to position 481 in the secretory glucose oxidase variant. In an implementation where the first 24 amino acid residues are cleaved during secretion (or in a cell-free production system), this would correspond to position 479 in the mature form of the glucose oxidase variant.

[0033] The glucose oxidase variant disclosed herein shares at least 70% and less than 100% amino acid sequence identity with SEQ ID NO: 1. Therefore, the glucose oxidase variant comprises amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1. Amino acid modifications may include at least one amino acid addition, at least one amino acid deletion, and / or at least one amino acid substitution. In some specific embodiments, the glucose oxidase variant comprises amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 1. In some additional embodiments, the glucose oxidase variant comprises at least two, three, four, five, six, seven, eight, nine, or more amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 1.

[0034] In some additional embodiments, the glucose oxidase variant comprises at least one amino acid substitution at any of positions 159, 411, 443, 468, and / or 491. In further embodiments, the glucose oxidase variant comprises at least two amino acid substitutions at any combination of positions 159, 411, 443, 468, and / or 491. In further embodiments, the glucose oxidase variant comprises at least three amino acid substitutions at any combination of positions 159, 411, 443, 468, and / or 491. In further embodiments, the glucose oxidase variant comprises at least four amino acid substitutions at any combination of positions 159, 411, 443, 468, and / or 491. In still some additional embodiments, the glucose oxidase variant comprises amino acid substitutions at positions 159, 411, 443, 468, and 491. Embodiments of glucose oxidase variants comprising at least one amino acid substitution at any of positions 159, 411, 443, 468, and / or 491 are provided in Table 1.

[0035] This disclosure provides variants of glucose oxidase variants that contain at least one amino acid substitution at any of positions 159, 411, 443, 468, and / or 491. Such variants contain at least one amino acid substitution at any of positions 159, 411, 443, 468, and / or 491, as well as other modifications. As used in the context of this disclosure, a “variant” of glucose oxidase variant contains at least one amino acid difference (e.g., at least one amino acid addition, deletion, or substitution) compared to the amino acid sequence of the original glucose oxidase variant. The variants exhibit substantially similar biological activity compared to the biological activity of the original glucose oxidase variant. In some embodiments, the variants (including fragments) may also have at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or higher biological activity compared to the biological activity of the original glucose oxidase variant. In some specific embodiments, the variants (including fragments) may also have higher biological activity compared to the biological activity of the original glucose oxidase variant. At least one amino acid difference may refer to an amino acid residue that has been added, substituted, or deleted. As used in the context of this disclosure, a "fragment" is a variant type that contains at least one missing amino acid residue when compared to the amino acid sequence of the original polypeptide. In some embodiments, a fragment may refer to a mature form of a secretory glucose oxidase fragment from which the signal sequence has been cleaved. In some embodiments, variants (including fragments) may also have at least 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence of a glucose oxidase variant.

[0036] The glucose oxidase variants described herein may be: (i) variants in which one or more amino acid residues are replaced by conserved or non-conserved (preferably conserved) amino acid residues and such substituted amino acid residues may or may not be encoded by the genetic code; or (ii) variants in which one or more amino acid residues contain substituent groups; or (iii) variants in which the mature polypeptide is fused with another compound (such as a compound for increasing the half-life of the polypeptide, e.g., polyethylene glycol); or (iv) variants in which additional amino acids are fused to the mature polypeptide for the purpose of purifying the polypeptide. Conservative substitutions typically involve replacing one amino acid with another amino acid that has similar characteristics, for example, replacing an amino acid with another amino acid belonging to the same class determined by its side chain: within amino acids with hydrophobic side chains (alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, or tryptophan); within amino acids with positively charged side chains (arginine, histidine, or lysine); with negatively charged side chains (aspartic acid or glutamic acid) and polar uncharged side chains (serine, threonine, asparagine, or glutamine); or within the group consisting of: valine, glycine; glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. Other conservative amino acid substitutions are known in the art and are included herein. Non-conservative substitutions, such as replacing basic amino acids with hydrophobic amino acids, are also well known in the art.

[0037] Variants of glucose oxidase variants can be conserved variants or allelic variants. As used herein, a conserved variant is a change in the amino acid sequence that does not adversely affect the biological function of the polypeptide. When an altered sequence prevents or disrupts the biological function associated with a polypeptide, it is said that substitution, insertion, or deletion adversely affects the polypeptide. For example, the overall charge, structure, or hydrophobic-hydrophilic properties of a polypeptide can be altered without adversely affecting its biological activity. Therefore, the amino acid sequence can be altered, for example, to make the polypeptide more hydrophobic or more hydrophilic without adversely affecting its biological activity.

[0038] The fragment may correspond to a polypeptide with the signal peptide sequence removed. In an additional embodiment, the fragment may be, for example, a fragment obtained by truncating one or more, two or more, three or more, four, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, twenty-one or more, twenty-two or more, twenty-three or more, twenty-four or more amino acids at the amino terminus of an untruncated polypeptide or variant. In additional embodiments, the fragment may be, for example, a fragment obtained by truncating one or more, two or more, three or more, four, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, sixteen or more, seventeen or more, eighteen or more, nineteen or more, twenty or more, twenty-one or more, twenty-two or more, twenty-three or more, twenty-four or more amino acids at the carboxyl terminus of an untruncated polypeptide or variant. Alternatively, or in combination, the fragment may be generated by removing one or more internal amino acid residues. In one embodiment, the polypeptide fragment may have at least 100, 150, 200, 250, 300, 350, 400, 450 or more consecutive amino acid residues of the original amino acid sequence or polypeptide variant. This disclosure also provides variants of glucose oxidase variants that contain at least one amino acid substitution at any of positions 159, 411, 443, 468 and / or 491. Such variants contain at least one amino acid substitution at any of positions 159, 411, 443, 468 and / or 491, as well as other modifications.

[0039] A glucose oxidase variant having at least one amino acid substitution at any of positions 159, 411, 443, 468, and / or 491 may further contain at least one amino acid substitution at any of positions 92, 433, 440, and / or 503. In an additional embodiment, a glucose oxidase variant having at least one amino acid substitution at any of positions 159, 411, 443, 468, and / or 491 may further contain at least two amino acid substitutions at any combination of positions 92, 433, 440, and / or 503. In an additional embodiment, a glucose oxidase variant having at least one amino acid substitution at any of positions 159, 411, 443, 468, and / or 491 may further contain at least three amino acid substitutions at any combination of positions 92, 433, 440, and / or 503. In additional embodiments, glucose oxidase variants having at least one amino acid substitution at any of positions 159, 411, 443, 468, and / or 491 may further comprise substitutions at positions 92, 433, 440, and 503. Embodiments of glucose oxidase variants comprising at least one amino acid substitution at any of positions 159, 411, 443, 468, and / or 491 and at least one additional amino acid substitution at any of positions 92, 433, 440, and / or 503 are provided in Table 1. The glucose oxidase variants of this disclosure may have the amino acid sequence of SEQ ID NO: 19.

[0040] Table 1This disclosure describes embodiments of glucose oxidase variants with amino acid identities at positions 92, 159, 411, 433, 440, 443, 468, 491, and 503. The amino acid numbers are based on the amino acid sequence of SEQ ID NO: 1. X1 (position 92) refers to any naturally occurring amino acid residue that is not D; in some embodiments, X1 can be E, Q, A, K, R, S, or Y; in some other embodiments, X1 can be E. X2 (position 159) refers to any naturally occurring amino acid residue that is not A; in some embodiments, X2 can be F, L, K, R, Y, T, V, or S; in some other embodiments, X2 can be F. X3 (position 411) refers to any naturally occurring amino acid residue that is not T; in some embodiments, X3 can be V, S, A, Q, E, or K; in some other embodiments, X3 can be V. X4 (position 433) refers to any naturally occurring amino acid residue that is not S; in some embodiments, X4 can be A, V, L, G, F, Y, or I; in some other embodiments, X4 can be A. X5 (position 440) refers to any naturally occurring amino acid residue that is not A; in some embodiments, X5 can be G, E, D, S, F, or K; in some other embodiments, X5 can be G. X6 (position 443) refers to any naturally occurring amino acid residue that is not A; in some embodiments, X6 can be I, L, F, M, Y, or V; in some other embodiments, X6 can be I. X7 (position 468) refers to any naturally occurring amino acid residue that is not H; in some embodiments, X7 can be R, A, K, G, or S; in some other embodiments, X7 can be R. X8 (position 491) refers to any naturally occurring amino acid residue that is not Q; in some embodiments, X8 can be K, R, or E; in some other embodiments, X8 can be K. X9 (position 503) refers to any naturally occurring amino acid residue that is not Q; in some embodiments, X9 may be K, A, R, S or E; in other embodiments, X9 may be K.

[0041]

[0042] In some embodiments, the glucose oxidase variant contains a naturally occurring amino acid residue different from A at position 159. In some embodiments, the glucose oxidase variant containing the substitution at position 159 may contain at least one additional substitution at any of positions 411, 443, 468, and / or 491. In some embodiments, the glucose oxidase variant containing the substitution at position 159 may contain at least two additional substitutions at any of positions 411, 443, 468, and / or 491. In some embodiments, the glucose oxidase variant containing the substitution at position 159 may contain at least three additional substitutions at any of positions 411, 443, 468, and / or 491. In some embodiments, the glucose oxidase variant containing the substitution at position 159 may contain substitutions at positions 411, 443, 468, and 491. For example, glucose oxidase variants may contain one of the following amino acid residues at position 159: R (A159R), N (A159N), C (A159C), D (A159D), E (A159E), Q (A159Q), G (A159G), H (A159H), I (A159I), L (A159L), K (A159K), M (A159M), F (A159F), P (A159P), S (A159S), T (A159T), W (A159W), Y (A159Y), or V (A159V). For example, a glucose oxidase variant may contain one of the following amino acid residues at position 159: R (A159R), L (A159L), K (A159K), F (A159F), S (A159S), T (A159T), Y (A159Y), or V (A159V). In another example, a glucose oxidase variant may contain one of the following amino acid residues at position 159: K (A159K), F (A159F), S (A159S), T (A159T), Y (A159Y), or V (A159V). In yet another example, a glucose oxidase variant may contain one of the following amino acid residues at position 159: L (A159L) or F (A159F). In yet another example, a glucose oxidase variant may contain F (A159F) at position 159. In some embodiments, the glucose oxidase variant does not contain Q (D159Q) at position 159. In some embodiments, the glucose oxidase variant does not contain L at position 159 (A159L). Specific embodiments containing a substituted glucose oxidase at position 159 include, but are not limited to, polypeptides (including fragments thereof) containing the amino acid sequence of SEQ ID NO: 5 or 7 or a variant thereof, which in some embodiments contain amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 5 or 7.

[0043] In some embodiments, the glucose oxidase variant contains a naturally occurring amino acid residue different from T at position 411. In some embodiments, a glucose oxidase variant containing a substitution at position 411 may contain at least one additional substitution at any of positions 159, 443, 468, and / or 491. In some embodiments, a glucose oxidase variant containing a substitution at position 411 may contain at least two additional substitutions at any of positions 159, 443, 468, and / or 491. In some embodiments, a glucose oxidase variant containing a substitution at position 411 may contain at least three additional substitutions at any of positions 159, 443, 468, and / or 491. In some embodiments, a glucose oxidase variant containing a substitution at position 411 may contain substitutions at positions 159, 443, 468, and 491. For example, glucose oxidase variants may contain one of the following amino acid residues at position 411: A (T411A), R (T411R), N (T411N), D (T411D), C (T411C), E (T411E), Q (T411Q), G (T411G), H (T411H), I (T411I), L (T411L), K (T411K), M (T411M), F (T411F), P (T411P), S (T411S), W (T411W), Y (T411Y), or V (T411V). In another example, the glucose oxidase variant may contain one of the following amino acid residues at position 411: Q (T411Q), K (T411K), S (T411S), or V (T411V). In yet another example, the glucose oxidase variant may contain one of the following amino acid residues at position 411: S (T411S) or V (T411V). In yet another example, the glucose oxidase variant may contain V (T411V) at position 411. In some embodiments, the glucose oxidase variant does not contain A (T411A) at position 411. In some embodiments, the glucose oxidase variant does not contain E (T411E) at position 411. In some embodiments, the glucose oxidase variant does not contain either A (T411A) or E (T411E) at position 411. Specific embodiments containing a substituted glucose oxidase at position 411 include, but are not limited to, polypeptides (including fragments thereof containing the amino acid sequence of SEQ ID NO: 5 or 7 or a variant thereof, in some embodiments of which fragments contain amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 5 or 7).

[0044] In some embodiments, the glucose oxidase variant contains a naturally occurring amino acid residue different from A at position 443. In some embodiments, the glucose oxidase variant containing a substitution at position 443 may contain at least one additional substitution at any of positions 159, 411, 468, and / or 491. In some embodiments, the glucose oxidase variant containing a substitution at position 443 may contain at least two additional substitutions at any of positions 159, 411, 468, and / or 491. In some embodiments, the glucose oxidase variant containing a substitution at position 443 may contain at least three additional substitutions at any of positions 159, 411, 468, and / or 491. In some embodiments, the glucose oxidase variant containing a substitution at position 443 may contain substitutions at positions 159, 411, 468, and 491. For example, glucose oxidase variants may contain one of the following amino acid residues at position 443: R (A443R), N (A443N), D (A443D), C (A443C), E (A443E), Q (A443Q), G (A443G), H (A443H), I (A443I), L (A443L), K (A443K), M (A443M), F (A443F), P (A443P), S (A443S), T (A443T), W (A443W), Y (A443Y), or V (A443V). For example, glucose oxidase variants may contain one of the following amino acid residues at position 443: I (A443I), L (A443L), M (A443M), F (A443F), Y (A443Y), or V (A443V). In another example, the glucose oxidase variant may contain one of the following amino acid residues at position 443: M (A443M), F (A443F), Y (A443Y), or V (A443V). In yet another example, the glucose oxidase variant may contain one of the following amino acid residues at position 443: I (A443I) or L (A443L). In yet another example, the glucose oxidase variant may contain I (A443I) at position 443. In some embodiments, the glucose oxidase variant does not contain I (A443I) at position 443. In some embodiments, the glucose oxidase variant does not contain L (A443L) at position 443. In some embodiments, the glucose oxidase variant does not contain either I (A443I) or L (A443L) at position 443. Specific embodiments containing a substituted glucose oxidase at position 443 include, but are not limited to, polypeptides (including fragments thereof containing the amino acid sequence of SEQ ID NO: 5 or 7 or variants thereof, in some embodiments of which fragments contain amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 5 or 7).

[0045] In some embodiments, the glucose oxidase variant contains a naturally occurring amino acid residue different from H at position 468. In some embodiments, the glucose oxidase variant containing a substitution at position 468 may contain at least one additional substitution at any of positions 159, 411, 443, and / or 491. In some embodiments, the glucose oxidase variant containing a substitution at position 468 may contain at least two additional substitutions at any of positions 159, 411, 443, and / or 491. In some embodiments, the glucose oxidase variant containing a substitution at position 468 may contain at least three additional substitutions at any of positions 159, 411, 443, and / or 491. In some embodiments, the glucose oxidase variant containing a substitution at position 468 may contain substitutions at positions 159, 411, 443, and 491. For example, glucose oxidase variants may contain one of the following amino acid residues at position 468: A (H468A), R (H468R), N (H468N), D (H468D), C (H468C), E (H468E), Q (H468Q), G (H468G), I (H468I), L (H468L), K (H468K), M (H468M), F (H468F), P (H468P), S (H468S), T (H468T), W (H468W), Y (H468Y), or V (H468V). For example, glucose oxidase variants may contain one of the following amino acid residues at position 468: A (H468A), R (H468R), (H468G), K (H468K), or S (H468S). In another example, the glucose oxidase variant may contain one of the following amino acid residues at position 468: A (H468A), (H468G), K (H468K), or S (H468S). In yet another example, the glucose oxidase variant may contain one of the following amino acid residues at position 468: A (H468A), R (H468R), or K (H468K). In yet another example, the glucose oxidase variant may contain R (H468R) at position 468. In some embodiments, the glucose oxidase variant does not contain R (H468R) at position 468. Specific embodiments containing a substituted glucose oxidase at position 468 include, but are not limited to, polypeptides (including fragments thereof) containing the amino acid sequence of SEQ ID NO: 5 or 7 or a variant thereof, in some embodiments of which fragments contain amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 5 or 7.

[0046] In some embodiments, the glucose oxidase variant contains a naturally occurring amino acid residue different from Q at position 491. In some embodiments, a glucose oxidase variant containing a substitution at position 491 may contain at least one additional substitution at any of positions 159, 411, 443, and / or 468. In some embodiments, a glucose oxidase variant containing a substitution at position 491 may contain at least two additional substitutions at any of positions 159, 411, 443, and / or 468. In some embodiments, a glucose oxidase variant containing a substitution at position 491 may contain at least three additional substitutions at any of positions 159, 411, 443, and / or 468. In some embodiments, a glucose oxidase variant containing a substitution at position 491 may contain substitutions at positions 159, 411, 443, and 468. For example, glucose oxidase variants may contain one of the following amino acid residues at position 491: A (Q491A), R (Q491R), N (Q491N), D (Q491D), C (Q491C), E (Q491E), G (Q491G), H (Q491H), I (Q491I), L (Q491L), K (Q491K), M (Q491M), F (Q491F), P (Q491P), S (Q491S), T (Q491T), W (Q491W), Y (Q491Y), or V (Q491V). For example, glucose oxidase variants may contain one of the following amino acid residues at position 491: R (Q491R), E (Q491E), or K (Q491K). In another example, the glucose oxidase variant may contain one of the following amino acid residues at position 491: R (Q491R) or E (Q491E). In yet another example, the glucose oxidase variant may contain K (Q491K) at position 491. In some embodiments, the glucose oxidase variant does not contain K (Q491K) at position 491. Specific embodiments containing a substituted glucose oxidase at position 491 include, but are not limited to, polypeptides (including fragments thereof) containing the amino acid sequence of SEQ ID NO: 5 or 7 or variants thereof, in some embodiments of which fragments contain amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 5 or 7.

[0047] Glucose oxidase variants having amino acid substitutions at positions 159, 411, 443, 468, and 491 include, but are not limited to, those having the following combinations of substitutions: A159F, T411V, A443I, H468R, Q491K; A159F, T411V, A443I, H468R, Q491R; A159F, T411V, A443I, H468R, Q491E; A159F, T411V, A443I, H468A, Q491K; A159F, T411V, A443I, H468A, Q491R; A159F, T411V, A443I, H468A, Q491E ...R, Q491K; A159F, T411V, A443I, H468R, Q491K; A159 1V, A443I, H468K, Q491K; A159F, T411V, A443I, H468K, Q491R; A159F, T411 V, A443I, H468K, Q491E; A159F, T411V, A443I, H468G, Q491K; A159F, T411V, A443I, H468G, Q491R; A159F, T411V, A443I, H468G, Q491E; A159F, T411V, A4 43I, H468S, Q491K; A159F, T411V, A443I, H468S, Q491R; A159F, T411V, A443 I, H468S, Q491E; A159F, T411V, A443L, H468R, Q491K; A159F, T411V, A443L , H468R, Q491R; A159F, T411V, A443L, H468R, Q491E; A159F, T411V, A443L, H 468A, Q491K; A159F, T411V, A443L, H468A, Q491R; A159F, T411V, A443L, H46 8A, Q491E; A159F, T411V, A443L, H468K, Q491K; A159F, T411V, A443L, H468K , Q491R; A159F, T411V, A443L, H468K, Q491E; A159F, T411V, A443L, H468G, Q491K; A159F, T411V, A443L, H468G, Q491R; A159F, T411V, A443L, H468G, Q4 91E; A159F, T411V, A443L, H468S, Q491K; A159F, T411V, A443L, H468S, Q491 R; A159F, T411V, A443L, H468S, Q491E; A159F, T411V, A443F, H468R, Q491K;A159F、T411V、A443F、H468R、Q491R;A159F、T411V、A443F、H468R、Q491E;A159F、T411V、A443F、H468A、Q491K;A159F、T411V、A443F、H468A、Q491R;A159F、T411V、A443F、H468A、Q491E;A159F、T411V、A443F、H468K、Q491K;A159F、T411V、A443F、H468K、Q491R;A159F、T411V、A443F、H468K、Q491E;A159F、T411V、A443F、H468G、Q491K;A159F、T411V、A443F、H468G、Q491R;A159F、T411V、A443F、H468G、Q491E;A159F、T411V、A443F、H468S、Q491K;A159F、T411V、A443F、H468S、Q491R;A159F、T411V、A443F、H468S、Q491E;A159F、T411V、A443M、H468R、Q491K;A159F、T411V、A443M、H468R、Q491R;A159F、T411V、A443M、H468R、Q491E;A159F、T411V、A443M、H468A、Q491K;A159F、T411V、A443M、H468A、Q491R;A159F、T411V、A443M、H468A、Q491E;A159F、T411V、A443M、H468K、Q491K;A159F、T411V、A443M、H468K、Q491R;A159F、T411V、A443M、H468K、Q491E;A159F、T411V、A443M、H468G、Q491K;A159F、T411V、A443M、H468G、Q491R;A159F、T411V、A443M、H468G、Q491E;A159F、T411V、A443M、H468S、Q491K;A159F、T411V、A443M、H468S、Q491R;A159F、T411V、A443M、H468S、Q491E;A159F、T411V、A443Y、H468R、Q491K;A159F、T411V、A443Y、H468R、Q491R;A159F、T411V、A443Y、H468R、Q491E;A159F、T411V、A443Y、H468A、Q491K;A159F、T411V、A443Y、H468A、Q491R;A159F、T411V、A443Y、H468A、Q491E;A159F、T411V、A443Y、H468K、Q491K;A159F、T411V、A443Y、H468K、Q491R;A159F、T411V、A443Y、H468K、Q491E;A159F、T411V、A443Y、H468G、Q491K;A159F、T411V、A443Y、H468G、Q491R;A159F、T411V、A443Y、H468G、Q491E;A159F、T411V、A443Y、H468S、Q491K;A159F、T411V、A443Y、H468S、Q491R;A159F、T411V、A443Y、H468S、Q491E;A159F、T411V、A443V、H468R、Q491K;A159F、T411V、A443V、H468R、Q491R;A159F、T411V、A443V、H468R、Q491E;A159F、T411V、A443V、H468A、Q491K;A159F、T411V、A443V、H468A、Q491R;A159F、T411V、A443V、H468A、Q491E;A159F、T411V、A443V、H468K、Q491K;A159F、T411V、A443V、H468K、Q491R;A159F、T411V、A443V、H468K、Q491E;A159F、T411V、A443V、H468G、Q491K;A159F、T411V、A443V、H468G、Q491R;A159F、T411V、A443V、H468G、Q491E;A159F、T411V、A443V、H468S、Q491K;A159F、T411V、A443V、H468S、Q491R;A159F、T411V、A443V、H468S、Q491E;A159F、T411S、A443I、H468R、Q491K;A159F、T411S、A443I、H468R、Q491R;A159F、T411S、A443I、H468R、Q491E;A159F、T411S、A443I、H468A、Q491K;A159F、T411S、A443I、H468A、Q491R;A159F、T411S、A443I、H468A、Q491E;A159F、T411S、A443I、H468K、Q491K;A159F、T411S、A443I、H468K、Q491R;A159F、T411S、A443I、H468K、Q491E;A159F、T411S、A443I、H468G、Q491K;A159F、T411S、A443I、H468G、Q491R;A159F、T411S、A443I、H468G、Q491E;A159F、T411S、A443I、H468S、Q491K;A159F、T411S、A443I、H468S、Q491R;A159F、T411S、A443I、H468S、Q491E;A159F、T411S、A443L、H468R、Q491K;A159F、T411S、A443L、H468R、Q491R;A159F、T411S、A443L、H468R、Q491E;A159F、T411S、A443L、H468A、Q491K;A159F、T411S、A443L、H468A、Q491R;A159F、T411S、A443L、H468A、Q491E;A159F、T411S、A443L、H468K、Q491K;A159F、T411S、A443L、H468K、Q491R;A159F、T411S、A443L、H468K、Q491E;A159F、T411S、A443L、H468G、Q491K;A159F、T411S、A443L、H468G、Q491R;A159F、T411S、A443L、H468G、Q491E;A159F、T411S、A443L、H468S、Q491K;A159F、T411S、A443L、H468S、Q491R;A159F、T411S、A443L、H468S、Q491E;A159F、T411S、A443F、H468R、Q491K;A159F、T411S、A443F、H468R、Q491R;A159F、T411S、A443F、H468R、Q491E;A159F、T411S、A443F、H468A、Q491K;A159F、T411S、A443F、H468A、Q491R;A159F、T411S、A443F、H468A、Q491E;A159F、T411S、A443F、H468K、Q491K;A159F、T411S、A443F、H468K、Q491R;A159F、T411S、A443F、H468K、Q491E;A159F、T411S、A443F、H468G、Q491K;A159F、T411S、A443F、H468G、Q491R;A159F、T411S、A443F、H468G、Q491E;A159F、T411S、A443F、H468S、Q491K;A159F、T411S、A443F、H468S、Q491R;A159F、T411S、A443F、H468S、Q491E;A159F、T411S、A443M、H468R、Q491K;A159F、T411S、A443M、H468R、Q491R;A159F、T411S、A443M、H468R、Q491E;A159F、T411S、A443M、H468A、Q491K;A159F、T411S、A443M、H468A、Q491R;A159F、T411S、A443M、H468A、Q491E;A159F、T411S、A443M、H468K、Q491K;A159F、T411S、A443M、H468K、Q491R;A159F、T411S、A443M、H468K、Q491E;A159F、T411S、A443M、H468G、Q491K;A159F、T411S、A443M、H468G、Q491R;A159F、T411S、A443M、H468G、Q491E;A159F、T411S、A443M、H468S、Q491K;A159F、T411S、A443M、H468S、Q491R;A159F、T411S、A443M、H468S、Q491E;A159F、T411S、A443Y、H468R、Q491K;A159F、T411S、A443Y、H468R、Q491R;A159F、T411S、A443Y、H468R、Q491E;A159F、T411S、A443Y、H468A、Q491K;A159F、T411S、A443Y、H468A、Q491R;A159F、T411S、A443Y、H468A、Q491E;A159F、T411S、A443Y、H468K、Q491K;A159F、T411S、A443Y、H468K、Q491R;A159F、T411S、A443Y、H468K、Q491E;A159F、T411S、A443Y、H468G、Q491K;A159F、T411S、A443Y、H468G、Q491R;A159F、T411S、A443Y、H468G、Q491E;A159F、T411S、A443Y、H468S、Q491K;A159F、T411S、A443Y、H468S、Q491R;A159F、T411S、A443Y、H468S、Q491E;A159F、T411S、A443V、H468R、Q491K;A159F、T411S、A443V、H468R、Q491R;A159F、T411S、A443V、H468R、Q491E;A159F、T411S、A443V、H468A、Q491K;A159F、T411S、A443V、H468A、Q491R;A159F、T411S、A443V、H468A、Q491E;A159F、T411S、A443V、H468K、Q491K;A159F、T411S、A443V、H468K、Q491R;A159F、T411S、A443V、H468K、Q491E;A159F、T411S、A443V、H468G、Q491K;A159F、T411S、A443V、H468G、Q491R;A159F、T411S、A443V、H468G、Q491E;A159F、T411S、A443V、H468S、Q491K;A159F、T411S、A443V、H468S、Q491R;A159F、T411S、A443V、H468S、Q491E;A159F、T411A、A443I、H468R、Q491K;A159F、T411A、A443I、H468R、Q491R;A159F、T411A、A443I、H468R、Q491E;A159F、T411A、A443I、H468A、Q491K;A159F、T411A、A443I、H468A、Q491R;A159F、T411A、A443I、H468A、Q491E;A159F、T411A、A443I、H468K、Q491K;A159F、T411A、A443I、H468K、Q491R;A159F、T411A、A443I、H468K、Q491E;A159F、T411A、A443I、H468G、Q491K;A159F、T411A、A443I、H468G、Q491R;A159F、T411A、A443I、H468G、Q491E;A159F、T411A、A443I、H468S、Q491K;A159F、T411A、A443I、H468S、Q491R;A159F、T411A、A443I、H468S、Q491E;A159F、T411A、A443L、H468R、Q491K;A159F、T411A、A443L、H468R、Q491R;A159F、T411A、A443L、H468R、Q491E;A159F、T411A、A443L、H468A、Q491K;A159F、T411A、A443L、H468A、Q491R;A159F、T411A、A443L、H468A、Q491E;A159F、T411A、A443L、H468K、Q491K;A159F、T411A、A443L、H468K、Q491R;A159F、T411A、A443L、H468K、Q491E;A159F、T411A、A443L、H468G、Q491K;A159F、T411A、A443L、H468G、Q491R;A159F、T411A、A443L、H468G、Q491E;A159F、T411A、A443L、H468S、Q491K;A159F、T411A、A443L、H468S、Q491R;A159F、T411A、A443L、H468S、Q491E;A159F、T411A、A443F、H468R、Q491K;A159F、T411A、A443F、H468R、Q491R;A159F、T411A、A443F、H468R、Q491E;A159F、T411A、A443F、H468A、Q491K;A159F、T411A、A443F、H468A、Q491R;A159F、T411A、A443F、H468A、Q491E;A159F、T411A、A443F、H468K、Q491K;A159F、T411A、A443F、H468K、Q491R;A159F、T411A、A443F、H468K、Q491E;A159F、T411A、A443F、H468G、Q491K;A159F、T411A、A443F、H468G、Q491R;A159F、T411A、A443F、H468G、Q491E;A159F、T411A、A443F、H468S、Q491K;A159F、T411A、A443F、H468S、Q491R;A159F、T411A、A443F、H468S、Q491E;A159F、T411A、A443M、H468R、Q491K;A159F、T411A、A443M、H468R、Q491R;A159F、T411A、A443M、H468R、Q491E;A159F、T411A、A443M、H468A、Q491K;A159F、T411A、A443M、H468A、Q491R;A159F、T411A、A443M、H468A、Q491E;A159F、T411A、A443M、H468K、Q491K;A159F、T411A、A443M、H468K、Q491R;A159F、T411A、A443M、H468K、Q491E;A159F、T411A、A443M、H468G、Q491K;A159F、T411A、A443M、H468G、Q491R;A159F、T411A、A443M、H468G、Q491E;A159F、T411A、A443M、H468S、Q491K;A159F、T411A、A443M、H468S、Q491R;A159F、T411A、A443M、H468S、Q491E;A159F、T411A、A443Y、H468R、Q491K;A159F、T411A、A443Y、H468R、Q491R;A159F、T411A、A443Y、H468R、Q491E;A159F、T411A、A443Y、H468A、Q491K;A159F、T411A、A443Y、H468A、Q491R;A159F、T411A、A443Y、H468A、Q491E;A159F、T411A、A443Y、H468K、Q491K;A159F、T411A、A443Y、H468K、Q491R;A159F、T411A、A443Y、H468K、Q491E;A159F、T411A、A443Y、H468G、Q491K;A159F、T411A、A443Y、H468G、Q491R;A159F、T411A、A443Y、H468G、Q491E;A159F、T411A、A443Y、H468S、Q491K;A159F、T411A、A443Y、H468S、Q491R;A159F、T411A、A443Y、H468S、Q491E;A159F、T411A、A443V、H468R、Q491K;A159F、T411A、A443V、H468R、Q491R;A159F、T411A、A443V、H468R、Q491E;A159F、T411A、A443V、H468A、Q491K;A159F、T411A、A443V、H468A、Q491R;A159F、T411A、A443V、H468A、Q491E;A159F、T411A、A443V、H468K、Q491K;A159F、T411A、A443V、H468K、Q491R;A159F、T411A、A443V、H468K、Q491E;A159F、T411A、A443V、H468G、Q491K;A159F、T411A、A443V、H468G、Q491R;A159F、T411A、A443V、H468G、Q491E;A159F、T411A、A443V、H468S、Q491K;A159F、T411A、A443V、H468S、Q491R;A159F、T411A、A443V、H468S、Q491E;A159F、T411Q、A443I、H468R、Q491K;A159F、T411Q、A443I、H468R、Q491R;A159F、T411Q、A443I、H468R、Q491E;A159F、T411Q、A443I、H468A、Q491K;A159F、T411Q、A443I、H468A、Q491R;A159F、T411Q、A443I、H468A、Q491E;A159F、T411Q、A443I、H468K、Q491K;A159F、T411Q、A443I、H468K、Q491R;A159F、T411Q、A443I、H468K、Q491E;A159F、T411Q、A443I、H468G、Q491K;A159F、T411Q、A443I、H468G、Q491R;A159F、T411Q、A443I、H468G、Q491E;A159F、T411Q、A443I、H468S、Q491K;A159F、T411Q、A443I、H468S、Q491R;A159F、T411Q、A443I、H468S、Q491E;A159F、T411Q、A443L、H468R、Q491K;A159F、T411Q、A443L、H468R、Q491R;A159F、T411Q、A443L、H468R、Q491E;A159F、T411Q、A443L、H468A、Q491K;A159F、T411Q、A443L、H468A、Q491R;A159F、T411Q、A443L、H468A、Q491E;A159F、T411Q、A443L、H468K、Q491K;A159F、T411Q、A443L、H468K、Q491R;A159F、T411Q、A443L、H468K、Q491E;A159F、T411Q、A443L、H468G、Q491K;A159F、T411Q、A443L、H468G、Q491R;A159F、T411Q、A443L、H468G、Q491E;A159F、T411Q、A443L、H468S、Q491K;A159F、T411Q、A443L、H468S、Q491R;A159F、T411Q、A443L、H468S、Q491E;A159F、T411Q、A443F、H468R、Q491K;A159F、T411Q、A443F、H468R、Q491R;A159F、T411Q、A443F、H468R、Q491E;A159F、T411Q、A443F、H468A、Q491K;A159F、T411Q、A443F、H468A、Q491R;A159F、T411Q、A443F、H468A、Q491E;A159F、T411Q、A443F、H468K、Q491K;A159F、T411Q、A443F、H468K、Q491R;A159F、T411Q、A443F、H468K、Q491E;A159F、T411Q、A443F、H468G、Q491K;A159F、T411Q、A443F、H468G、Q491R;A159F、T411Q、A443F、H468G、Q491E;A159F、T411Q、A443F、H468S、Q491K;A159F、T411Q、A443F、H468S、Q491R;A159F、T411Q、A443F、H468S、Q491E;A159F、T411Q、A443M、H468R、Q491K;A159F、T411Q、A443M、H468R、Q491R;A159F、T411Q、A443M、H468R、Q491E;A159F、T411Q、A443M、H468A、Q491K;A159F、T411Q、A443M、H468A、Q491R;A159F、T411Q、A443M、H468A、Q491E;A159F、T411Q、A443M、H468K、Q491K;A159F、T411Q、A443M、H468K、Q491R;A159F、T411Q、A443M、H468K、Q491E;A159F、T411Q、A443M、H468G、Q491K;A159F、T411Q、A443M、H468G、Q491R;A159F、T411Q、A443M、H468G、Q491E;A159F、T411Q、A443M、H468S、Q491K;A159F、T411Q、A443M、H468S、Q491R;A159F、T411Q、A443M、H468S、Q491E;A159F、T411Q、A443Y、H468R、Q491K;A159F、T411Q、A443Y、H468R、Q491R;A159F、T411Q、A443Y、H468R、Q491E;A159F、T411Q、A443Y、H468A、Q491K;A159F、T411Q、A443Y、H468A、Q491R;A159F、T411Q、A443Y、H468A、Q491E;A159F、T411Q、A443Y、H468K、Q491K;A159F、T411Q、A443Y、H468K、Q491R;A159F、T411Q、A443Y、H468K、Q491E;A159F、T411Q、A443Y、H468G、Q491K;A159F、T411Q、A443Y、H468G、Q491R;A159F、T411Q、A443Y、H468G、Q491E;A159F、T411Q、A443Y、H468S、Q491K;A159F、T411Q、A443Y、H468S、Q491R;A159F、T411Q、A443Y、H468S、Q491E;A159F、T411Q、A443V、H468R、Q491K;A159F、T411Q、A443V、H468R、Q491R;A159F、T411Q、A443V、H468R、Q491E;A159F、T411Q、A443V、H468A、Q491K;A159F、T411Q、A443V、H468A、Q491R;A159F、T411Q、A443V、H468A、Q491E;A159F、T411Q、A443V、H468K、Q491K;A159F、T411Q、A443V、H468K、Q491R;A159F、T411Q、A443V、H468K、Q491E;A159F、T411Q、A443V、H468G、Q491K;A159F、T411Q、A443V、H468G、Q491R;A159F、T411Q、A443V、H468G、Q491E;A159F、T411Q、A443V、H468S、Q491K;A159F、T411Q、A443V、H468S、Q491R;A159F、T411Q、A443V、H468S、Q491E;A159F、T411E、A443I、H468R、Q491K;A159F、T411E、A443I、H468R、Q491R;A159F、T411E、A443I、H468R、Q491E;A159F、T411E、A443I、H468A、Q491K;A159F、T411E、A443I、H468A、Q491R;A159F、T411E、A443I、H468A、Q491E;A159F、T411E、A443I、H468K、Q491K;A159F、T411E、A443I、H468K、Q491R;A159F、T411E、A443I、H468K、Q491E;A159F、T411E、A443I、H468G、Q491K;A159F、T411E、A443I、H468G、Q491R;A159F、T411E、A443I、H468G、Q491E;A159F、T411E、A443I、H468S、Q491K;A159F、T411E、A443I、H468S、Q491R;A159F、T411E、A443I、H468S、Q491E;A159F、T411E、A443L、H468R、Q491K;A159F、T411E、A443L、H468R、Q491R;A159F、T411E、A443L、H468R、Q491E;A159F、T411E、A443L、H468A、Q491K;A159F、T411E、A443L、H468A、Q491R;A159F、T411E、A443L、H468A、Q491E;A159F、T411E、A443L、H468K、Q491K;A159F、T411E、A443L、H468K、Q491R;A159F、T411E、A443L、H468K、Q491E;A159F、T411E、A443L、H468G、Q491K;A159F、T411E、A443L、H468G、Q491R;A159F、T411E、A443L、H468G、Q491E;A159F、T411E、A443L、H468S、Q491K;A159F、T411E、A443L、H468S、Q491R;A159F、T411E、A443L、H468S、Q491E;A159F、T411E、A443F、H468R、Q491K;A159F、T411E、A443F、H468R、Q491R;A159F、T411E、A443F、H468R、Q491E;A159F、T411E、A443F、H468A、Q491K;A159F、T411E、A443F、H468A、Q491R;A159F、T411E、A443F、H468A、Q491E;A159F、T411E、A443F、H468K、Q491K;A159F、T411E、A443F、H468K、Q491R;A159F、T411E、A443F、H468K、Q491E;A159F、T411E、A443F、H468G、Q491K;A159F、T411E、A443F、H468G、Q491R;A159F、T411E、A443F、H468G、Q491E;A159F、T411E、A443F、H468S、Q491K;A159F、T411E、A443F、H468S、Q491R;A159F、T411E、A443F、H468S、Q491E;A159F、T411E、A443M、H468R、Q491K;A159F、T411E、A443M、H468R、Q491R;A159F、T411E、A443M、H468R、Q491E;A159F、T411E、A443M、H468A、Q491K;A159F、T411E、A443M、H468A、Q491R;A159F、T411E、A443M、H468A、Q491E;A159F、T411E、A443M、H468K、Q491K;A159F、T411E、A443M、H468K、Q491R;A159F、T411E、A443M、H468K、Q491E;A159F、T411E、A443M、H468G、Q491K;A159F、T411E、A443M、H468G、Q491R;A159F、T411E、A443M、H468G、Q491E;A159F、T411E、A443M、H468S、Q491K;A159F、T411E、A443M、H468S、Q491R;A159F、T411E、A443M、H468S、Q491E;A159F、T411E、A443Y、H468R、Q491K;A159F、T411E、A443Y、H468R、Q491R;A159F、T411E、A443Y、H468R、Q491E;A159F、T411E、A443Y、H468A、Q491K;A159F、T411E、A443Y、H468A、Q491R;A159F、T411E、A443Y、H468A、Q491E;A159F、T411E、A443Y、H468K、Q491K;A159F、T411E、A443Y、H468K、Q491R;A159F、T411E、A443Y、H468K、Q491E;A159F、T411E、A443Y、H468G、Q491K;A159F、T411E、A443Y、H468G、Q491R;A159F、T411E、A443Y、H468G、Q491E;A159F、T411E、A443Y、H468S、Q491K;A159F、T411E、A443Y、H468S、Q491R;A159F、T411E、A443Y、H468S、Q491E;A159F、T411E、A443V、H468R、Q491K;A159F、T411E、A443V、H468R、Q491R;A159F、T411E、A443V、H468R、Q491E;A159F、T411E、A443V、H468A、Q491K;A159F、T411E、A443V、H468A、Q491R;A159F、T411E、A443V、H468A、Q491E;A159F、T411E、A443V、H468K、Q491K;A159F、T411E、A443V、H468K、Q491R;A159F、T411E、A443V、H468K、Q491E;A159F、T411E、A443V、H468G、Q491K;A159F、T411E、A443V、H468G、Q491R;A159F、T411E、A443V、H468G、Q491E;A159F、T411E、A443V、H468S、Q491K;A159F、T411E、A443V、H468S、Q491R;A159F、T411E、A443V、H468S、Q491E;A159F、T411K、A443I、H468R、Q491K;A159F、T411K、A443I、H468R、Q491R;A159F、T411K、A443I、H468R、Q491E;A159F、T411K、A443I、H468A、Q491K;A159F、T411K、A443I、H468A、Q491R;A159F、T411K、A443I、H468A、Q491E;A159F、T411K、A443I、H468K、Q491K;A159F、T411K、A443I、H468K、Q491R;A159F、T411K、A443I、H468K、Q491E;A159F、T411K、A443I、H468G、Q491K;A159F、T411K、A443I、H468G、Q491R;A159F、T411K、A443I、H468G、Q491E;A159F、T411K、A443I、H468S、Q491K;A159F、T411K、A443I、H468S、Q491R;A159F、T411K、A443I、H468S、Q491E;A159F、T411K、A443L、H468R、Q491K;A159F、T411K、A443L、H468R、Q491R;A159F、T411K、A443L、H468R、Q491E;A159F、T411K、A443L、H468A、Q491K;A159F、T411K、A443L、H468A、Q491R;A159F、T411K、A443L、H468A、Q491E;A159F、T411K、A443L、H468K、Q491K;A159F、T411K、A443L、H468K、Q491R;A159F、T411K、A443L、H468K、Q491E;A159F、T411K、A443L、H468G、Q491K;A159F、T411K、A443L、H468G、Q491R;A159F、T411K、A443L、H468G、Q491E;A159F、T411K、A443L、H468S、Q491K;A159F、T411K、A443L、H468S、Q491R;A159F、T411K、A443L、H468S、Q491E;A159F、T411K、A443F、H468R、Q491K;A159F、T411K、A443F、H468R、Q491R;A159F、T411K、A443F、H468R、Q491E;A159F、T411K、A443F、H468A、Q491K;A159F、T411K、A443F、H468A、Q491R;A159F、T411K、A443F、H468A、Q491E;A159F、T411K、A443F、H468K、Q491K;A159F、T411K、A443F、H468K、Q491R;A159F、T411K、A443F、H468K、Q491E;A159F、T411K、A443F、H468G、Q491K;A159F、T411K、A443F、H468G、Q491R;A159F、T411K、A443F、H468G、Q491E;A159F、T411K、A443F、H468S、Q491K;A159F、T411K、A443F、H468S、Q491R;A159F、T411K、A443F、H468S、Q491E;A159F、T411K、A443M、H468R、Q491K;A159F、T411K、A443M、H468R、Q491R;A159F、T411K、A443M、H468R、Q491E;A159F、T411K、A443M、H468A、Q491K;A159F、T411K、A443M、H468A、Q491R;A159F、T411K、A443M、H468A、Q491E;A159F、T411K、A443M、H468K、Q491K;A159F、T411K、A443M、H468K、Q491R;A159F、T411K、A443M、H468K、Q491E;A159F、T411K、A443M、H468G、Q491K;A159F、T411K、A443M、H468G、Q491R;A159F、T411K、A443M、H468G、Q491E;A159F、T411K、A443M、H468S、Q491K;A159F、T411K、A443M、H468S、Q491R;A159F、T411K、A443M、H468S、Q491E;A159F、T411K、A443Y、H468R、Q491K;A159F、T411K、A443Y、H468R、Q491R;A159F、T411K、A443Y、H468R、Q491E;A159F、T411K、A443Y、H468A、Q491K;A159F、T411K、A443Y、H468A、Q491R;A159F、T411K、A443Y、H468A、Q491E;A159F、T411K、A443Y、H468K、Q491K;A159F、T411K、A443Y、H468K、Q491R;A159F、T411K、A443Y、H468K、Q491E;A159F、T411K、A443Y、H468G、Q491K;A159F、T411K、A443Y、H468G、Q491R;A159F、T411K、A443Y、H468G、Q491E;A159F、T411K、A443Y、H468S、Q491K;A159F、T411K、A443Y、H468S、Q491R;A159F、T411K、A443Y、H468S、Q491E;A159F、T411K、A443V、H468R、Q491K;A159F、T411K、A443V、H468R、Q491R;A159F、T411K、A443V、H468R、Q491E;A159F、T411K、A443V、H468A、Q491K;A159F、T411K、A443V、H468A、Q491R;A159F、T411K、A443V、H468A、Q491E;A159F、T411K、A443V、H468K、Q491K;A159F、T411K、A443V、H468K、Q491R;A159F、T411K、A443V、H468K、Q491E;A159F、T411K、A443V、H468G、Q491K;A159F、T411K、A443V、H468G、Q491R;A159F、T411K、A443V、H468G、Q491E;A159F、T411K、A443V、H468S、Q491K;A159F、T411K、A443V、H468S、Q491R;A159F、T411K、A443V、H468S、Q491E;A159L、T411V、A443I、H468R、Q491K;A159L、T411V、A443I、H468R、Q491R;A159L、T411V、A443I、H468R、Q491E;A159L、T411V、A443I、H468A、Q491K;A159L、T411V、A443I、H468A、Q491R;A159L、T411V、A443I、H468A、Q491E;A159L、T411V、A443I、H468K、Q491K;A159L、T411V、A443I、H468K、Q491R;A159L、T411V、A443I、H468K、Q491E;A159L、T411V、A443I、H468G、Q491K;A159L、T411V、A443I、H468G、Q491R;A159L、T411V、A443I、H468G、Q491E;A159L、T411V、A443I、H468S、Q491K;A159L、T411V、A443I、H468S、Q491R;A159L、T411V、A443I、H468S、Q491E;A159L、T411V、A443L、H468R、Q491K;A159L、T411V、A443L、H468R、Q491R;A159L、T411V、A443L、H468R、Q491E;A159L、T411V、A443L、H468A、Q491K;A159L、T411V、A443L、H468A、Q491R;A159L、T411V、A443L、H468A、Q491E;A159L、T411V、A443L、H468K、Q491K;A159L、T411V、A443L、H468K、Q491R;A159L、T411V、A443L、H468K、Q491E;A159L、T411V、A443L、H468G、Q491K;A159L、T411V、A443L、H468G、Q491R;A159L、T411V、A443L、H468G、Q491E;A159L、T411V、A443L、H468S、Q491K;A159L、T411V、A443L、H468S、Q491R;A159L、T411V、A443L、H468S、Q491E;A159L、T411V、A443F、H468R、Q491K;A159L、T411V、A443F、H468R、Q491R;A159L、T411V、A443F、H468R、Q491E;A159L、T411V、A443F、H468A、Q491K;A159L、T411V、A443F、H468A、Q491R;A159L、T411V、A443F、H468A、Q491E;A159L、T411V、A443F、H468K、Q491K;A159L、T411V、A443F、H468K、Q491R;A159L、T411V、A443F、H468K、Q491E;A159L、T411V、A443F、H468G、Q491K;A159L、T411V、A443F、H468G、Q491R;A159L、T411V、A443F、H468G、Q491E;A159L、T411V、A443F、H468S、Q491K;A159L、T411V、A443F、H468S、Q491R;A159L、T411V、A443F、H468S、Q491E;A159L、T411V、A443M、H468R、Q491K;A159L、T411V、A443M、H468R、Q491R;A159L、T411V、A443M、H468R、Q491E;A159L、T411V、A443M、H468A、Q491K;A159L、T411V、A443M、H468A、Q491R;A159L、T411V、A443M、H468A、Q491E;A159L、T411V、A443M、H468K、Q491K;A159L、T411V、A443M、H468K、Q491R;A159L、T411V、A443M、H468K、Q491E;A159L、T411V、A443M、H468G、Q491K;A159L、T411V、A443M、H468G、Q491R;A159L、T411V、A443M、H468G、Q491E;A159L、T411V、A443M、H468S、Q491K;A159L、T411V、A443M、H468S、Q491R;A159L、T411V、A443M、H468S、Q491E;A159L、T411V、A443Y、H468R、Q491K;A159L、T411V、A443Y、H468R、Q491R;A159L、T411V、A443Y、H468R、Q491E;A159L、T411V、A443Y、H468A、Q491K;A159L、T411V、A443Y、H468A、Q491R;A159L、T411V、A443Y、H468A、Q491E;A159L、T411V、A443Y、H468K、Q491K;A159L、T411V、A443Y、H468K、Q491R;A159L、T411V、A443Y、H468K、Q491E;A159L、T411V、A443Y、H468G、Q491K;A159L、T411V、A443Y、H468G、Q491R;A159L、T411V、A443Y、H468G、Q491E;A159L、T411V、A443Y、H468S、Q491K;A159L、T411V、A443Y、H468S、Q491R;A159L、T411V、A443Y、H468S、Q491E;A159L、T411V、A443V、H468R、Q491K;A159L、T411V、A443V、H468R、Q491R;A159L、T411V、A443V、H468R、Q491E;A159L、T411V、A443V、H468A、Q491K;A159L、T411V、A443V、H468A、Q491R;A159L、T411V、A443V、H468A、Q491E;A159L、T411V、A443V、H468K、Q491K;A159L、T411V、A443V、H468K、Q491R;A159L、T411V、A443V、H468K、Q491E;A159L、T411V、A443V、H468G、Q491K;A159L、T411V、A443V、H468G、Q491R;A159L、T411V、A443V、H468G、Q491E;A159L、T411V、A443V、H468S、Q491K;A159L、T411V、A443V、H468S、Q491R;A159L、T411V、A443V、H468S、Q491E;A159L、T411S、A443I、H468R、Q491K;A159L、T411S、A443I、H468R、Q491R;A159L、T411S、A443I、H468R、Q491E;A159L、T411S、A443I、H468A、Q491K;A159L、T411S、A443I、H468A、Q491R;A159L、T411S、A443I、H468A、Q491E;A159L、T411S、A443I、H468K、Q491K;A159L、T411S、A443I、H468K、Q491R;A159L、T411S、A443I、H468K、Q491E;A159L、T411S、A443I、H468G、Q491K;A159L、T411S、A443I、H468G、Q491R;A159L、T411S、A443I、H468G、Q491E;A159L、T411S、A443I、H468S、Q491K;A159L、T411S、A443I、H468S、Q491R;A159L、T411S、A443I、H468S、Q491E;A159L、T411S、A443L、H468R、Q491K;A159L、T411S、A443L、H468R、Q491R;A159L、T411S、A443L、H468R、Q491E;A159L、T411S、A443L、H468A、Q491K;A159L、T411S、A443L、H468A、Q491R;A159L、T411S、A443L、H468A、Q491E;A159L、T411S、A443L、H468K、Q491K;A159L、T411S、A443L、H468K、Q491R;A159L、T411S、A443L、H468K、Q491E;A159L、T411S、A443L、H468G、Q491K;A159L、T411S、A443L、H468G、Q491R;A159L、T411S、A443L、H468G、Q491E;A159L、T411S、A443L、H468S、Q491K;A159L、T411S、A443L、H468S、Q491R;A159L、T411S、A443L、H468S、Q491E;A159L、T411S、A443F、H468R、Q491K;A159L、T411S、A443F、H468R、Q491R;A159L、T411S、A443F、H468R、Q491E;A159L、T411S、A443F、H468A、Q491K;A159L、T411S、A443F、H468A、Q491R;A159L、T411S、A443F、H468A、Q491E;A159L、T411S、A443F、H468K、Q491K;A159L、T411S、A443F、H468K、Q491R;A159L、T411S、A443F、H468K、Q491E;A159L、T411S、A443F、H468G、Q491K;A159L、T411S、A443F、H468G、Q491R;A159L、T411S、A443F、H468G、Q491E;A159L、T411S、A443F、H468S、Q491K;A159L、T411S、A443F、H468S、Q491R;A159L、T411S、A443F、H468S、Q491E;A159L、T411S、A443M、H468R、Q491K;A159L、T411S、A443M、H468R、Q491R;A159L、T411S、A443M、H468R、Q491E;A159L、T411S、A443M、H468A、Q491K;A159L、T411S、A443M、H468A、Q491R;A159L、T411S、A443M、H468A、Q491E;A159L、T411S、A443M、H468K、Q491K;A159L、T411S、A443M、H468K、Q491R;A159L、T411S、A443M、H468K、Q491E;A159L、T411S、A443M、H468G、Q491K;A159L、T411S、A443M、H468G、Q491R;A159L、T411S、A443M、H468G、Q491E;A159L、T411S、A443M、H468S、Q491K;A159L、T411S、A443M、H468S、Q491R;A159L、T411S、A443M、H468S、Q491E;A159L、T411S、A443Y、H468R、Q491K;A159L、T411S、A443Y、H468R、Q491R;A159L、T411S、A443Y、H468R、Q491E;A159L、T411S、A443Y、H468A、Q491K;A159L、T411S、A443Y、H468A、Q491R;A159L、T411S、A443Y、H468A、Q491E;A159L、T411S、A443Y、H468K、Q491K;A159L、T411S、A443Y、H468K、Q491R;A159L、T411S、A443Y、H468K、Q491E;A159L、T411S、A443Y、H468G、Q491K;A159L、T411S、A443Y、H468G、Q491R;A159L、T411S、A443Y、H468G、Q491E;A159L、T411S、A443Y、H468S、Q491K;A159L、T411S、A443Y、H468S、Q491R;A159L、T411S、A443Y、H468S、Q491E;A159L、T411S、A443V、H468R、Q491K;A159L、T411S、A443V、H468R、Q491R;A159L、T411S、A443V、H468R、Q491E;A159L、T411S、A443V、H468A、Q491K;A159L、T411S、A443V、H468A、Q491R;A159L、T411S、A443V、H468A、Q491E;A159L、T411S、A443V、H468K、Q491K;A159L、T411S、A443V、H468K、Q491R;A159L、T411S、A443V、H468K、Q491E;A159L、T411S、A443V、H468G、Q491K;A159L、T411S、A443V、H468G、Q491R;A159L、T411S、A443V、H468G、Q491E;A159L、T411S、A443V、H468S、Q491K;A159L、T411S、A443V、H468S、Q491R;A159L、T411S、A443V、H468S、Q491E;A159L、T411A、A443I、H468R、Q491K;A159L、T411A、A443I、H468R、Q491R;A159L、T411A、A443I、H468R、Q491E;A159L、T411A、A443I、H468A、Q491K;A159L、T411A、A443I、H468A、Q491R;A159L、T411A、A443I、H468A、Q491E;A159L、T411A、A443I、H468K、Q491K;A159L、T411A、A443I、H468K、Q491R;A159L、T411A、A443I、H468K、Q491E;A159L、T411A、A443I、H468G、Q491K;A159L、T411A、A443I、H468G、Q491R;A159L、T411A、A443I、H468G、Q491E;A159L、T411A、A443I、H468S、Q491K;A159L、T411A、A443I、H468S、Q491R;A159L、T411A、A443I、H468S、Q491E;A159L、T411A、A443L、H468R、Q491K;A159L、T411A、A443L、H468R、Q491R;A159L、T411A、A443L、H468R、Q491E;A159L、T411A、A443L、H468A、Q491K;A159L、T411A、A443L、H468A、Q491R;A159L、T411A、A443L、H468A、Q491E;A159L、T411A、A443L、H468K、Q491K;A159L、T411A、A443L、H468K、Q491R;A159L、T411A、A443L、H468K、Q491E;A159L、T411A、A443L、H468G、Q491K;A159L、T411A、A443L、H468G、Q491R;A159L、T411A、A443L、H468G、Q491E;A159L、T411A、A443L、H468S、Q491K;A159L、T411A、A443L、H468S、Q491R;A159L、T411A、A443L、H468S、Q491E;A159L、T411A、A443F、H468R、Q491K;A159L、T411A、A443F、H468R、Q491R;A159L、T411A、A443F、H468R、Q491E;A159L、T411A、A443F、H468A、Q491K;A159L、T411A、A443F、H468A、Q491R;A159L、T411A、A443F、H468A、Q491E;A159L、T411A、A443F、H468K、Q491K;A159L、T411A、A443F、H468K、Q491R;A159L、T411A、A443F、H468K、Q491E;A159L、T411A、A443F、H468G、Q491K;A159L、T411A、A443F、H468G、Q491R;A159L、T411A、A443F、H468G、Q491E;A159L、T411A、A443F、H468S、Q491K;A159L、T411A、A443F、H468S、Q491R;A159L、T411A、A443F、H468S、Q491E;A159L、T411A、A443M、H468R、Q491K;A159L、T411A、A443M、H468R、Q491R;A159L、T411A、A443M、H468R、Q491E;A159L、T411A、A443M、H468A、Q491K;A159L、T411A、A443M、H468A、Q491R;A159L、T411A、A443M、H468A、Q491E;A159L、T411A、A443M、H468K、Q491K;A159L、T411A、A443M、H468K、Q491R;A159L、T411A、A443M、H468K、Q491E;A159L、T411A、A443M、H468G、Q491K;A159L、T411A、A443M、H468G、Q491R;A159L、T411A、A443M、H468G、Q491E;A159L、T411A、A443M、H468S、Q491K;A159L、T411A、A443M、H468S、Q491R;A159L、T411A、A443M、H468S、Q491E;A159L、T411A、A443Y、H468R、Q491K;A159L、T411A、A443Y、H468R、Q491R;A159L、T411A、A443Y、H468R、Q491E;A159L、T411A、A443Y、H468A、Q491K;A159L、T411A、A443Y、H468A、Q491R;A159L、T411A、A443Y、H468A、Q491E;A159L、T411A、A443Y、H468K、Q491K;A159L、T411A、A443Y、H468K、Q491R;A159L、T411A、A443Y、H468K、Q491E;A159L、T411A、A443Y、H468G、Q491K;A159L、T411A、A443Y、H468G、Q491R;A159L、T411A、A443Y、H468G、Q491E;A159L、T411A、A443Y、H468S、Q491K;A159L、T411A、A443Y、H468S、Q491R;A159L、T411A、A443Y、H468S、Q491E;A159L、T411A、A443V、H468R、Q491K;A159L、T411A、A443V、H468R、Q491R;A159L、T411A、A443V、H468R、Q491E;A159L、T411A、A443V、H468A、Q491K;A159L、T411A、A443V、H468A、Q491R;A159L、T411A、A443V、H468A、Q491E;A159L、T411A、A443V、H468K、Q491K;A159L、T411A、A443V、H468K、Q491R;A159L、T411A、A443V、H468K、Q491E;A159L、T411A、A443V、H468G、Q491K;A159L、T411A、A443V、H468G、Q491R;A159L、T411A、A443V、H468G、Q491E;A159L、T411A、A443V、H468S、Q491K;A159L、T411A、A443V、H468S、Q491R;A159L、T411A、A443V、H468S、Q491E;A159L、T411Q、A443I、H468R、Q491K;A159L、T411Q、A443I、H468R、Q491R;A159L、T411Q、A443I、H468R、Q491E;A159L、T411Q、A443I、H468A、Q491K;A159L、T411Q、A443I、H468A、Q491R;A159L、T411Q、A443I、H468A、Q491E;A159L、T411Q、A443I、H468K、Q491K;A159L、T411Q、A443I、H468K、Q491R;A159L、T411Q、A443I、H468K、Q491E;A159L、T411Q、A443I、H468G、Q491K;A159L、T411Q、A443I、H468G、Q491R;A159L、T411Q、A443I、H468G、Q491E;A159L、T411Q、A443I、H468S、Q491K;A159L、T411Q、A443I、H468S、Q491R;A159L、T411Q、A443I、H468S、Q491E;A159L、T411Q、A443L、H468R、Q491K;A159L、T411Q、A443L、H468R、Q491R;A159L、T411Q、A443L、H468R、Q491E;A159L、T411Q、A443L、H468A、Q491K;A159L、T411Q、A443L、H468A、Q491R;A159L、T411Q、A443L、H468A、Q491E;A159L、T411Q、A443L、H468K、Q491K;A159L、T411Q、A443L、H468K、Q491R;A159L、T411Q、A443L、H468K、Q491E;A159L、T411Q、A443L、H468G、Q491K;A159L、T411Q、A443L、H468G、Q491R;A159L、T411Q、A443L、H468G、Q491E;A159L、T411Q、A443L、H468S、Q491K;A159L、T411Q、A443L、H468S、Q491R;A159L、T411Q、A443L、H468S、Q491E;A159L、T411Q、A443F、H468R、Q491K;A159L、T411Q、A443F、H468R、Q491R;A159L、T411Q、A443F、H468R、Q491E;A159L、T411Q、A443F、H468A、Q491K;A159L、T411Q、A443F、H468A、Q491R;A159L、T411Q、A443F、H468A、Q491E;A159L、T411Q、A443F、H468K、Q491K;A159L、T411Q、A443F、H468K、Q491R;A159L、T411Q、A443F、H468K、Q491E;A159L、T411Q、A443F、H468G、Q491K;A159L、T411Q、A443F、H468G、Q491R;A159L、T411Q、A443F、H468G、Q491E;A159L、T411Q、A443F、H468S、Q491K;A159L、T411Q、A443F、H468S、Q491R;A159L、T411Q、A443F、H468S、Q491E;A159L、T411Q、A443M、H468R、Q491K;A159L、T411Q、A443M、H468R、Q491R;A159L、T411Q、A443M、H468R、Q491E;A159L、T411Q、A443M、H468A、Q491K;A159L、T411Q、A443M、H468A、Q491R;A159L、T411Q、A443M、H468A、Q491E;A159L、T411Q、A443M、H468K、Q491K;A159L、T411Q、A443M、H468K、Q491R;A159L、T411Q、A443M、H468K、Q491E;A159L、T411Q、A443M、H468G、Q491K;A159L、T411Q、A443M、H468G、Q491R;A159L、T411Q、A443M、H468G、Q491E;A159L、T411Q、A443M、H468S、Q491K;A159L、T411Q、A443M、H468S、Q491R;A159L、T411Q、A443M、H468S、Q491E;A159L、T411Q、A443Y、H468R、Q491K;A159L、T411Q、A443Y、H468R、Q491R;A159L、T411Q、A443Y、H468R、Q491E;A159L、T411Q、A443Y、H468A、Q491K;A159L、T411Q、A443Y、H468A、Q491R;A159L、T411Q、A443Y、H468A、Q491E;A159L、T411Q、A443Y、H468K、Q491K;A159L、T411Q、A443Y、H468K、Q491R;A159L、T411Q、A443Y、H468K、Q491E;A159L、T411Q、A443Y、H468G、Q491K;A159L、T411Q、A443Y、H468G、Q491R;A159L、T411Q、A443Y、H468G、Q491E;A159L、T411Q、A443Y、H468S、Q491K;A159L、T411Q、A443Y、H468S、Q491R;A159L、T411Q、A443Y、H468S、Q491E;A159L、T411Q、A443V、H468R、Q491K;A159L、T411Q、A443V、H468R、Q491R;A159L、T411Q、A443V、H468R、Q491E;A159L、T411Q、A443V、H468A、Q491K;A159L、T411Q、A443V、H468A、Q491R;A159L、T411Q、A443V、H468A、Q491E;A159L、T411Q、A443V、H468K、Q491K;A159L、T411Q、A443V、H468K、Q491R;A159L、T411Q、A443V、H468K、Q491E;A159L、T411Q、A443V、H468G、Q491K;A159L、T411Q、A443V、H468G、Q491R;A159L、T411Q、A443V、H468G、Q491E;A159L、T411Q、A443V、H468S、Q491K;A159L、T411Q、A443V、H468S、Q491R;A159L、T411Q、A443V、H468S、Q491E;A159L、T411E、A443I、H468R、Q491K;A159L、T411E、A443I、H468R、Q491R;A159L、T411E、A443I、H468R、Q491E;A159L、T411E、A443I、H468A、Q491K;A159L、T411E、A443I、H468A、Q491R;A159L、T411E、A443I、H468A、Q491E;A159L、T411E、A443I、H468K、Q491K;A159L、T411E、A443I、H468K、Q491R;A159L、T411E、A443I、H468K、Q491E;A159L、T411E、A443I、H468G、Q491K;A159L、T411E、A443I、H468G、Q491R;A159L、T411E、A443I、H468G、Q491E;A159L、T411E、A443I、H468S、Q491K;A159L、T411E、A443I、H468S、Q491R;A159L、T411E、A443I、H468S、Q491E;A159L、T411E、A443L、H468R、Q491K;A159L、T411E、A443L、H468R、Q491R;A159L、T411E、A443L、H468R、Q491E;A159L、T411E、A443L、H468A、Q491K;A159L、T411E、A443L、H468A、Q491R;A159L、T411E、A443L、H468A、Q491E;A159L、T411E、A443L、H468K、Q491K;A159L、T411E、A443L、H468K、Q491R;A159L、T411E、A443L、H468K、Q491E;A159L、T411E、A443L、H468G、Q491K;A159L、T411E、A443L、H468G、Q491R;A159L、T411E、A443L、H468G、Q491E;A159L、T411E、A443L、H468S、Q491K;A159L、T411E、A443L、H468S、Q491R;A159L、T411E、A443L、H468S、Q491E;A159L、T411E、A443F、H468R、Q491K;A159L、T411E、A443F、H468R、Q491R;A159L、T411E、A443F、H468R、Q491E;A159L、T411E、A443F、H468A、Q491K;A159L、T411E、A443F、H468A、Q491R;A159L、T411E、A443F、H468A、Q491E;A159L、T411E、A443F、H468K、Q491K;A159L、T411E、A443F、H468K、Q491R;A159L、T411E、A443F、H468K、Q491E;A159L、T411E、A443F、H468G、Q491K;A159L、T411E、A443F、H468G、Q491R;A159L、T411E、A443F、H468G、Q491E;A159L、T411E、A443F、H468S、Q491K;A159L、T411E、A443F、H468S、Q491R;A159L、T411E、A443F、H468S、Q491E;A159L、T411E、A443M、H468R、Q491K;A159L、T411E、A443M、H468R、Q491R;A159L、T411E、A443M、H468R、Q491E;A159L、T411E、A443M、H468A、Q491K;A159L、T411E、A443M、H468A、Q491R;A159L、T411E、A443M、H468A、Q491E;A159L、T411E、A443M、H468K、Q491K;A159L、T411E、A443M、H468K、Q491R;A159L、T411E、A443M、H468K、Q491E;A159L、T411E、A443M、H468G、Q491K;A159L、T411E、A443M、H468G、Q491R;A159L、T411E、A443M、H468G、Q491E;A159L、T411E、A443M、H468S、Q491K;A159L、T411E、A443M、H468S、Q491R;A159L、T411E、A443M、H468S、Q491E;A159L、T411E、A443Y、H468R、Q491K;A159L、T411E、A443Y、H468R、Q491R;A159L、T411E、A443Y、H468R、Q491E;A159L、T411E、A443Y、H468A、Q491K;A159L、T411E、A443Y、H468A、Q491R;A159L、T411E、A443Y、H468A、Q491E;A159L、T411E、A443Y、H468K、Q491K;A159L、T411E、A443Y、H468K、Q491R;A159L、T411E、A443Y、H468K、Q491E;A159L、T411E、A443Y、H468G、Q491K;A159L、T411E、A443Y、H468G、Q491R;A159L、T411E、A443Y、H468G、Q491E;A159L、T411E、A443Y、H468S、Q491K;A159L、T411E、A443Y、H468S、Q491R;A159L、T411E、A443Y、H468S、Q491E;A159L、T411E、A443V、H468R、Q491K;A159L、T411E、A443V、H468R、Q491R;A159L、T411E、A443V、H468R、Q491E;A159L、T411E、A443V、H468A、Q491K;A159L、T411E、A443V、H468A、Q491R;A159L、T411E、A443V、H468A、Q491E;A159L、T411E、A443V、H468K、Q491K;A159L、T411E、A443V、H468K、Q491R;A159L、T411E、A443V、H468K、Q491E;A159L、T411E、A443V、H468G、Q491K;A159L、T411E、A443V、H468G、Q491R;A159L、T411E、A443V、H468G、Q491E;A159L、T411E、A443V、H468S、Q491K;A159L、T411E、A443V、H468S、Q491R;A159L、T411E、A443V、H468S、Q491E;A159L、T411K、A443I、H468R、Q491K;A159L、T411K、A443I、H468R、Q491R;A159L、T411K、A443I、H468R、Q491E;A159L、T411K、A443I、H468A、Q491K;A159L、T411K、A443I、H468A、Q491R;A159L、T411K、A443I、H468A、Q491E;A159L、T411K、A443I、H468K、Q491K;A159L、T411K、A443I、H468K、Q491R;A159L、T411K、A443I、H468K、Q491E;A159L、T411K、A443I、H468G、Q491K;A159L、T411K、A443I、H468G、Q491R;A159L、T411K、A443I、H468G、Q491E;A159L、T411K、A443I、H468S、Q491K;A159L、T411K、A443I、H468S、Q491R;A159L、T411K、A443I、H468S、Q491E;A159L、T411K、A443L、H468R、Q491K;A159L、T411K、A443L、H468R、Q491R;A159L、T411K、A443L、H468R、Q491E;A159L、T411K、A443L、H468A、Q491K;A159L、T411K、A443L、H468A、Q491R;A159L、T411K、A443L、H468A、Q491E;A159L、T411K、A443L、H468K、Q491K;A159L、T411K、A443L、H468K、Q491R;A159L、T411K、A443L、H468K、Q491E;A159L、T411K、A443L、H468G、Q491K;A159L、T411K、A443L、H468G、Q491R;A159L、T411K、A443L、H468G、Q491E;A159L、T411K、A443L、H468S、Q491K;A159L、T411K、A443L、H468S、Q491R;A159L、T411K、A443L、H468S、Q491E;A159L、T411K、A443F、H468R、Q491K;A159L、T411K、A443F、H468R、Q491R;A159L、T411K、A443F、H468R、Q491E;A159L、T411K、A443F、H468A、Q491K;A159L、T411K、A443F、H468A、Q491R;A159L、T411K、A443F、H468A、Q491E;A159L、T411K、A443F、H468K、Q491K;A159L、T411K、A443F、H468K、Q491R;A159L、T411K、A443F、H468K、Q491E;A159L、T411K、A443F、H468G、Q491K;A159L、T411K、A443F、H468G、Q491R;A159L、T411K、A443F、H468G、Q491E;A159L、T411K、A443F、H468S、Q491K;A159L、T411K、A443F、H468S、Q491R;A159L、T411K、A443F、H468S、Q491E;A159L、T411K、A443M、H468R、Q491K;A159L、T411K、A443M、H468R、Q491R;A159L、T411K、A443M、H468R、Q491E;A159L、T411K、A443M、H468A、Q491K;A159L、T411K、A443M、H468A、Q491R;A159L、T411K、A443M、H468A、Q491E;A159L、T411K、A443M、H468K、Q491K;A159L、T411K、A443M、H468K、Q491R;A159L、T411K、A443M、H468K、Q491E;A159L、T411K、A443M、H468G、Q491K;A159L、T411K、A443M、H468G、Q491R;A159L、T411K、A443M、H468G、Q491E;A159L、T411K、A443M、H468S、Q491K;A159L、T411K、A443M、H468S、Q491R;A159L、T411K、A443M、H468S、Q491E;A159L、T411K、A443Y、H468R、Q491K;A159L、T411K、A443Y、H468R、Q491R;A159L、T411K、A443Y、H468R、Q491E;A159L、T411K、A443Y、H468A、Q491K;A159L、T411K、A443Y、H468A、Q491R;A159L、T411K、A443Y、H468A、Q491E;A159L、T411K、A443Y、H468K、Q491K;A159L、T411K、A443Y、H468K、Q491R;A159L、T411K、A443Y、H468K、Q491E;A159L、T411K、A443Y、H468G、Q491K;A159L、T411K、A443Y、H468G、Q491R;A159L、T411K、A443Y、H468G、Q491E;A159L、T411K、A443Y、H468S、Q491K;A159L、T411K、A443Y、H468S、Q491R;A159L、T411K、A443Y、H468S、Q491E;A159L、T411K、A443V、H468R、Q491K;A159L、T411K、A443V、H468R、Q491R;A159L、T411K、A443V、H468R、Q491E;A159L、T411K、A443V、H468A、Q491K;A159L、T411K、A443V、H468A、Q491R;A159L、T411K、A443V、H468A、Q491E;A159L、T411K、A443V、H468K、Q491K;A159L、T411K、A443V、H468K、Q491R;A159L、T411K、A443V、H468K、Q491E;A159L、T411K、A443V、H468G、Q491K;A159L、T411K、A443V、H468G、Q491R;A159L、T411K、A443V、H468G、Q491E;A159L、T411K、A443V、H468S、Q491K;A159L、T411K、A443V、H468S、Q491R;A159L、T411K、A443V、H468S、Q491E;A159K、T411V、A443I、H468R、Q491K;A159K、T411V、A443I、H468R、Q491R;A159K、T411V、A443I、H468R、Q491E;A159K、T411V、A443I、H468A、Q491K;A159K、T411V、A443I、H468A、Q491R;A159K、T411V、A443I、H468A、Q491E;A159K、T411V、A443I、H468K、Q491K;A159K、T411V、A443I、H468K、Q491R;A159K、T411V、A443I、H468K、Q491E;A159K、T411V、A443I、H468G、Q491K;A159K、T411V、A443I、H468G、Q491R;A159K、T411V、A443I、H468G、Q491E;A159K、T411V、A443I、H468S、Q491K;A159K、T411V、A443I、H468S、Q491R;A159K、T411V、A443I、H468S、Q491E;A159K、T411V、A443L、H468R、Q491K;A159K、T411V、A443L、H468R、Q491R;A159K、T411V、A443L、H468R、Q491E;A159K、T411V、A443L、H468A、Q491K;A159K、T411V、A443L、H468A、Q491R;A159K、T411V、A443L、H468A、Q491E;A159K、T411V、A443L、H468K、Q491K;A159K、T411V、A443L、H468K、Q491R;A159K、T411V、A443L、H468K、Q491E;A159K、T411V、A443L、H468G、Q491K;A159K、T411V、A443L、H468G、Q491R;A159K、T411V、A443L、H468G、Q491E;A159K、T411V、A443L、H468S、Q491K;A159K、T411V、A443L、H468S、Q491R;A159K、T411V、A443L、H468S、Q491E;A159K、T411V、A443F、H468R、Q491K;A159K、T411V、A443F、H468R、Q491R;A159K、T411V、A443F、H468R、Q491E;A159K、T411V、A443F、H468A、Q491K;A159K、T411V、A443F、H468A、Q491R;A159K、T411V、A443F、H468A、Q491E;A159K、T411V、A443F、H468K、Q491K;A159K、T411V、A443F、H468K、Q491R;A159K、T411V、A443F、H468K、Q491E;A159K、T411V、A443F、H468G、Q491K;A159K、T411V、A443F、H468G、Q491R;A159K、T411V、A443F、H468G、Q491E;A159K、T411V、A443F、H468S、Q491K;A159K、T411V、A443F、H468S、Q491R;A159K、T411V、A443F、H468S、Q491E;A159K、T411V、A443M、H468R、Q491K;A159K、T411V、A443M、H468R、Q491R;A159K、T411V、A443M、H468R、Q491E;A159K、T411V、A443M、H468A、Q491K;A159K、T411V、A443M、H468A、Q491R;A159K、T411V、A443M、H468A、Q491E;A159K、T411V、A443M、H468K、Q491K;A159K、T411V、A443M、H468K、Q491R;A159K、T411V、A443M、H468K、Q491E;A159K、T411V、A443M、H468G、Q491K;A159K、T411V、A443M、H468G、Q491R;A159K、T411V、A443M、H468G、Q491E;A159K、T411V、A443M、H468S、Q491K;A159K、T411V、A443M、H468S、Q491R;A159K、T411V、A443M、H468S、Q491E;A159K、T411V、A443Y、H468R、Q491K;A159K、T411V、A443Y、H468R、Q491R;A159K、T411V、A443Y、H468R、Q491E;A159K、T411V、A443Y、H468A、Q491K;A159K、T411V、A443Y、H468A、Q491R;A159K、T411V、A443Y、H468A、Q491E;A159K、T411V、A443Y、H468K、Q491K;A159K、T411V、A443Y、H468K、Q491R;A159K、T411V、A443Y、H468K、Q491E;A159K、T411V、A443Y、H468G、Q491K;A159K、T411V、A443Y、H468G、Q491R;A159K、T411V、A443Y、H468G、Q491E;A159K、T411V、A443Y、H468S、Q491K;A159K、T411V、A443Y、H468S、Q491R;A159K、T411V、A443Y、H468S、Q491E;A159K、T411V、A443V、H468R、Q491K;A159K、T411V、A443V、H468R、Q491R;A159K、T411V、A443V、H468R、Q491E;A159K、T411V、A443V、H468A、Q491K;A159K、T411V、A443V、H468A、Q491R;A159K、T411V、A443V、H468A、Q491E;A159K、T411V、A443V、H468K、Q491K;A159K、T411V、A443V、H468K、Q491R;A159K、T411V、A443V、H468K、Q491E;A159K、T411V、A443V、H468G、Q491K;A159K、T411V、A443V、H468G、Q491R;A159K、T411V、A443V、H468G、Q491E;A159K、T411V、A443V、H468S、Q491K;A159K、T411V、A443V、H468S、Q491R;A159K、T411V、A443V、H468S、Q491E;A159K、T411S、A443I、H468R、Q491K;A159K、T411S、A443I、H468R、Q491R;A159K、T411S、A443I、H468R、Q491E;A159K、T411S、A443I、H468A、Q491K;A159K、T411S、A443I、H468A、Q491R;A159K、T411S、A443I、H468A、Q491E;A159K、T411S、A443I、H468K、Q491K;A159K、T411S、A443I、H468K、Q491R;A159K、T411S、A443I、H468K、Q491E;A159K、T411S、A443I、H468G、Q491K;A159K、T411S、A443I、H468G、Q491R;A159K、T411S、A443I、H468G、Q491E;A159K、T411S、A443I、H468S、Q491K;A159K、T411S、A443I、H468S、Q491R;A159K、T411S、A443I、H468S、Q491E;A159K、T411S、A443L、H468R、Q491K;A159K、T411S、A443L、H468R、Q491R;A159K、T411S、A443L、H468R、Q491E;A159K、T411S、A443L、H468A、Q491K;A159K、T411S、A443L、H468A、Q491R;A159K、T411S、A443L、H468A、Q491E;A159K、T411S、A443L、H468K、Q491K;A159K、T411S、A443L、H468K、Q491R;A159K、T411S、A443L、H468K、Q491E;A159K、T411S、A443L、H468G、Q491K;A159K、T411S、A443L、H468G、Q491R;A159K、T411S、A443L、H468G、Q491E;A159K、T411S、A443L、H468S、Q491K;A159K、T411S、A443L、H468S、Q491R;A159K、T411S、A443L、H468S、Q491E;A159K、T411S、A443F、H468R、Q491K;A159K、T411S、A443F、H468R、Q491R;A159K、T411S、A443F、H468R、Q491E;A159K、T411S、A443F、H468A、Q491K;A159K、T411S、A443F、H468A、Q491R;A159K、T411S、A443F、H468A、Q491E;A159K、T411S、A443F、H468K、Q491K;A159K、T411S、A443F、H468K、Q491R;A159K、T411S、A443F、H468K、Q491E;A159K、T411S、A443F、H468G、Q491K;A159K、T411S、A443F、H468G、Q491R;A159K、T411S、A443F、H468G、Q491E;A159K、T411S、A443F、H468S、Q491K;A159K、T411S、A443F、H468S、Q491R;A159K、T411S、A443F、H468S、Q491E;A159K、T411S、A443M、H468R、Q491K;A159K、T411S、A443M、H468R、Q491R;A159K、T411S、A443M、H468R、Q491E;A159K、T411S、A443M、H468A、Q491K;A159K、T411S、A443M、H468A、Q491R;A159K、T411S、A443M、H468A、Q491E;A159K、T411S、A443M、H468K、Q491K;A159K、T411S、A443M、H468K、Q491R;A159K、T411S、A443M、H468K、Q491E;A159K、T411S、A443M、H468G、Q491K;A159K、T411S、A443M、H468G、Q491R;A159K、T411S、A443M、H468G、Q491E;A159K、T411S、A443M、H468S、Q491K;A159K、T411S、A443M、H468S、Q491R;A159K、T411S、A443M、H468S、Q491E;A159K、T411S、A443Y、H468R、Q491K;A159K、T411S、A443Y、H468R、Q491R;A159K、T411S、A443Y、H468R、Q491E;A159K、T411S、A443Y、H468A、Q491K;A159K、T411S、A443Y、H468A、Q491R;A159K、T411S、A443Y、H468A、Q491E;A159K、T411S、A443Y、H468K、Q491K;A159K、T411S、A443Y、H468K、Q491R;A159K、T411S、A443Y、H468K、Q491E;A159K、T411S、A443Y、H468G、Q491K;A159K、T411S、A443Y、H468G、Q491R;A159K、T411S、A443Y、H468G、Q491E;A159K、T411S、A443Y、H468S、Q491K;A159K、T411S、A443Y、H468S、Q491R;A159K、T411S、A443Y、H468S、Q491E;A159K、T411S、A443V、H468R、Q491K;A159K、T411S、A443V、H468R、Q491R;A159K、T411S、A443V、H468R、Q491E;A159K、T411S、A443V、H468A、Q491K;A159K、T411S、A443V、H468A、Q491R;A159K、T411S、A443V、H468A、Q491E;A159K、T411S、A443V、H468K、Q491K;A159K、T411S、A443V、H468K、Q491R;A159K、T411S、A443V、H468K、Q491E;A159K、T411S、A443V、H468G、Q491K;A159K、T411S、A443V、H468G、Q491R;A159K、T411S、A443V、H468G、Q491E;A159K、T411S、A443V、H468S、Q491K;A159K、T411S、A443V、H468S、Q491R;A159K、T411S、A443V、H468S、Q491E;A159K、T411A、A443I、H468R、Q491K;A159K、T411A、A443I、H468R、Q491R;A159K、T411A、A443I、H468R、Q491E;A159K、T411A、A443I、H468A、Q491K;A159K、T411A、A443I、H468A、Q491R;A159K、T411A、A443I、H468A、Q491E;A159K、T411A、A443I、H468K、Q491K;A159K、T411A、A443I、H468K、Q491R;A159K、T411A、A443I、H468K、Q491E;A159K、T411A、A443I、H468G、Q491K;A159K、T411A、A443I、H468G、Q491R;A159K、T411A、A443I、H468G、Q491E;A159K、T411A、A443I、H468S、Q491K;A159K、T411A、A443I、H468S、Q491R;A159K、T411A、A443I、H468S、Q491E;A159K、T411A、A443L、H468R、Q491K;A159K、T411A、A443L、H468R、Q491R;A159K、T411A、A443L、H468R、Q491E;A159K、T411A、A443L、H468A、Q491K;A159K、T411A、A443L、H468A、Q491R;A159K、T411A、A443L、H468A、Q491E;A159K、T411A、A443L、H468K、Q491K;A159K、T411A、A443L、H468K、Q491R;A159K、T411A、A443L、H468K、Q491E;A159K、T411A、A443L、H468G、Q491K;A159K、T411A、A443L、H468G、Q491R;A159K、T411A、A443L、H468G、Q491E;A159K、T411A、A443L、H468S、Q491K;A159K、T411A、A443L、H468S、Q491R;A159K、T411A、A443L、H468S、Q491E;A159K、T411A、A443F、H468R、Q491K;A159K、T411A、A443F、H468R、Q491R;A159K、T411A、A443F、H468R、Q491E;A159K、T411A、A443F、H468A、Q491K;A159K、T411A、A443F、H468A、Q491R;A159K、T411A、A443F、H468A、Q491E;A159K、T411A、A443F、H468K、Q491K;A159K、T411A、A443F、H468K、Q491R;A159K、T411A、A443F、H468K、Q491E;A159K、T411A、A443F、H468G、Q491K;A159K、T411A、A443F、H468G、Q491R;A159K、T411A、A443F、H468G、Q491E;A159K、T411A、A443F、H468S、Q491K;A159K、T411A、A443F、H468S、Q491R;A159K、T411A、A443F、H468S、Q491E;A159K、T411A、A443M、H468R、Q491K;A159K、T411A、A443M、H468R、Q491R;A159K、T411A、A443M、H468R、Q491E;A159K、T411A、A443M、H468A、Q491K;A159K、T411A、A443M、H468A、Q491R;A159K、T411A、A443M、H468A、Q491E;A159K、T411A、A443M、H468K、Q491K;A159K、T411A、A443M、H468K、Q491R;A159K、T411A、A443M、H468K、Q491E;A159K、T411A、A443M、H468G、Q491K;A159K、T411A、A443M、H468G、Q491R;A159K、T411A、A443M、H468G、Q491E;A159K、T411A、A443M、H468S、Q491K;A159K、T411A、A443M、H468S、Q491R;A159K、T411A、A443M、H468S、Q491E;A159K、T411A、A443Y、H468R、Q491K;A159K、T411A、A443Y、H468R、Q491R;A159K、T411A、A443Y、H468R、Q491E;A159K、T411A、A443Y、H468A、Q491K;A159K、T411A、A443Y、H468A、Q491R;A159K、T411A、A443Y、H468A、Q491E;A159K、T411A、A443Y、H468K、Q491K;A159K、T411A、A443Y、H468K、Q491R;A159K、T411A、A443Y、H468K、Q491E;A159K、T411A、A443Y、H468G、Q491K;A159K、T411A、A443Y、H468G、Q491R;A159K、T411A、A443Y、H468G、Q491E;A159K、T411A、A443Y、H468S、Q491K;A159K、T411A、A443Y、H468S、Q491R;A159K、T411A、A443Y、H468S、Q491E;A159K、T411A、A443V、H468R、Q491K;A159K、T411A、A443V、H468R、Q491R;A159K、T411A、A443V、H468R、Q491E;A159K、T411A、A443V、H468A、Q491K;A159K、T411A、A443V、H468A、Q491R;A159K、T411A、A443V、H468A、Q491E;A159K、T411A、A443V、H468K、Q491K;A159K、T411A、A443V、H468K、Q491R;A159K、T411A、A443V、H468K、Q491E;A159K、T411A、A443V、H468G、Q491K;A159K、T411A、A443V、H468G、Q491R;A159K、T411A、A443V、H468G、Q491E;A159K、T411A、A443V、H468S、Q491K;A159K、T411A、A443V、H468S、Q491R;A159K、T411A、A443V、H468S、Q491E;A159K、T411Q、A443I、H468R、Q491K;A159K、T411Q、A443I、H468R、Q491R;A159K、T411Q、A443I、H468R、Q491E;A159K、T411Q、A443I、H468A、Q491K;A159K、T411Q、A443I、H468A、Q491R;A159K、T411Q、A443I、H468A、Q491E;A159K、T411Q、A443I、H468K、Q491K;A159K、T411Q、A443I、H468K、Q491R;A159K、T411Q、A443I、H468K、Q491E;A159K、T411Q、A443I、H468G、Q491K;A159K、T411Q、A443I、H468G、Q491R;A159K、T411Q、A443I、H468G、Q491E;A159K、T411Q、A443I、H468S、Q491K;A159K、T411Q、A443I、H468S、Q491R;A159K、T411Q、A443I、H468S、Q491E;A159K、T411Q、A443L、H468R、Q491K;A159K、T411Q、A443L、H468R、Q491R;A159K、T411Q、A443L、H468R、Q491E;A159K、T411Q、A443L、H468A、Q491K;A159K、T411Q、A443L、H468A、Q491R;A159K、T411Q、A443L、H468A、Q491E;A159K、T411Q、A443L、H468K、Q491K;A159K、T411Q、A443L、H468K、Q491R;A159K、T411Q、A443L、H468K、Q491E;A159K、T411Q、A443L、H468G、Q491K;A159K、T411Q、A443L、H468G、Q491R;A159K、T411Q、A443L、H468G、Q491E;A159K、T411Q、A443L、H468S、Q491K;A159K、T411Q、A443L、H468S、Q491R;A159K、T411Q、A443L、H468S、Q491E;A159K、T411Q、A443F、H468R、Q491K;A159K、T411Q、A443F、H468R、Q491R;A159K、T411Q、A443F、H468R、Q491E;A159K、T411Q、A443F、H468A、Q491K;A159K、T411Q、A443F、H468A、Q491R;A159K、T411Q、A443F、H468A、Q491E;A159K、T411Q、A443F、H468K、Q491K;A159K、T411Q、A443F、H468K、Q491R;A159K、T411Q、A443F、H468K、Q491E;A159K、T411Q、A443F、H468G、Q491K;A159K、T411Q、A443F、H468G、Q491R;A159K、T411Q、A443F、H468G、Q491E;A159K、T411Q、A443F、H468S、Q491K;A159K、T411Q、A443F、H468S、Q491R;A159K、T411Q、A443F、H468S、Q491E;A159K、T411Q、A443M、H468R、Q491K;A159K、T411Q、A443M、H468R、Q491R;A159K、T411Q、A443M、H468R、Q491E;A159K、T411Q、A443M、H468A、Q491K;A159K、T411Q、A443M、H468A、Q491R;A159K、T411Q、A443M、H468A、Q491E;A159K、T411Q、A443M、H468K、Q491K;A159K、T411Q、A443M、H468K、Q491R;A159K、T411Q、A443M、H468K、Q491E;A159K、T411Q、A443M、H468G、Q491K;A159K、T411Q、A443M、H468G、Q491R;A159K、T411Q、A443M、H468G、Q491E;A159K、T411Q、A443M、H468S、Q491K;A159K、T411Q、A443M、H468S、Q491R;A159K、T411Q、A443M、H468S、Q491E;A159K、T411Q、A443Y、H468R、Q491K;A159K、T411Q、A443Y、H468R、Q491R;A159K、T411Q、A443Y、H468R、Q491E;A159K、T411Q、A443Y、H468A、Q491K;A159K、T411Q、A443Y、H468A、Q491R;A159K、T411Q、A443Y、H468A、Q491E;A159K、T411Q、A443Y、H468K、Q491K;A159K、T411Q、A443Y、H468K、Q491R;A159K、T411Q、A443Y、H468K、Q491E;A159K、T411Q、A443Y、H468G、Q491K;A159K、T411Q、A443Y、H468G、Q491R;A159K、T411Q、A443Y、H468G、Q491E;A159K、T411Q、A443Y、H468S、Q491K;A159K、T411Q、A443Y、H468S、Q491R;A159K、T411Q、A443Y、H468S、Q491E;A159K、T411Q、A443V、H468R、Q491K;A159K、T411Q、A443V、H468R、Q491R;A159K、T411Q、A443V、H468R、Q491E;A159K、T411Q、A443V、H468A、Q491K;A159K、T411Q、A443V、H468A、Q491R;A159K、T411Q、A443V、H468A、Q491E;A159K、T411Q、A443V、H468K、Q491K;A159K、T411Q、A443V、H468K、Q491R;A159K、T411Q、A443V、H468K、Q491E;A159K、T411Q、A443V、H468G、Q491K;A159K、T411Q、A443V、H468G、Q491R;A159K、T411Q、A443V、H468G、Q491E;A159K、T411Q、A443V、H468S、Q491K;A159K、T411Q、A443V、H468S、Q491R;A159K、T411Q、A443V、H468S、Q491E;A159K、T411E、A443I、H468R、Q491K;A159K、T411E、A443I、H468R、Q491R;A159K、T411E、A443I、H468R、Q491E;A159K、T411E、A443I、H468A、Q491K;A159K、T411E、A443I、H468A、Q491R;A159K、T411E、A443I、H468A、Q491E;A159K、T411E、A443I、H468K、Q491K;A159K、T411E、A443I、H468K、Q491R;A159K、T411E、A443I、H468K、Q491E;A159K、T411E、A443I、H468G、Q491K;A159K、T411E、A443I、H468G、Q491R;A159K、T411E、A443I、H468G、Q491E;A159K、T411E、A443I、H468S、Q491K;A159K、T411E、A443I、H468S、Q491R;A159K、T411E、A443I、H468S、Q491E;A159K、T411E、A443L、H468R、Q491K;A159K、T411E、A443L、H468R、Q491R;A159K、T411E、A443L、H468R、Q491E;A159K、T411E、A443L、H468A、Q491K;A159K、T411E、A443L、H468A、Q491R;A159K、T411E、A443L、H468A、Q491E;A159K、T411E、A443L、H468K、Q491K;A159K、T411E、A443L、H468K、Q491R;A159K、T411E、A443L、H468K、Q491E;A159K、T411E、A443L、H468G、Q491K;A159K、T411E、A443L、H468G、Q491R;A159K、T411E、A443L、H468G、Q491E;A159K、T411E、A443L、H468S、Q491K;A159K、T411E、A443L、H468S、Q491R;A159K、T411E、A443L、H468S、Q491E;A159K、T411E、A443F、H468R、Q491K;A159K、T411E、A443F、H468R、Q491R;A159K、T411E、A443F、H468R、Q491E;A159K、T411E、A443F、H468A、Q491K;A159K、T411E、A443F、H468A、Q491R;A159K、T411E、A443F、H468A、Q491E;A159K、T411E、A443F、H468K、Q491K;A159K、T411E、A443F、H468K、Q491R;A159K、T411E、A443F、H468K、Q491E;A159K、T411E、A443F、H468G、Q491K;A159K、T411E、A443F、H468G、Q491R;A159K、T411E、A443F、H468G、Q491E;A159K、T411E、A443F、H468S、Q491K;A159K、T411E、A443F、H468S、Q491R;A159K、T411E、A443F、H468S、Q491E;A159K、T411E、A443M、H468R、Q491K;A159K、T411E、A443M、H468R、Q491R;A159K、T411E、A443M、H468R、Q491E;A159K、T411E、A443M、H468A、Q491K;A159K、T411E、A443M、H468A、Q491R;A159K、T411E、A443M、H468A、Q491E;A159K、T411E、A443M、H468K、Q491K;A159K、T411E、A443M、H468K、Q491R;A159K、T411E、A443M、H468K、Q491E;A159K、T411E、A443M、H468G、Q491K;A159K、T411E、A443M、H468G、Q491R;A159K、T411E、A443M、H468G、Q491E;A159K、T411E、A443M、H468S、Q491K;A159K、T411E、A443M、H468S、Q491R;A159K、T411E、A443M、H468S、Q491E;A159K、T411E、A443Y、H468R、Q491K;A159K、T411E、A443Y、H468R、Q491R;A159K、T411E、A443Y、H468R、Q491E;A159K、T411E、A443Y、H468A、Q491K;A159K、T411E、A443Y、H468A、Q491R;A159K、T411E、A443Y、H468A、Q491E;A159K、T411E、A443Y、H468K、Q491K;A159K、T411E、A443Y、H468K、Q491R;A159K、T411E、A443Y、H468K、Q491E;A159K、T411E、A443Y、H468G、Q491K;A159K、T411E、A443Y、H468G、Q491R;A159K、T411E、A443Y、H468G、Q491E;A159K、T411E、A443Y、H468S、Q491K;A159K、T411E、A443Y、H468S、Q491R;A159K、T411E、A443Y、H468S、Q491E;A159K、T411E、A443V、H468R、Q491K;A159K、T411E、A443V、H468R、Q491R;A159K、T411E、A443V、H468R、Q491E;A159K、T411E、A443V、H468A、Q491K;A159K、T411E、A443V、H468A、Q491R;A159K、T411E、A443V、H468A、Q491E;A159K、T411E、A443V、H468K、Q491K;A159K、T411E、A443V、H468K、Q491R;A159K、T411E、A443V、H468K、Q491E;A159K、T411E、A443V、H468G、Q491K;A159K、T411E、A443V、H468G、Q491R;A159K、T411E、A443V、H468G、Q491E;A159K、T411E、A443V、H468S、Q491K;A159K、T411E、A443V、H468S、Q491R;A159K、T411E、A443V、H468S、Q491E;A159K、T411K、A443I、H468R、Q491K;A159K、T411K、A443I、H468R、Q491R;A159K、T411K、A443I、H468R、Q491E;A159K、T411K、A443I、H468A、Q491K;A159K、T411K、A443I、H468A、Q491R;A159K、T411K、A443I、H468A、Q491E;A159K、T411K、A443I、H468K、Q491K;A159K、T411K、A443I、H468K、Q491R;A159K、T411K、A443I、H468K、Q491E;A159K、T411K、A443I、H468G、Q491K;A159K、T411K、A443I、H468G、Q491R;A159K、T411K、A443I、H468G、Q491E;A159K、T411K、A443I、H468S、Q491K;A159K、T411K、A443I、H468S、Q491R;A159K、T411K、A443I、H468S、Q491E;A159K、T411K、A443L、H468R、Q491K;A159K、T411K、A443L、H468R、Q491R;A159K、T411K、A443L、H468R、Q491E;A159K、T411K、A443L、H468A、Q491K;A159K、T411K、A443L、H468A、Q491R;A159K、T411K、A443L、H468A、Q491E;A159K、T411K、A443L、H468K、Q491K;A159K、T411K、A443L、H468K、Q491R;A159K、T411K、A443L、H468K、Q491E;A159K、T411K、A443L、H468G、Q491K;A159K、T411K、A443L、H468G、Q491R;A159K、T411K、A443L、H468G、Q491E;A159K、T411K、A443L、H468S、Q491K;A159K、T411K、A443L、H468S、Q491R;A159K、T411K、A443L、H468S、Q491E;A159K、T411K、A443F、H468R、Q491K;A159K、T411K、A443F、H468R、Q491R;A159K、T411K、A443F、H468R、Q491E;A159K、T411K、A443F、H468A、Q491K;A159K、T411K、A443F、H468A、Q491R;A159K、T411K、A443F、H468A、Q491E;A159K、T411K、A443F、H468K、Q491K;A159K、T411K、A443F、H468K、Q491R;A159K、T411K、A443F、H468K、Q491E;A159K、T411K、A443F、H468G、Q491K;A159K、T411K、A443F、H468G、Q491R;A159K、T411K、A443F、H468G、Q491E;A159K、T411K、A443F、H468S、Q491K;A159K、T411K、A443F、H468S、Q491R;A159K、T411K、A443F、H468S、Q491E;A159K、T411K、A443M、H468R、Q491K;A159K、T411K、A443M、H468R、Q491R;A159K、T411K、A443M、H468R、Q491E;A159K、T411K、A443M、H468A、Q491K;A159K、T411K、A443M、H468A、Q491R;A159K、T411K、A443M、H468A、Q491E;A159K、T411K、A443M、H468K、Q491K;A159K、T411K、A443M、H468K、Q491R;A159K、T411K、A443M、H468K、Q491E;A159K、T411K、A443M、H468G、Q491K;A159K、T411K、A443M、H468G、Q491R;A159K、T411K、A443M、H468G、Q491E;A159K、T411K、A443M、H468S、Q491K;A159K、T411K、A443M、H468S、Q491R;A159K、T411K、A443M、H468S、Q491E;A159K、T411K、A443Y、H468R、Q491K;A159K、T411K、A443Y、H468R、Q491R;A159K、T411K、A443Y、H468R、Q491E;A159K、T411K、A443Y、H468A、Q491K;A159K、T411K、A443Y、H468A、Q491R;A159K、T411K、A443Y、H468A、Q491E;A159K、T411K、A443Y、H468K、Q491K;A159K、T411K、A443Y、H468K、Q491R;A159K、T411K、A443Y、H468K、Q491E;A159K、T411K、A443Y、H468G、Q491K;A159K、T411K、A443Y、H468G、Q491R;A159K、T411K、A443Y、H468G、Q491E;A159K、T411K、A443Y、H468S、Q491K;A159K、T411K、A443Y、H468S、Q491R;A159K、T411K、A443Y、H468S、Q491E;A159K、T411K、A443V、H468R、Q491K;A159K、T411K、A443V、H468R、Q491R;A159K、T411K、A443V、H468R、Q491E;A159K、T411K、A443V、H468A、Q491K;A159K、T411K、A443V、H468A、Q491R;A159K、T411K、A443V、H468A、Q491E;A159K、T411K、A443V、H468K、Q491K;A159K、T411K、A443V、H468K、Q491R;A159K、T411K、A443V、H468K、Q491E;A159K、T411K、A443V、H468G、Q491K;A159K、T411K、A443V、H468G、Q491R;A159K、T411K、A443V、H468G、Q491E;A159K、T411K、A443V、H468S、Q491K;A159K、T411K、A443V、H468S、Q491R;A159K、T411K、A443V、H468S、Q491E;A159R、T411V、A443I、H468R、Q491K;A159R、T411V、A443I、H468R、Q491R;A159R、T411V、A443I、H468R、Q491E;A159R、T411V、A443I、H468A、Q491K;A159R、T411V、A443I、H468A、Q491R;A159R、T411V、A443I、H468A、Q491E;A159R、T411V、A443I、H468K、Q491K;A159R、T411V、A443I、H468K、Q491R;A159R、T411V、A443I、H468K、Q491E;A159R、T411V、A443I、H468G、Q491K;A159R、T411V、A443I、H468G、Q491R;A159R、T411V、A443I、H468G、Q491E;A159R、T411V、A443I、H468S、Q491K;A159R、T411V、A443I、H468S、Q491R;A159R、T411V、A443I、H468S、Q491E;A159R、T411V、A443L、H468R、Q491K;A159R、T411V、A443L、H468R、Q491R;A159R、T411V、A443L、H468R、Q491E;A159R、T411V、A443L、H468A、Q491K;A159R、T411V、A443L、H468A、Q491R;A159R、T411V、A443L、H468A、Q491E;A159R、T411V、A443L、H468K、Q491K;A159R、T411V、A443L、H468K、Q491R;A159R、T411V、A443L、H468K、Q491E;A159R、T411V、A443L、H468G、Q491K;A159R、T411V、A443L、H468G、Q491R;A159R、T411V、A443L、H468G、Q491E;A159R、T411V、A443L、H468S、Q491K;A159R、T411V、A443L、H468S、Q491R;A159R、T411V、A443L、H468S、Q491E;A159R、T411V、A443F、H468R、Q491K;A159R、T411V、A443F、H468R、Q491R;A159R、T411V、A443F、H468R、Q491E;A159R、T411V、A443F、H468A、Q491K;A159R、T411V、A443F、H468A、Q491R;A159R、T411V、A443F、H468A、Q491E;A159R、T411V、A443F、H468K、Q491K;A159R、T411V、A443F、H468K、Q491R;A159R、T411V、A443F、H468K、Q491E;A159R、T411V、A443F、H468G、Q491K;A159R、T411V、A443F、H468G、Q491R;A159R、T411V、A443F、H468G、Q491E;A159R、T411V、A443F、H468S、Q491K;A159R、T411V、A443F、H468S、Q491R;A159R、T411V、A443F、H468S、Q491E;A159R、T411V、A443M、H468R、Q491K;A159R、T411V、A443M、H468R、Q491R;A159R、T411V、A443M、H468R、Q491E;A159R、T411V、A443M、H468A、Q491K;A159R、T411V、A443M、H468A、Q491R;A159R、T411V、A443M、H468A、Q491E;A159R、T411V、A443M、H468K、Q491K;A159R、T411V、A443M、H468K、Q491R;A159R、T411V、A443M、H468K、Q491E;A159R、T411V、A443M、H468G、Q491K;A159R、T411V、A443M、H468G、Q491R;A159R、T411V、A443M、H468G、Q491E;A159R、T411V、A443M、H468S、Q491K;A159R、T411V、A443M、H468S、Q491R;A159R、T411V、A443M、H468S、Q491E;A159R、T411V、A443Y、H468R、Q491K;A159R、T411V、A443Y、H468R、Q491R;A159R、T411V、A443Y、H468R、Q491E;A159R、T411V、A443Y、H468A、Q491K;A159R、T411V、A443Y、H468A、Q491R;A159R、T411V、A443Y、H468A、Q491E;A159R、T411V、A443Y、H468K、Q491K;A159R、T411V、A443Y、H468K、Q491R;A159R、T411V、A443Y、H468K、Q491E;A159R、T411V、A443Y、H468G、Q491K;A159R、T411V、A443Y、H468G、Q491R;A159R、T411V、A443Y、H468G、Q491E;A159R、T411V、A443Y、H468S、Q491K;A159R、T411V、A443Y、H468S、Q491R;A159R、T411V、A443Y、H468S、Q491E;A159R、T411V、A443V、H468R、Q491K;A159R、T411V、A443V、H468R、Q491R;A159R、T411V、A443V、H468R、Q491E;A159R、T411V、A443V、H468A、Q491K;A159R、T411V、A443V、H468A、Q491R;A159R、T411V、A443V、H468A、Q491E;A159R、T411V、A443V、H468K、Q491K;A159R、T411V、A443V、H468K、Q491R;A159R、T411V、A443V、H468K、Q491E;A159R、T411V、A443V、H468G、Q491K;A159R、T411V、A443V、H468G、Q491R;A159R、T411V、A443V、H468G、Q491E;A159R、T411V、A443V、H468S、Q491K;A159R、T411V、A443V、H468S、Q491R;A159R、T411V、A443V、H468S、Q491E;A159R、T411S、A443I、H468R、Q491K;A159R、T411S、A443I、H468R、Q491R;A159R、T411S、A443I、H468R、Q491E;A159R、T411S、A443I、H468A、Q491K;A159R、T411S、A443I、H468A、Q491R;A159R、T411S、A443I、H468A、Q491E;A159R、T411S、A443I、H468K、Q491K;A159R、T411S、A443I、H468K、Q491R;A159R、T411S、A443I、H468K、Q491E;A159R、T411S、A443I、H468G、Q491K;A159R、T411S、A443I、H468G、Q491R;A159R、T411S、A443I、H468G、Q491E;A159R、T411S、A443I、H468S、Q491K;A159R、T411S、A443I、H468S、Q491R;A159R、T411S、A443I、H468S、Q491E;A159R、T411S、A443L、H468R、Q491K;A159R、T411S、A443L、H468R、Q491R;A159R、T411S、A443L、H468R、Q491E;A159R、T411S、A443L、H468A、Q491K;A159R、T411S、A443L、H468A、Q491R;A159R、T411S、A443L、H468A、Q491E;A159R、T411S、A443L、H468K、Q491K;A159R、T411S、A443L、H468K、Q491R;A159R、T411S、A443L、H468K、Q491E;A159R、T411S、A443L、H468G、Q491K;A159R、T411S、A443L、H468G、Q491R;A159R、T411S、A443L、H468G、Q491E;A159R、T411S、A443L、H468S、Q491K;A159R、T411S、A443L、H468S、Q491R;A159R、T411S、A443L、H468S、Q491E;A159R、T411S、A443F、H468R、Q491K;A159R、T411S、A443F、H468R、Q491R;A159R、T411S、A443F、H468R、Q491E;A159R、T411S、A443F、H468A、Q491K;A159R、T411S、A443F、H468A、Q491R;A159R、T411S、A443F、H468A、Q491E;A159R、T411S、A443F、H468K、Q491K;A159R、T411S、A443F、H468K、Q491R;A159R、T411S、A443F、H468K、Q491E;A159R、T411S、A443F、H468G、Q491K;A159R、T411S、A443F、H468G、Q491R;A159R、T411S、A443F、H468G、Q491E;A159R、T411S、A443F、H468S、Q491K;A159R、T411S、A443F、H468S、Q491R;A159R、T411S、A443F、H468S、Q491E;A159R、T411S、A443M、H468R、Q491K;A159R、T411S、A443M、H468R、Q491R;A159R、T411S、A443M、H468R、Q491E;A159R、T411S、A443M、H468A、Q491K;A159R、T411S、A443M、H468A、Q491R;A159R、T411S、A443M、H468A、Q491E;A159R、T411S、A443M、H468K、Q491K;A159R、T411S、A443M、H468K、Q491R;A159R、T411S、A443M、H468K、Q491E;A159R、T411S、A443M、H468G、Q491K;A159R、T411S、A443M、H468G、Q491R;A159R、T411S、A443M、H468G、Q491E;A159R、T411S、A443M、H468S、Q491K;A159R、T411S、A443M、H468S、Q491R;A159R、T411S、A443M、H468S、Q491E;A159R、T411S、A443Y、H468R、Q491K;A159R、T411S、A443Y、H468R、Q491R;A159R、T411S、A443Y、H468R、Q491E;A159R、T411S、A443Y、H468A、Q491K;A159R、T411S、A443Y、H468A、Q491R;A159R、T411S、A443Y、H468A、Q491E;A159R、T411S、A443Y、H468K、Q491K;A159R、T411S、A443Y、H468K、Q491R;A159R、T411S、A443Y、H468K、Q491E;A159R、T411S、A443Y、H468G、Q491K;A159R、T411S、A443Y、H468G、Q491R;A159R、T411S、A443Y、H468G、Q491E;A159R、T411S、A443Y、H468S、Q491K;A159R、T411S、A443Y、H468S、Q491R;A159R、T411S、A443Y、H468S、Q491E;A159R、T411S、A443V、H468R、Q491K;A159R、T411S、A443V、H468R、Q491R;A159R、T411S、A443V、H468R、Q491E;A159R、T411S、A443V、H468A、Q491K;A159R、T411S、A443V、H468A、Q491R;A159R、T411S、A443V、H468A、Q491E;A159R、T411S、A443V、H468K、Q491K;A159R、T411S、A443V、H468K、Q491R;A159R、T411S、A443V、H468K、Q491E;A159R、T411S、A443V、H468G、Q491K;A159R、T411S、A443V、H468G、Q491R;A159R、T411S、A443V、H468G、Q491E;A159R、T411S、A443V、H468S、Q491K;A159R、T411S、A443V、H468S、Q491R;A159R、T411S、A443V、H468S、Q491E;A159R、T411A、A443I、H468R、Q491K;A159R、T411A、A443I、H468R、Q491R;A159R、T411A、A443I、H468R、Q491E;A159R、T411A、A443I、H468A、Q491K;A159R、T411A、A443I、H468A、Q491R;A159R、T411A、A443I、H468A、Q491E;A159R、T411A、A443I、H468K、Q491K;A159R、T411A、A443I、H468K、Q491R;A159R、T411A、A443I、H468K、Q491E;A159R、T411A、A443I、H468G、Q491K;A159R、T411A、A443I、H468G、Q491R;A159R、T411A、A443I、H468G、Q491E;A159R、T411A、A443I、H468S、Q491K;A159R、T411A、A443I、H468S、Q491R;A159R、T411A、A443I、H468S、Q491E;A159R、T411A、A443L、H468R、Q491K;A159R、T411A、A443L、H468R、Q491R;A159R、T411A、A443L、H468R、Q491E;A159R、T411A、A443L、H468A、Q491K;A159R、T411A、A443L、H468A、Q491R;A159R、T411A、A443L、H468A、Q491E;A159R、T411A、A443L、H468K、Q491K;A159R、T411A、A443L、H468K、Q491R;A159R、T411A、A443L、H468K、Q491E;A159R、T411A、A443L、H468G、Q491K;A159R、T411A、A443L、H468G、Q491R;A159R、T411A、A443L、H468G、Q491E;A159R、T411A、A443L、H468S、Q491K;A159R、T411A、A443L、H468S、Q491R;A159R、T411A、A443L、H468S、Q491E;A159R、T411A、A443F、H468R、Q491K;A159R、T411A、A443F、H468R、Q491R;A159R、T411A、A443F、H468R、Q491E;A159R、T411A、A443F、H468A、Q491K;A159R、T411A、A443F、H468A、Q491R;A159R、T411A、A443F、H468A、Q491E;A159R、T411A、A443F、H468K、Q491K;A159R、T411A、A443F、H468K、Q491R;A159R、T411A、A443F、H468K、Q491E;A159R、T411A、A443F、H468G、Q491K;A159R、T411A、A443F、H468G、Q491R;A159R、T411A、A443F、H468G、Q491E;A159R、T411A、A443F、H468S、Q491K;A159R、T411A、A443F、H468S、Q491R;A159R、T411A、A443F、H468S、Q491E;A159R、T411A、A443M、H468R、Q491K;A159R、T411A、A443M、H468R、Q491R;A159R、T411A、A443M、H468R、Q491E;A159R、T411A、A443M、H468A、Q491K;A159R、T411A、A443M、H468A、Q491R;A159R、T411A、A443M、H468A、Q491E;A159R、T411A、A443M、H468K、Q491K;A159R、T411A、A443M、H468K、Q491R;A159R、T411A、A443M、H468K、Q491E;A159R、T411A、A443M、H468G、Q491K;A159R、T411A、A443M、H468G、Q491R;A159R、T411A、A443M、H468G、Q491E;A159R、T411A、A443M、H468S、Q491K;A159R、T411A、A443M、H468S、Q491R;A159R、T411A、A443M、H468S、Q491E;A159R、T411A、A443Y、H468R、Q491K;A159R、T411A、A443Y、H468R、Q491R;A159R、T411A、A443Y、H468R、Q491E;A159R、T411A、A443Y、H468A、Q491K;A159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43F、H468K、Q491R;A159Y、T411V、A443F、H468K、Q491E;A159Y、T411V、A443F、H468G、Q491K;A159Y、T411V、A443F、H468G、Q491R;A159Y、T411V、A443F、H468G、Q491E;A159Y、T411V、A443F、H468S、Q491K;A159Y、T411V、A443F、H468S、Q491R;A159Y、T411V、A443F、H468S、Q491E;A159Y、T411V、A443M、H468R、Q491K;A159Y、T411V、A443M、H468R、Q491R;A159Y、T411V、A443M、H468R、Q491E;A159Y、T411V、A443M、H468A、Q491K;A159Y、T411V、A443M、H468A、Q491R;A159Y、T411V、A443M、H468A、Q491E;A159Y、T411V、A443M、H468K、Q491K;A159Y、T411V、A443M、H468K、Q491R;A159Y、T411V、A443M、H468K、Q491E;A159Y、T411V、A443M、H468G、Q491K;A159Y、T411V、A443M、H468G、Q491R;A159Y、T411V、A443M、H468G、Q491E;A159Y、T411V、A443M、H468S、Q491K;A159Y、T411V、A443M、H468S、Q491R;A159Y、T411V、A443M、H468S、Q491E;A159Y、T411V、A443Y、H468R、Q491K;A159Y、T411V、A443Y、H468R、Q491R;A159Y、T411V、A443Y、H468R、Q491E;A159Y、T411V、A443Y、H468A、Q491K;A159Y、T411V、A443Y、H468A、Q491R;A159Y、T411V、A443Y、H468A、Q491E;A159Y、T411V、A443Y、H468K、Q491K;A159Y、T411V、A443Y、H468K、Q491R;A159Y、T411V、A443Y、H468K、Q491E;A159Y、T411V、A443Y、H468G、Q491K;A159Y、T411V、A443Y、H468G、Q491R;A159Y、T411V、A443Y、H468G、Q491E;A159Y、T411V、A443Y、H468S、Q491K;A159Y、T411V、A443Y、H468S、Q491R;A159Y、T411V、A443Y、H468S、Q491E;A159Y、T411V、A443V、H468R、Q491K;A159Y、T411V、A443V、H468R、Q491R;A159Y、T411V、A443V、H468R、Q491E;A159Y、T411V、A443V、H468A、Q491K;A159Y、T411V、A443V、H468A、Q491R;A159Y、T411V、A443V、H468A、Q491E;A159Y、T411V、A443V、H468K、Q491K;A159Y、T411V、A443V、H468K、Q491R;A159Y、T411V、A443V、H468K、Q491E;A159Y、T411V、A443V、H468G、Q491K;A159Y、T411V、A443V、H468G、Q491R;A159Y、T411V、A443V、H468G、Q491E;A159Y、T411V、A443V、H468S、Q491K;A159Y、T411V、A443V、H468S、Q491R;A159Y、T411V、A443V、H468S、Q491E;A159Y、T411S、A443I、H468R、Q491K;A159Y、T411S、A443I、H468R、Q491R;A159Y、T411S、A443I、H468R、Q491E;A159Y、T411S、A443I、H468A、Q491K;A159Y、T411S、A443I、H468A、Q491R;A159Y、T411S、A443I、H468A、Q491E;A159Y、T411S、A443I、H468K、Q491K;A159Y、T411S、A443I、H468K、Q491R;A159Y、T411S、A443I、H468K、Q491E;A159Y、T411S、A443I、H468G、Q491K;A159Y、T411S、A443I、H468G、Q491R;A159Y、T411S、A443I、H468G、Q491E;A159Y、T411S、A443I、H468S、Q491K;A159Y、T411S、A443I、H468S、Q491R;A159Y、T411S、A443I、H468S、Q491E;A159Y、T411S、A443L、H468R、Q491K;A159Y、T411S、A443L、H468R、Q491R;A159Y、T411S、A443L、H468R、Q491E;A159Y、T411S、A443L、H468A、Q491K;A159Y、T411S、A443L、H468A、Q491R;A159Y、T411S、A443L、H468A、Q491E;A159Y、T411S、A443L、H468K、Q491K;A159Y、T411S、A443L、H468K、Q491R;A159Y、T411S、A443L、H468K、Q491E;A159Y、T411S、A443L、H468G、Q491K;A159Y、T411S、A443L、H468G、Q491R;A159Y、T411S、A443L、H468G、Q491E;A159Y、T411S、A443L、H468S、Q491K;A159Y、T411S、A443L、H468S、Q491R;A159Y、T411S、A443L、H468S、Q491E;A159Y、T411S、A443F、H468R、Q491K;A159Y、T411S、A443F、H468R、Q491R;A159Y、T411S、A443F、H468R、Q491E;A159Y、T411S、A443F、H468A、Q491K;A159Y、T411S、A443F、H468A、Q491R;A159Y、T411S、A443F、H468A、Q491E;A159Y、T411S、A443F、H468K、Q491K;A159Y、T411S、A443F、H468K、Q491R;A159Y、T411S、A443F、H468K、Q491E;A159Y、T411S、A443F、H468G、Q491K;A159Y、T411S、A443F、H468G、Q491R;A159Y、T411S、A443F、H468G、Q491E;A159Y、T411S、A443F、H468S、Q491K;A159Y、T411S、A443F、H468S、Q491R;A159Y、T411S、A443F、H468S、Q491E;A159Y、T411S、A443M、H468R、Q491K;A159Y、T411S、A443M、H468R、Q491R;A159Y、T411S、A443M、H468R、Q491E;A159Y、T411S、A443M、H468A、Q491K;A159Y、T411S、A443M、H468A、Q491R;A159Y、T411S、A443M、H468A、Q491E;A159Y、T411S、A443M、H468K、Q491K;A159Y、T411S、A443M、H468K、Q491R;A159Y、T411S、A443M、H468K、Q491E;A159Y、T411S、A443M、H468G、Q491K;A159Y、T411S、A443M、H468G、Q491R;A159Y、T411S、A443M、H468G、Q491E;A159Y、T411S、A443M、H468S、Q491K;A159Y、T411S、A443M、H468S、Q491R;A159Y、T411S、A443M、H468S、Q491E;A159Y、T411S、A443Y、H468R、Q491K;A159Y、T411S、A443Y、H468R、Q491R;A159Y、T411S、A443Y、H468R、Q491E;A159Y、T411S、A443Y、H468A、Q491K;A159Y、T411S、A443Y、H468A、Q491R;A159Y、T411S、A443Y、H468A、Q491E;A159Y、T411S、A443Y、H468K、Q491K;A159Y、T411S、A443Y、H468K、Q491R;A159Y、T411S、A443Y、H468K、Q491E;A159Y、T411S、A443Y、H468G、Q491K;A159Y、T411S、A443Y、H468G、Q491R;A159Y、T411S、A443Y、H468G、Q491E;A159Y、T411S、A443Y、H468S、Q491K;A159Y、T411S、A443Y、H468S、Q491R;A159Y、T411S、A443Y、H468S、Q491E;A159Y、T411S、A443V、H468R、Q491K;A159Y、T411S、A443V、H468R、Q491R;A159Y、T411S、A443V、H468R、Q491E;A159Y、T411S、A443V、H468A、Q491K;A159Y、T411S、A443V、H468A、Q491R;A159Y、T411S、A443V、H468A、Q491E;A159Y、T411S、A443V、H468K、Q491K;A159Y、T411S、A443V、H468K、Q491R;A159Y、T411S、A443V、H468K、Q491E;A159Y、T411S、A443V、H468G、Q491K;A159Y、T411S、A443V、H468G、Q491R;A159Y、T411S、A443V、H468G、Q491E;A159Y、T411S、A443V、H468S、Q491K;A159Y、T411S、A443V、H468S、Q491R;A159Y、T411S、A443V、H468S、Q491E;A159Y、T411A、A443I、H468R、Q491K;A159Y、T411A、A443I、H468R、Q491R;A159Y、T411A、A443I、H468R、Q491E;A159Y、T411A、A443I、H468A、Q491K;A159Y、T411A、A443I、H468A、Q491R;A159Y、T411A、A443I、H468A、Q491E;A159Y、T411A、A443I、H468K、Q491K;A159Y、T411A、A443I、H468K、Q491R;A159Y、T411A、A443I、H468K、Q491E;A159Y、T411A、A443I、H468G、Q491K;A159Y、T411A、A443I、H468G、Q491R;A159Y、T411A、A443I、H468G、Q491E;A159Y、T411A、A443I、H468S、Q491K;A159Y、T411A、A443I、H468S、Q491R;A159Y、T411A、A443I、H468S、Q491E;A159Y、T411A、A443L、H468R、Q491K;A159Y、T411A、A443L、H468R、Q491R;A159Y、T411A、A443L、H468R、Q491E;A159Y、T411A、A443L、H468A、Q491K;A159Y、T411A、A443L、H468A、Q491R;A159Y、T411A、A443L、H468A、Q491E;A159Y、T411A、A443L、H468K、Q491K;A159Y、T411A、A443L、H468K、Q491R;A159Y、T411A、A443L、H468K、Q491E;A159Y、T411A、A443L、H468G、Q491K;A159Y、T411A、A443L、H468G、Q491R;A159Y、T411A、A443L、H468G、Q491E;A159Y、T411A、A443L、H468S、Q491K;A159Y、T411A、A443L、H468S、Q491R;A159Y、T411A、A443L、H468S、Q491E;A159Y、T411A、A443F、H468R、Q491K;A159Y、T411A、A443F、H468R、Q491R;A159Y、T411A、A443F、H468R、Q491E;A159Y、T411A、A443F、H468A、Q491K;A159Y、T411A、A443F、H468A、Q491R;A159Y、T411A、A443F、H468A、Q491E;A159Y、T411A、A443F、H468K、Q491K;A159Y、T411A、A443F、H468K、Q491R;A159Y、T411A、A443F、H468K、Q491E;A159Y、T411A、A443F、H468G、Q491K;A159Y、T411A、A443F、H468G、Q491R;A159Y、T411A、A443F、H468G、Q491E;A159Y、T411A、A443F、H468S、Q491K;A159Y、T411A、A443F、H468S、Q491R;A159Y、T411A、A443F、H468S、Q491E;A159Y、T411A、A443M、H468R、Q491K;A159Y、T411A、A443M、H468R、Q491R;A159Y、T411A、A443M、H468R、Q491E;A159Y、T411A、A443M、H468A、Q491K;A159Y、T411A、A443M、H468A、Q491R;A159Y、T411A、A443M、H468A、Q491E;A159Y、T411A、A443M、H468K、Q491K;A159Y、T411A、A443M、H468K、Q491R;A159Y、T411A、A443M、H468K、Q491E;A159Y、T411A、A443M、H468G、Q491K;A159Y、T411A、A443M、H468G、Q491R;A159Y、T411A、A443M、H468G、Q491E;A159Y、T411A、A443M、H468S、Q491K;A159Y、T411A、A443M、H468S、Q491R;A159Y、T411A、A443M、H468S、Q491E;A159Y、T411A、A443Y、H468R、Q491K;A159Y、T411A、A443Y、H468R、Q491R;A159Y、T411A、A443Y、H468R、Q491E;A159Y、T411A、A443Y、H468A、Q491K;A159Y、T411A、A443Y、H468A、Q491R;A159Y、T411A、A443Y、H468A、Q491E;A159Y、T411A、A443Y、H468K、Q491K;A159Y、T411A、A443Y、H468K、Q491R;A159Y、T411A、A443Y、H468K、Q491E;A159Y、T411A、A443Y、H468G、Q491K;A159Y、T411A、A443Y、H468G、Q491R;A159Y、T411A、A443Y、H468G、Q491E;A159Y、T411A、A443Y、H468S、Q491K;A159Y、T411A、A443Y、H468S、Q491R;A159Y、T411A、A443Y、H468S、Q491E;A159Y、T411A、A443V、H468R、Q491K;A159Y、T411A、A443V、H468R、Q491R;A159Y、T411A、A443V、H468R、Q491E;A159Y、T411A、A443V、H468A、Q491K;A159Y、T411A、A443V、H468A、Q491R;A159Y、T411A、A443V、H468A、Q491E;A159Y、T411A、A443V、H468K、Q491K;A159Y、T411A、A443V、H468K、Q491R;A159Y、T411A、A443V、H468K、Q491E;A159Y、T411A、A443V、H468G、Q491K;A159Y、T411A、A443V、H468G、Q491R;A159Y、T411A、A443V、H468G、Q491E;A159Y、T411A、A443V、H468S、Q491K;A159Y、T411A、A443V、H468S、Q491R;A159Y、T411A、A443V、H468S、Q491E;A159Y、T411Q、A443I、H468R、Q491K;A159Y、T411Q、A443I、H468R、Q491R;A159Y、T411Q、A443I、H468R、Q491E;A159Y、T411Q、A443I、H468A、Q491K;A159Y、T411Q、A443I、H468A、Q491R;A159Y、T411Q、A443I、H468A、Q491E;A159Y、T411Q、A443I、H468K、Q491K;A159Y、T411Q、A443I、H468K、Q491R;A159Y、T411Q、A443I、H468K、Q491E;A159Y、T411Q、A443I、H468G、Q491K;A159Y、T411Q、A443I、H468G、Q491R;A159Y、T411Q、A443I、H468G、Q491E;A159Y、T411Q、A443I、H468S、Q491K;A159Y、T411Q、A443I、H468S、Q491R;A159Y、T411Q、A443I、H468S、Q491E;A159Y、T411Q、A443L、H468R、Q491K;A159Y、T411Q、A443L、H468R、Q491R;A159Y、T411Q、A443L、H468R、Q491E;A159Y、T411Q、A443L、H468A、Q491K;A159Y、T411Q、A443L、H468A、Q491R;A159Y、T411Q、A443L、H468A、Q491E;A159Y、T411Q、A443L、H468K、Q491K;A159Y、T411Q、A443L、H468K、Q491R;A159Y、T411Q、A443L、H468K、Q491E;A159Y、T411Q、A443L、H468G、Q491K;A159Y、T411Q、A443L、H468G、Q491R;A159Y、T411Q、A443L、H468G、Q491E;A159Y、T411Q、A443L、H468S、Q491K;A159Y、T411Q、A443L、H468S、Q491R;A159Y、T411Q、A443L、H468S、Q491E;A159Y、T411Q、A443F、H468R、Q491K;A159Y、T411Q、A443F、H468R、Q491R;A159Y、T411Q、A443F、H468R、Q491E;A159Y、T411Q、A443F、H468A、Q491K;A159Y、T411Q、A443F、H468A、Q491R;A159Y、T411Q、A443F、H468A、Q491E;A159Y、T411Q、A443F、H468K、Q491K;A159Y、T411Q、A443F、H468K、Q491R;A159Y、T411Q、A443F、H468K、Q491E;A159Y、T411Q、A443F、H468G、Q491K;A159Y、T411Q、A443F、H468G、Q491R;A159Y、T411Q、A443F、H468G、Q491E;A159Y、T411Q、A443F、H468S、Q491K;A159Y、T411Q、A443F、H468S、Q491R;A159Y、T411Q、A443F、H468S、Q491E;A159Y、T411Q、A443M、H468R、Q491K;A159Y、T411Q、A443M、H468R、Q491R;A159Y、T411Q、A443M、H468R、Q491E;A159Y、T411Q、A443M、H468A、Q491K;A159Y、T411Q、A443M、H468A、Q491R;A159Y、T411Q、A443M、H468A、Q491E;A159Y、T411Q、A443M、H468K、Q491K;A159Y、T411Q、A443M、H468K、Q491R;A159Y、T411Q、A443M、H468K、Q491E;A159Y、T411Q、A443M、H468G、Q491K;A159Y、T411Q、A443M、H468G、Q491R;A159Y、T411Q、A443M、H468G、Q491E;A159Y、T411Q、A443M、H468S、Q491K;A159Y、T411Q、A443M、H468S、Q491R;A159Y、T411Q、A443M、H468S、Q491E;A159Y、T411Q、A443Y、H468R、Q491K;A159Y、T411Q、A443Y、H468R、Q491R;A159Y、T411Q、A443Y、H468R、Q491E;A159Y、T411Q、A443Y、H468A、Q491K;A159Y、T411Q、A443Y、H468A、Q491R;A159Y、T411Q、A443Y、H468A、Q491E;A159Y、T411Q、A443Y、H468K、Q491K;A159Y、T411Q、A443Y、H468K、Q491R;A159Y、T411Q、A443Y、H468K、Q491E;A159Y、T411Q、A443Y、H468G、Q491K;A159Y、T411Q、A443Y、H468G、Q491R;A159Y、T411Q、A443Y、H468G、Q491E;A159Y、T411Q、A443Y、H468S、Q491K;A159Y、T411Q、A443Y、H468S、Q491R;A159Y、T411Q、A443Y、H468S、Q491E;A159Y、T411Q、A443V、H468R、Q491K;A159Y、T411Q、A443V、H468R、Q491R;A159Y、T411Q、A443V、H468R、Q491E;A159Y、T411Q、A443V、H468A、Q491K;A159Y、T411Q、A443V、H468A、Q491R;A159Y、T411Q、A443V、H468A、Q491E;A159Y、T411Q、A443V、H468K、Q491K;A159Y、T411Q、A443V、H468K、Q491R;A159Y、T411Q、A443V、H468K、Q491E;A159Y、T411Q、A443V、H468G、Q491K;A159Y、T411Q、A443V、H468G、Q491R;A159Y、T411Q、A443V、H468G、Q491E;A159Y、T411Q、A443V、H468S、Q491K;A159Y、T411Q、A443V、H468S、Q491R;A159Y、T411Q、A443V、H468S、Q491E;A159Y、T411E、A443I、H468R、Q491K;A159Y、T411E、A443I、H468R、Q491R;A159Y、T411E、A443I、H468R、Q491E;A159Y、T411E、A443I、H468A、Q491K;A159Y、T411E、A443I、H468A、Q491R;A159Y、T411E、A443I、H468A、Q491E;A159Y、T411E、A443I、H468K、Q491K;A159Y、T411E、A443I、H468K、Q491R;A159Y、T411E、A443I、H468K、Q491E;A159Y、T411E、A443I、H468G、Q491K;A159Y、T411E、A443I、H468G、Q491R;A159Y、T411E、A443I、H468G、Q491E;A159Y、T411E、A443I、H468S、Q491K;A159Y、T411E、A443I、H468S、Q491R;A159Y、T411E、A443I、H468S、Q491E;A159Y、T411E、A443L、H468R、Q491K;A159Y、T411E、A443L、H468R、Q491R;A159Y、T411E、A443L、H468R、Q491E;A159Y、T411E、A443L、H468A、Q491K;A159Y、T411E、A443L、H468A、Q491R;A159Y、T411E、A443L、H468A、Q491E;A159Y、T411E、A443L、H468K、Q491K;A159Y、T411E、A443L、H468K、Q491R;A159Y、T411E、A443L、H468K、Q491E;A159Y、T411E、A443L、H468G、Q491K;A159Y、T411E、A443L、H468G、Q491R;A159Y、T411E、A443L、H468G、Q491E;A159Y、T411E、A443L、H468S、Q491K;A159Y、T411E、A443L、H468S、Q491R;A159Y、T411E、A443L、H468S、Q491E;A159Y、T411E、A443F、H468R、Q491K;A159Y、T411E、A443F、H468R、Q491R;A159Y、T411E、A443F、H468R、Q491E;A159Y、T411E、A443F、H468A、Q491K;A159Y、T411E、A443F、H468A、Q491R;A159Y、T411E、A443F、H468A、Q491E;A159Y、T411E、A443F、H468K、Q491K;A159Y、T411E、A443F、H468K、Q491R;A159Y、T411E、A443F、H468K、Q491E;A159Y、T411E、A443F、H468G、Q491K;A159Y、T411E、A443F、H468G、Q491R;A159Y、T411E、A443F、H468G、Q491E;A159Y、T411E、A443F、H468S、Q491K;A159Y、T411E、A443F、H468S、Q491R;A159Y、T411E、A443F、H468S、Q491E;A159Y、T411E、A443M、H468R、Q491K;A159Y、T411E、A443M、H468R、Q491R;A159Y、T411E、A443M、H468R、Q491E;A159Y、T411E、A443M、H468A、Q491K;A159Y、T411E、A443M、H468A、Q491R;A159Y、T411E、A443M、H468A、Q491E;A159Y、T411E、A443M、H468K、Q491K;A159Y、T411E、A443M、H468K、Q491R;A159Y、T411E、A443M、H468K、Q491E;A159Y、T411E、A443M、H468G、Q491K;A159Y、T411E、A443M、H468G、Q491R;A159Y、T411E、A443M、H468G、Q491E;A159Y、T411E、A443M、H468S、Q491K;A159Y、T411E、A443M、H468S、Q491R;A159Y、T411E、A443M、H468S、Q491E;A159Y、T411E、A443Y、H468R、Q491K;A159Y、T411E、A443Y、H468R、Q491R;A159Y、T411E、A443Y、H468R、Q491E;A159Y、T411E、A443Y、H468A、Q491K;A159Y、T411E、A443Y、H468A、Q491R;A159Y、T411E、A443Y、H468A、Q491E;A159Y、T411E、A443Y、H468K、Q491K;A159Y、T411E、A443Y、H468K、Q491R;A159Y、T411E、A443Y、H468K、Q491E;A159Y、T411E、A443Y、H468G、Q491K;A159Y、T411E、A443Y、H468G、Q491R;A159Y、T411E、A443Y、H468G、Q491E;A159Y、T411E、A443Y、H468S、Q491K;A159Y、T411E、A443Y、H468S、Q491R;A159Y、T411E、A443Y、H468S、Q491E;A159Y、T411E、A443V、H468R、Q491K;A159Y、T411E、A443V、H468R、Q491R;A159Y、T411E、A443V、H468R、Q491E;A159Y、T411E、A443V、H468A、Q491K;A159Y、T411E、A443V、H468A、Q491R;A159Y、T411E、A443V、H468A、Q491E;A159Y、T411E、A443V、H468K、Q491K;A159Y、T411E、A443V、H468K、Q491R;A159Y、T411E、A443V、H468K、Q491E;A159Y、T411E、A443V、H468G、Q491K;A159Y、T411E、A443V、H468G、Q491R;A159Y、T411E、A443V、H468G、Q491E;A159Y、T411E、A443V、H468S、Q491K;A159Y、T411E、A443V、H468S、Q491R;A159Y、T411E、A443V、H468S、Q491E;A159Y、T411K、A443I、H468R、Q491K;A159Y、T411K、A443I、H468R、Q491R;A159Y、T411K、A443I、H468R、Q491E;A159Y、T411K、A443I、H468A、Q491K;A159Y、T411K、A443I、H468A、Q491R;A159Y、T411K、A443I、H468A、Q491E;A159Y、T411K、A443I、H468K、Q491K;A159Y、T411K、A443I、H468K、Q491R;A159Y、T411K、A443I、H468K、Q491E;A159Y、T411K、A443I、H468G、Q491K;A159Y、T411K、A443I、H468G、Q491R;A159Y、T411K、A443I、H468G、Q491E;A159Y、T411K、A443I、H468S、Q491K;A159Y、T411K、A443I、H468S、Q491R;A159Y、T411K、A443I、H468S、Q491E;A159Y、T411K、A443L、H468R、Q491K;A159Y、T411K、A443L、H468R、Q491R;A159Y、T411K、A443L、H468R、Q491E;A159Y、T411K、A443L、H468A、Q491K;A159Y、T411K、A443L、H468A、Q491R;A159Y、T411K、A443L、H468A、Q491E;A159Y、T411K、A443L、H468K、Q491K;A159Y、T411K、A443L、H468K、Q491R;A159Y、T411K、A443L、H468K、Q491E;A159Y、T411K、A443L、H468G、Q491K;A159Y、T411K、A443L、H468G、Q491R;A159Y、T411K、A443L、H468G、Q491E;A159Y、T411K、A443L、H468S、Q491K;A159Y、T411K、A443L、H468S、Q491R;A159Y、T411K、A443L、H468S、Q491E;A159Y、T411K、A443F、H468R、Q491K;A159Y、T411K、A443F、H468R、Q491R;A159Y、T411K、A443F、H468R、Q491E;A159Y、T411K、A443F、H468A、Q491K;A159Y、T411K、A443F、H468A、Q491R;A159Y、T411K、A443F、H468A、Q491E;A159Y、T411K、A443F、H468K、Q491K;A159Y、T411K、A443F、H468K、Q491R;A159Y、T411K、A443F、H468K、Q491E;A159Y、T411K、A443F、H468G、Q491K;A159Y、T411K、A443F、H468G、Q491R;A159Y、T411K、A443F、H468G、Q491E;A159Y、T411K、A443F、H468S、Q491K;A159Y、T411K、A443F、H468S、Q491R;A159Y、T411K、A443F、H468S、Q491E;A159Y、T411K、A443M、H468R、Q491K;A159Y、T411K、A443M、H468R、Q491R;A159Y、T411K、A443M、H468R、Q491E;A159Y、T411K、A443M、H468A、Q491K;A159Y、T411K、A443M、H468A、Q491R;A159Y、T411K、A443M、H468A、Q491E;A159Y、T411K、A443M、H468K、Q491K;A159Y、T411K、A443M、H468K、Q491R;A159Y、T411K、A443M、H468K、Q491E;A159Y、T411K、A443M、H468G、Q491K;A159Y、T411K、A443M、H468G、Q491R;A159Y、T411K、A443M、H468G、Q491E;A159Y、T411K、A443M、H468S、Q491K;A159Y、T411K、A443M、H468S、Q491R;A159Y、T411K、A443M、H468S、Q491E;A159Y、T411K、A443Y、H468R、Q491K;A159Y、T411K、A443Y、H468R、Q491R;A159Y、T411K、A443Y、H468R、Q491E;A159Y、T411K、A443Y、H468A、Q491K;A159Y、T411K、A443Y、H468A、Q491R;A159Y、T411K、A443Y、H468A、Q491E;A159Y、T411K、A443Y、H468K、Q491K;A159Y、T411K、A443Y、H468K、Q491R;A159Y、T411K、A443Y、H468K、Q491E;A159Y、T411K、A443Y、H468G、Q491K;A159Y、T411K、A443Y、H468G、Q491R;A159Y、T411K、A443Y、H468G、Q491E;A159Y、T411K、A443Y、H468S、Q491K;A159Y、T411K、A443Y、H468S、Q491R;A159Y、T411K、A443Y、H468S、Q491E;A159Y、T411K、A443V、H468R、Q491K;A159Y、T411K、A443V、H468R、Q491R;A159Y、T411K、A443V、H468R、Q491E;A159Y、T411K、A443V、H468A、Q491K;A159Y、T411K、A443V、H468A、Q491R;A159Y、T411K、A443V、H468A、Q491E;A159Y、T411K、A443V、H468K、Q491K;A159Y、T411K、A443V、H468K、Q491R;A159Y、T411K、A443V、H468K、Q491E;A159Y、T411K、A443V、H468G、Q491K;A159Y、T411K、A443V、H468G、Q491R;A159Y、T411K、A443V、H468G、Q491E;A159Y、T411K、A443V、H468S、Q491K;A159Y、T411K、A443V、H468S、Q491R;A159Y、T411K、A443V、H468S、Q491E;A159T、T411V、A443I、H468R、Q491K;A159T、T411V、A443I、H468R、Q491R;A159T、T411V、A443I、H468R、Q491E;A159T、T411V、A443I、H468A、Q491K;A159T、T411V、A443I、H468A、Q491R;A159T、T411V、A443I、H468A、Q491E;A159T、T411V、A443I、H468K、Q491K;A159T、T411V、A443I、H468K、Q491R;A159T、T411V、A443I、H468K、Q491E;A159T、T411V、A443I、H468G、Q491K;A159T、T411V、A443I、H468G、Q491R;A159T、T411V、A443I、H468G、Q491E;A159T、T411V、A443I、H468S、Q491K;A159T、T411V、A443I、H468S、Q491R;A159T、T411V、A443I、H468S、Q491E;A159T、T411V、A443L、H468R、Q491K;A159T、T411V、A443L、H468R、Q491R;A159T、T411V、A443L、H468R、Q491E;A159T、T411V、A443L、H468A、Q491K;A159T、T411V、A443L、H468A、Q491R;A159T、T411V、A443L、H468A、Q491E;A159T、T411V、A443L、H468K、Q491K;A159T、T411V、A443L、H468K、Q491R;A159T、T411V、A443L、H468K、Q491E;A159T、T411V、A443L、H468G、Q491K;A159T、T411V、A443L、H468G、Q491R;A159T、T411V、A443L、H468G、Q491E;A159T、T411V、A443L、H468S、Q491K;A159T、T411V、A443L、H468S、Q491R;A159T、T411V、A443L、H468S、Q491E;A159T、T411V、A443F、H468R、Q491K;A159T、T411V、A443F、H468R、Q491R;A159T、T411V、A443F、H468R、Q491E;A159T、T411V、A443F、H468A、Q491K;A159T、T411V、A443F、H468A、Q491R;A159T、T411V、A443F、H468A、Q491E;A159T、T411V、A443F、H468K、Q491K;A159T、T411V、A443F、H468K、Q491R;A159T、T411V、A443F、H468K、Q491E;A159T、T411V、A443F、H468G、Q491K;A159T、T411V、A443F、H468G、Q491R;A159T、T411V、A443F、H468G、Q491E;A159T、T411V、A443F、H468S、Q491K;A159T、T411V、A443F、H468S、Q491R;A159T、T411V、A443F、H468S、Q491E;A159T、T411V、A443M、H468R、Q491K;A159T、T411V、A443M、H468R、Q491R;A159T、T411V、A443M、H468R、Q491E;A159T、T411V、A443M、H468A、Q491K;A159T、T411V、A443M、H468A、Q491R;A159T、T411V、A443M、H468A、Q491E;A159T、T411V、A443M、H468K、Q491K;A159T、T411V、A443M、H468K、Q491R;A159T、T411V、A443M、H468K、Q491E;A159T、T411V、A443M、H468G、Q491K;A159T、T411V、A443M、H468G、Q491R;A159T、T411V、A443M、H468G、Q491E;A159T、T411V、A443M、H468S、Q491K;A159T、T411V、A443M、H468S、Q491R;A159T、T411V、A443M、H468S、Q491E;A159T、T411V、A443Y、H468R、Q491K;A159T、T411V、A443Y、H468R、Q491R;A159T、T411V、A443Y、H468R、Q491E;A159T、T411V、A443Y、H468A、Q491K;A159T、T411V、A443Y、H468A、Q491R;A159T、T411V、A443Y、H468A、Q491E;A159T、T411V、A443Y、H468K、Q491K;A159T、T411V、A443Y、H468K、Q491R;A159T、T411V、A443Y、H468K、Q491E;A159T、T411V、A443Y、H468G、Q491K;A159T、T411V、A443Y、H468G、Q491R;A159T、T411V、A443Y、H468G、Q491E;A159T、T411V、A443Y、H468S、Q491K;A159T、T411V、A443Y、H468S、Q491R;A159T、T411V、A443Y、H468S、Q491E;A159T、T411V、A443V、H468R、Q491K;A159T、T411V、A443V、H468R、Q491R;A159T、T411V、A443V、H468R、Q491E;A159T、T411V、A443V、H468A、Q491K;A159T、T411V、A443V、H468A、Q491R;A159T、T411V、A443V、H468A、Q491E;A159T、T411V、A443V、H468K、Q491K;A159T、T411V、A443V、H468K、Q491R;A159T、T411V、A443V、H468K、Q491E;A159T、T411V、A443V、H468G、Q491K;A159T、T411V、A443V、H468G、Q491R;A159T、T411V、A443V、H468G、Q491E;A159T、T411V、A443V、H468S、Q491K;A159T、T411V、A443V、H468S、Q491R;A159T、T411V、A443V、H468S、Q491E;A159T、T411S、A443I、H468R、Q491K;A159T、T411S、A443I、H468R、Q491R;A159T、T411S、A443I、H468R、Q491E;A159T、T411S、A443I、H468A、Q491K;A159T、T411S、A443I、H468A、Q491R;A159T、T411S、A443I、H468A、Q491E;A159T、T411S、A443I、H468K、Q491K;A159T、T411S、A443I、H468K、Q491R;A159T、T411S、A443I、H468K、Q491E;A159T、T411S、A443I、H468G、Q491K;A159T、T411S、A443I、H468G、Q491R;A159T、T411S、A443I、H468G、Q491E;A159T、T411S、A443I、H468S、Q491K;A159T、T411S、A443I、H468S、Q491R;A159T、T411S、A443I、H468S、Q491E;A159T、T411S、A443L、H468R、Q491K;A159T、T411S、A443L、H468R、Q491R;A159T、T411S、A443L、H468R、Q491E;A159T、T411S、A443L、H468A、Q491K;A159T、T411S、A443L、H468A、Q491R;A159T、T411S、A443L、H468A、Q491E;A159T、T411S、A443L、H468K、Q491K;A159T、T411S、A443L、H468K、Q491R;A159T、T411S、A443L、H468K、Q491E;A159T、T411S、A443L、H468G、Q491K;A159T、T411S、A443L、H468G、Q491R;A159T、T411S、A443L、H468G、Q491E;A159T、T411S、A443L、H468S、Q491K;A159T、T411S、A443L、H468S、Q491R;A159T、T411S、A443L、H468S、Q491E;A159T、T411S、A443F、H468R、Q491K;A159T、T411S、A443F、H468R、Q491R;A159T、T411S、A443F、H468R、Q491E;A159T、T411S、A443F、H468A、Q491K;A159T、T411S、A443F、H468A、Q491R;A159T、T411S、A443F、H468A、Q491E;A159T、T411S、A443F、H468K、Q491K;A159T、T411S、A443F、H468K、Q491R;A159T、T411S、A443F、H468K、Q491E;A159T、T411S、A443F、H468G、Q491K;A159T、T411S、A443F、H468G、Q491R;A159T、T411S、A443F、H468G、Q491E;A159T、T411S、A443F、H468S、Q491K;A159T、T411S、A443F、H468S、Q491R;A159T、T411S、A443F、H468S、Q491E;A159T、T411S、A443M、H468R、Q491K;A159T、T411S、A443M、H468R、Q491R;A159T、T411S、A443M、H468R、Q491E;A159T、T411S、A443M、H468A、Q491K;A159T、T411S、A443M、H468A、Q491R;A159T、T411S、A443M、H468A、Q491E;A159T、T411S、A443M、H468K、Q491K;A159T、T411S、A443M、H468K、Q491R;A159T、T411S、A443M、H468K、Q491E;A159T、T411S、A443M、H468G、Q491K;A159T、T411S、A443M、H468G、Q491R;A159T、T411S、A443M、H468G、Q491E;A159T、T411S、A443M、H468S、Q491K;A159T、T411S、A443M、H468S、Q491R;A159T、T411S、A443M、H468S、Q491E;A159T、T411S、A443Y、H468R、Q491K;A159T、T411S、A443Y、H468R、Q491R;A159T、T411S、A443Y、H468R、Q491E;A159T、T411S、A443Y、H468A、Q491K;A159T、T411S、A443Y、H468A、Q491R;A159T、T411S、A443Y、H468A、Q491E;A159T、T411S、A443Y、H468K、Q491K;A159T、T411S、A443Y、H468K、Q491R;A159T、T411S、A443Y、H468K、Q491E;A159T、T411S、A443Y、H468G、Q491K;A159T、T411S、A443Y、H468G、Q491R;A159T、T411S、A443Y、H468G、Q491E;A159T、T411S、A443Y、H468S、Q491K;A159T、T411S、A443Y、H468S、Q491R;A159T、T411S、A443Y、H468S、Q491E;A159T、T411S、A443V、H468R、Q491K;A159T、T411S、A443V、H468R、Q491R;A159T、T411S、A443V、H468R、Q491E;A159T、T411S、A443V、H468A、Q491K;A159T、T411S、A443V、H468A、Q491R;A159T、T411S、A443V、H468A、Q491E;A159T、T411S、A443V、H468K、Q491K;A159T、T411S、A443V、H468K、Q491R;A159T、T411S、A443V、H468K、Q491E;A159T、T411S、A443V、H468G、Q491K;A159T、T411S、A443V、H468G、Q491R;A159T、T411S、A443V、H468G、Q491E;A159T、T411S、A443V、H468S、Q491K;A159T、T411S、A443V、H468S、Q491R;A159T、T411S、A443V、H468S、Q491E;A159T、T411A、A443I、H468R、Q491K;A159T、T411A、A443I、H468R、Q491R;A159T、T411A、A443I、H468R、Q491E;A159T、T411A、A443I、H468A、Q491K;A159T、T411A、A443I、H468A、Q491R;A159T、T411A、A443I、H468A、Q491E;A159T、T411A、A443I、H468K、Q491K;A159T、T411A、A443I、H468K、Q491R;A159T、T411A、A443I、H468K、Q491E;A159T、T411A、A443I、H468G、Q491K;A159T、T411A、A443I、H468G、Q491R;A159T、T411A、A443I、H468G、Q491E;A159T、T411A、A443I、H468S、Q491K;A159T、T411A、A443I、H468S、Q491R;A159T、T411A、A443I、H468S、Q491E;A159T、T411A、A443L、H468R、Q491K;A159T、T411A、A443L、H468R、Q491R;A159T、T411A、A443L、H468R、Q491E;A159T、T411A、A443L、H468A、Q491K;A159T、T411A、A443L、H468A、Q491R;A159T、T411A、A443L、H468A、Q491E;A159T、T411A、A443L、H468K、Q491K;A159T、T411A、A443L、H468K、Q491R;A159T、T411A、A443L、H468K、Q491E;A159T、T411A、A443L、H468G、Q491K;A159T、T411A、A443L、H468G、Q491R;A159T、T411A、A443L、H468G、Q491E;A159T、T411A、A443L、H468S、Q491K;A159T、T411A、A443L、H468S、Q491R;A159T、T411A、A443L、H468S、Q491E;A159T、T411A、A443F、H468R、Q491K;A159T、T411A、A443F、H468R、Q491R;A159T、T411A、A443F、H468R、Q491E;A159T、T411A、A443F、H468A、Q491K;A159T、T411A、A443F、H468A、Q491R;A159T、T411A、A443F、H468A、Q491E;A159T、T411A、A443F、H468K、Q491K;A159T、T411A、A443F、H468K、Q491R;A159T、T411A、A443F、H468K、Q491E;A159T、T411A、A443F、H468G、Q491K;A159T、T411A、A443F、H468G、Q491R;A159T、T411A、A443F、H468G、Q491E;A159T、T411A、A443F、H468S、Q491K;A159T、T411A、A443F、H468S、Q491R;A159T、T411A、A443F、H468S、Q491E;A159T、T411A、A443M、H468R、Q491K;A159T、T411A、A443M、H468R、Q491R;A159T、T411A、A443M、H468R、Q491E;A159T、T411A、A443M、H468A、Q491K;A159T、T411A、A443M、H468A、Q491R;A159T、T411A、A443M、H468A、Q491E;A159T、T411A、A443M、H468K、Q491K;A159T、T411A、A443M、H468K、Q491R;A159T、T411A、A443M、H468K、Q491E;A159T、T411A、A443M、H468G、Q491K;A159T、T411A、A443M、H468G、Q491R;A159T、T411A、A443M、H468G、Q491E;A159T、T411A、A443M、H468S、Q491K;A159T、T411A、A443M、H468S、Q491R;A159T、T411A、A443M、H468S、Q491E;A159T、T411A、A443Y、H468R、Q491K;A159T、T411A、A443Y、H468R、Q491R;A159T、T411A、A443Y、H468R、Q491E;A159T、T411A、A443Y、H468A、Q491K;A159T、T411A、A443Y、H468A、Q491R;A159T、T411A、A443Y、H468A、Q491E;A159T、T411A、A443Y、H468K、Q491K;A159T、T411A、A443Y、H468K、Q491R;A159T、T411A、A443Y、H468K、Q491E;A159T、T411A、A443Y、H468G、Q491K;A159T、T411A、A443Y、H468G、Q491R;A159T、T411A、A443Y、H468G、Q491E;A159T、T411A、A443Y、H468S、Q491K;A159T、T411A、A443Y、H468S、Q491R;A159T、T411A、A443Y、H468S、Q491E;A159T、T411A、A443V、H468R、Q491K;A159T、T411A、A443V、H468R、Q491R;A159T、T411A、A443V、H468R、Q491E;A159T、T411A、A443V、H468A、Q491K;A159T、T411A、A443V、H468A、Q491R;A159T、T411A、A443V、H468A、Q491E;A159T、T411A、A443V、H468K、Q491K;A159T、T411A、A443V、H468K、Q491R;A159T、T411A、A443V、H468K、Q491E;A159T、T411A、A443V、H468G、Q491K;A159T、T411A、A443V、H468G、Q491R;A159T、T411A、A443V、H468G、Q491E;A159T、T411A、A443V、H468S、Q491K;A159T、T411A、A443V、H468S、Q491R;A159T、T411A、A443V、H468S、Q491E;A159T、T411Q、A443I、H468R、Q491K;A159T、T411Q、A443I、H468R、Q491R;A159T、T411Q、A443I、H468R、Q491E;A159T、T411Q、A443I、H468A、Q491K;A159T、T411Q、A443I、H468A、Q491R;A159T、T411Q、A443I、H468A、Q491E;A159T、T411Q、A443I、H468K、Q491K;A159T、T411Q、A443I、H468K、Q491R;A159T、T411Q、A443I、H468K、Q491E;A159T、T411Q、A443I、H468G、Q491K;A159T、T411Q、A443I、H468G、Q491R;A159T、T411Q、A443I、H468G、Q491E;A159T、T411Q、A443I、H468S、Q491K;A159T、T411Q、A443I、H468S、Q491R;A159T、T411Q、A443I、H468S、Q491E;A159T、T411Q、A443L、H468R、Q491K;A159T、T411Q、A443L、H468R、Q491R;A159T、T411Q、A443L、H468R、Q491E;A159T、T411Q、A443L、H468A、Q491K;A159T、T411Q、A443L、H468A、Q491R;A159T、T411Q、A443L、H468A、Q491E;A159T、T411Q、A443L、H468K、Q491K;A159T、T411Q、A443L、H468K、Q491R;A159T、T411Q、A443L、H468K、Q491E;A159T、T411Q、A443L、H468G、Q491K;A159T、T411Q、A443L、H468G、Q491R;A159T、T411Q、A443L、H468G、Q491E;A159T、T411Q、A443L、H468S、Q491K;A159T、T411Q、A443L、H468S、Q491R;A159T、T411Q、A443L、H468S、Q491E;A159T、T411Q、A443F、H468R、Q491K;A159T、T411Q、A443F、H468R、Q491R;A159T、T411Q、A443F、H468R、Q491E;A159T、T411Q、A443F、H468A、Q491K;A159T、T411Q、A443F、H468A、Q491R;A159T、T411Q、A443F、H468A、Q491E;A159T、T411Q、A443F、H468K、Q491K;A159T、T411Q、A443F、H468K、Q491R;A159T、T411Q、A443F、H468K、Q491E;A159T、T411Q、A443F、H468G、Q491K;A159T、T411Q、A443F、H468G、Q491R;A159T、T411Q、A443F、H468G、Q491E;A159T、T411Q、A443F、H468S、Q491K;A159T、T411Q、A443F、H468S、Q491R;A159T、T411Q、A443F、H468S、Q491E;A159T、T411Q、A443M、H468R、Q491K;A159T、T411Q、A443M、H468R、Q491R;A159T、T411Q、A443M、H468R、Q491E;A159T、T411Q、A443M、H468A、Q491K;A159T、T411Q、A443M、H468A、Q491R;A159T、T411Q、A443M、H468A、Q491E;A159T、T411Q、A443M、H468K、Q491K;A159T、T411Q、A443M、H468K、Q491R;A159T、T411Q、A443M、H468K、Q491E;A159T、T411Q、A443M、H468G、Q491K;A159T、T411Q、A443M、H468G、Q491R;A159T、T411Q、A443M、H468G、Q491E;A159T、T411Q、A443M、H468S、Q491K;A159T、T411Q、A443M、H468S、Q491R;A159T、T411Q、A443M、H468S、Q491E;A159T、T411Q、A443Y、H468R、Q491K;A159T、T411Q、A443Y、H468R、Q491R;A159T、T411Q、A443Y、H468R、Q491E;A159T、T411Q、A443Y、H468A、Q491K;A159T、T411Q、A443Y、H468A、Q491R;A159T、T411Q、A443Y、H468A、Q491E;A159T、T411Q、A443Y、H468K、Q491K;A159T、T411Q、A443Y、H468K、Q491R;A159T、T411Q、A443Y、H468K、Q491E;A159T、T411Q、A443Y、H468G、Q491K;A159T、T411Q、A443Y、H468G、Q491R;A159T、T411Q、A443Y、H468G、Q491E;A159T、T411Q、A443Y、H468S、Q491K;A159T、T411Q、A443Y、H468S、Q491R;A159T、T411Q、A443Y、H468S、Q491E;A159T、T411Q、A443V、H468R、Q491K;A159T、T411Q、A443V、H468R、Q491R;A159T、T411Q、A443V、H468R、Q491E;A159T、T411Q、A443V、H468A、Q491K;A159T、T411Q、A443V、H468A、Q491R;A159T、T411Q、A443V、H468A、Q491E;A159T、T411Q、A443V、H468K、Q491K;A159T、T411Q、A443V、H468K、Q491R;A159T、T411Q、A443V、H468K、Q491E;A159T、T411Q、A443V、H468G、Q491K;A159T、T411Q、A443V、H468G、Q491R;A159T、T411Q、A443V、H468G、Q491E;A159T、T411Q、A443V、H468S、Q491K;A159T、T411Q、A443V、H468S、Q491R;A159T、T411Q、A443V、H468S、Q491E;A159T、T411E、A443I、H468R、Q491K;A159T、T411E、A443I、H468R、Q491R;A159T、T411E、A443I、H468R、Q491E;A159T、T411E、A443I、H468A、Q491K;A159T、T411E、A443I、H468A、Q491R;A159T、T411E、A443I、H468A、Q491E;A159T、T411E、A443I、H468K、Q491K;A159T、T411E、A443I、H468K、Q491R;A159T、T411E、A443I、H468K、Q491E;A159T、T411E、A443I、H468G、Q491K;A159T、T411E、A443I、H468G、Q491R;A159T、T411E、A443I、H468G、Q491E;A159T、T411E、A443I、H468S、Q491K;A159T、T411E、A443I、H468S、Q491R;A159T、T411E、A443I、H468S、Q491E;A159T、T411E、A443L、H468R、Q491K;A159T、T411E、A443L、H468R、Q491R;A159T、T411E、A443L、H468R、Q491E;A159T、T411E、A443L、H468A、Q491K;A159T、T411E、A443L、H468A、Q491R;A159T、T411E、A443L、H468A、Q491E;A159T、T411E、A443L、H468K、Q491K;A159T、T411E、A443L、H468K、Q491R;A159T、T411E、A443L、H468K、Q491E;A159T、T411E、A443L、H468G、Q491K;A159T、T411E、A443L、H468G、Q491R;A159T、T411E、A443L、H468G、Q491E;A159T、T411E、A443L、H468S、Q491K;A159T、T411E、A443L、H468S、Q491R;A159T、T411E、A443L、H468S、Q491E;A159T、T411E、A443F、H468R、Q491K;A159T、T411E、A443F、H468R、Q491R;A159T、T411E、A443F、H468R、Q491E;A159T、T411E、A443F、H468A、Q491K;A159T、T411E、A443F、H468A、Q491R;A159T、T411E、A443F、H468A、Q491E;A159T、T411E、A443F、H468K、Q491K;A159T、T411E、A443F、H468K、Q491R;A159T、T411E、A443F、H468K、Q491E;A159T、T411E、A443F、H468G、Q491K;A159T、T411E、A443F、H468G、Q491R;A159T、T411E、A443F、H468G、Q491E;A159T、T411E、A443F、H468S、Q491K;A159T、T411E、A443F、H468S、Q491R;A159T、T411E、A443F、H468S、Q491E;A159T、T411E、A443M、H468R、Q491K;A159T、T411E、A443M、H468R、Q491R;A159T、T411E、A443M、H468R、Q491E;A159T、T411E、A443M、H468A、Q491K;A159T、T411E、A443M、H468A、Q491R;A159T、T411E、A443M、H468A、Q491E;A159T、T411E、A443M、H468K、Q491K;A159T、T411E、A443M、H468K、Q491R;A159T、T411E、A443M、H468K、Q491E;A159T、T411E、A443M、H468G、Q491K;A159T、T411E、A443M、H468G、Q491R;A159T、T411E、A443M、H468G、Q491E;A159T、T411E、A443M、H468S、Q491K;A159T、T411E、A443M、H468S、Q491R;A159T、T411E、A443M、H468S、Q491E;A159T、T411E、A443Y、H468R、Q491K;A159T、T411E、A443Y、H468R、Q491R;A159T、T411E、A443Y、H468R、Q491E;A159T、T411E、A443Y、H468A、Q491K;A159T、T411E、A443Y、H468A、Q491R;A159T、T411E、A443Y、H468A、Q491E;A159T、T411E、A443Y、H468K、Q491K;A159T、T411E、A443Y、H468K、Q491R;A159T、T411E、A443Y、H468K、Q491E;A159T、T411E、A443Y、H468G、Q491K;A159T、T411E、A443Y、H468G、Q491R;A159T、T411E、A443Y、H468G、Q491E;A159T、T411E、A443Y、H468S、Q491K;A159T、T411E、A443Y、H468S、Q491R;A159T、T411E、A443Y、H468S、Q491E;A159T、T411E、A443V、H468R、Q491K;A159T、T411E、A443V、H468R、Q491R;A159T、T411E、A443V、H468R、Q491E;A159T、T411E、A443V、H468A、Q491K;A159T、T411E、A443V、H468A、Q491R;A159T、T411E、A443V、H468A、Q491E;A159T、T411E、A443V、H468K、Q491K;A159T、T411E、A443V、H468K、Q491R;A159T、T411E、A443V、H468K、Q491E;A159T、T411E、A443V、H468G、Q491K;A159T、T411E、A443V、H468G、Q491R;A159T、T411E、A443V、H468G、Q491E;A159T、T411E、A443V、H468S、Q491K;A159T、T411E、A443V、H468S、Q491R;A159T、T411E、A443V、H468S、Q491E;A159T、T411K、A443I、H468R、Q491K;A159T、T411K、A443I、H468R、Q491R;A159T、T411K、A443I、H468R、Q491E;A159T、T411K、A443I、H468A、Q491K;A159T、T411K、A443I、H468A、Q491R;A159T、T411K、A443I、H468A、Q491E;A159T、T411K、A443I、H468K、Q491K;A159T、T411K、A443I、H468K、Q491R;A159T、T411K、A443I、H468K、Q491E;A159T、T411K、A443I、H468G、Q491K;A159T、T411K、A443I、H468G、Q491R;A159T、T411K、A443I、H468G、Q491E;A159T、T411K、A443I、H468S、Q491K;A159T、T411K、A443I、H468S、Q491R;A159T、T411K、A443I、H468S、Q491E;A159T、T411K、A443L、H468R、Q491K;A159T、T411K、A443L、H468R、Q491R;A159T、T411K、A443L、H468R、Q491E;A159T、T411K、A443L、H468A、Q491K;A159T、T411K、A443L、H468A、Q491R;A159T、T411K、A443L、H468A、Q491E;A159T、T411K、A443L、H468K、Q491K;A159T、T411K、A443L、H468K、Q491R;A159T、T411K、A443L、H468K、Q491E;A159T、T411K、A443L、H468G、Q491K;A159T、T411K、A443L、H468G、Q491R;A159T、T411K、A443L、H468G、Q491E;A159T、T411K、A443L、H468S、Q491K;A159T、T411K、A443L、H468S、Q491R;A159T、T411K、A443L、H468S、Q491E;A159T、T411K、A443F、H468R、Q491K;A159T、T411K、A443F、H468R、Q491R;A159T、T411K、A443F、H468R、Q491E;A159T、T411K、A443F、H468A、Q491K;A159T、T411K、A443F、H468A、Q491R;A159T、T411K、A443F、H468A、Q491E;A159T、T411K、A443F、H468K、Q491K;A159T、T411K、A443F、H468K、Q491R;A159T、T411K、A443F、H468K、Q491E;A159T、T411K、A443F、H468G、Q491K;A159T、T411K、A443F、H468G、Q491R;A159T、T411K、A443F、H468G、Q491E;A159T、T411K、A443F、H468S、Q491K;A159T、T411K、A443F、H468S、Q491R;A159T、T411K、A443F、H468S、Q491E;A159T、T411K、A443M、H468R、Q491K;A159T、T411K、A443M、H468R、Q491R;A159T、T411K、A443M、H468R、Q491E;A159T、T411K、A443M、H468A、Q491K;A159T、T411K、A443M、H468A、Q491R;A159T、T411K、A443M、H468A、Q491E;A159T、T411K、A443M、H468K、Q491K;A159T、T411K、A443M、H468K、Q491R;A159T、T411K、A443M、H468K、Q491E;A159T、T411K、A443M、H468G、Q491K;A159T、T411K、A443M、H468G、Q491R;A159T、T411K、A443M、H468G、Q491E;A159T、T411K、A443M、H468S、Q491K;A159T、T411K、A443M、H468S、Q491R;A159T、T411K、A443M、H468S、Q491E;A159T、T411K、A443Y、H468R、Q491K;A159T、T411K、A443Y、H468R、Q491R;A159T、T411K、A443Y、H468R、Q491E;A159T、T411K、A443Y、H468A、Q491K;A159T、T411K、A443Y、H468A、Q491R;A159T、T411K、A443Y、H468A、Q491E;A159T、T411K、A443Y、H468K、Q491K;A159T、T411K、A443Y、H468K、Q491R;A159T、T411K、A443Y、H468K、Q491E;A159T、T411K、A443Y、H468G、Q491K;A159T、T411K、A443Y、H468G、Q491R;A159T、T411K、A443Y、H468G、Q491E;A159T、T411K、A443Y、H468S、Q491K;A159T、T411K、A443Y、H468S、Q491R;A159T、T411K、A443Y、H468S、Q491E;A159T、T411K、A443V、H468R、Q491K;A159T、T411K、A443V、H468R、Q491R;A159T、T411K、A443V、H468R、Q491E;A159T、T411K、A443V、H468A、Q491K;A159T、T411K、A443V、H468A、Q491R;A159T、T411K、A443V、H468A、Q491E;A159T、T411K、A443V、H468K、Q491K;A159T、T411K、A443V、H468K、Q491R;A159T、T411K、A443V、H468K、Q491E;A159T、T411K、A443V、H468G、Q491K;A159T、T411K、A443V、H468G、Q491R;A159T、T411K、A443V、H468G、Q491E;A159T、T411K、A443V、H468S、Q491K;A159T、T411K、A443V、H468S、Q491R;A159T、T411K、A443V、H468S、Q491E;A159V、T411V、A443I、H468R、Q491K;A159V、T411V、A443I、H468R、Q491R;A159V、T411V、A443I、H468R、Q491E;A159V、T411V、A443I、H468A、Q491K;A159V、T411V、A443I、H468A、Q491R;A159V、T411V、A443I、H468A、Q491E;A159V、T411V、A443I、H468K、Q491K;A159V、T411V、A443I、H468K、Q491R;A159V、T411V、A443I、H468K、Q491E;A159V、T411V、A443I、H468G、Q491K;A159V、T411V、A443I、H468G、Q491R;A159V、T411V、A443I、H468G、Q491E;A159V、T411V、A443I、H468S、Q491K;A159V、T411V、A443I、H468S、Q491R;A159V、T411V、A443I、H468S、Q491E;A159V、T411V、A443L、H468R、Q491K;A159V、T411V、A443L、H468R、Q491R;A159V、T411V、A443L、H468R、Q491E;A159V、T411V、A443L、H468A、Q491K;A159V、T411V、A443L、H468A、Q491R;A159V、T411V、A443L、H468A、Q491E;A159V、T411V、A443L、H468K、Q491K;A159V、T411V、A443L、H468K、Q491R;A159V、T411V、A443L、H468K、Q491E;A159V、T411V、A443L、H468G、Q491K;A159V、T411V、A443L、H468G、Q491R;A159V、T411V、A443L、H468G、Q491E;A159V、T411V、A443L、H468S、Q491K;A159V、T411V、A443L、H468S、Q491R;A159V、T411V、A443L、H468S、Q491E;A159V、T411V、A443F、H468R、Q491K;A159V、T411V、A443F、H468R、Q491R;A159V、T411V、A443F、H468R、Q491E;A159V、T411V、A443F、H468A、Q491K;A159V、T411V、A443F、H468A、Q491R;A159V、T411V、A443F、H468A、Q491E;A159V、T411V、A443F、H468K、Q491K;A159V、T411V、A443F、H468K、Q491R;A159V、T411V、A443F、H468K、Q491E;A159V、T411V、A443F、H468G、Q491K;A159V、T411V、A443F、H468G、Q491R;A159V、T411V、A443F、H468G、Q491E;A159V、T411V、A443F、H468S、Q491K;A159V、T411V、A443F、H468S、Q491R;A159V、T411V、A443F、H468S、Q491E;A159V、T411V、A443M、H468R、Q491K;A159V、T411V、A443M、H468R、Q491R;A159V、T411V、A443M、H468R、Q491E;A159V、T411V、A443M、H468A、Q491K;A159V、T411V、A443M、H468A、Q491R;A159V、T411V、A443M、H468A、Q491E;A159V、T411V、A443M、H468K、Q491K;A159V、T411V、A443M、H468K、Q491R;A159V、T411V、A443M、H468K、Q491E;A159V、T411V、A443M、H468G、Q491K;A159V、T411V、A443M、H468G、Q491R;A159V、T411V、A443M、H468G、Q491E;A159V、T411V、A443M、H468S、Q491K;A159V、T411V、A443M、H468S、Q491R;A159V、T411V、A443M、H468S、Q491E;A159V、T411V、A443Y、H468R、Q491K;A159V、T411V、A443Y、H468R、Q491R;A159V、T411V、A443Y、H468R、Q491E;A159V、T411V、A443Y、H468A、Q491K;A159V、T411V、A443Y、H468A、Q491R;A159V、T411V、A443Y、H468A、Q491E;A159V、T411V、A443Y、H468K、Q491K;A159V、T411V、A443Y、H468K、Q491R;A159V、T411V、A443Y、H468K、Q491E;A159V、T411V、A443Y、H468G、Q491K;A159V、T411V、A443Y、H468G、Q491R;A159V、T411V、A443Y、H468G、Q491E;A159V、T411V、A443Y、H468S、Q491K;A159V、T411V、A443Y、H468S、Q491R;A159V、T411V、A443Y、H468S、Q491E;A159V、T411V、A443V、H468R、Q491K;A159V、T411V、A443V、H468R、Q491R;A159V、T411V、A443V、H468R、Q491E;A159V、T411V、A443V、H468A、Q491K;A159V、T411V、A443V、H468A、Q491R;A159V、T411V、A443V、H468A、Q491E;A159V、T411V、A443V、H468K、Q491K;A159V、T411V、A443V、H468K、Q491R;A159V、T411V、A443V、H468K、Q491E;A159V、T411V、A443V、H468G、Q491K;A159V、T411V、A443V、H468G、Q491R;A159V、T411V、A443V、H468G、Q491E;A159V、T411V、A443V、H468S、Q491K;A159V、T411V、A443V、H468S、Q491R;A159V、T411V、A443V、H468S、Q491E;A159V、T411S、A443I、H468R、Q491K;A159V、T411S、A443I、H468R、Q491R;A159V、T411S、A443I、H468R、Q491E;A159V、T411S、A443I、H468A、Q491K;A159V、T411S、A443I、H468A、Q491R;A159V、T411S、A443I、H468A、Q491E;A159V、T411S、A443I、H468K、Q491K;A159V、T411S、A443I、H468K、Q491R;A159V、T411S、A443I、H468K、Q491E;A159V、T411S、A443I、H468G、Q491K;A159V、T411S、A443I、H468G、Q491R;A159V、T411S、A443I、H468G、Q491E;A159V、T411S、A443I、H468S、Q491K;A159V、T411S、A443I、H468S、Q491R;A159V、T411S、A443I、H468S、Q491E;A159V、T411S、A443L、H468R、Q491K;A159V、T411S、A443L、H468R、Q491R;A159V、T411S、A443L、H468R、Q491E;A159V、T411S、A443L、H468A、Q491K;A159V、T411S、A443L、H468A、Q491R;A159V、T411S、A443L、H468A、Q491E;A159V、T411S、A443L、H468K、Q491K;A159V、T411S、A443L、H468K、Q491R;A159V、T411S、A443L、H468K、Q491E;A159V、T411S、A443L、H468G、Q491K;A159V、T411S、A443L、H468G、Q491R;A159V、T411S、A443L、H468G、Q491E;A159V、T411S、A443L、H468S、Q491K;A159V、T411S、A443L、H468S、Q491R;A159V、T411S、A443L、H468S、Q491E;A159V、T411S、A443F、H468R、Q491K;A159V、T411S、A443F、H468R、Q491R;A159V、T411S、A443F、H468R、Q491E;A159V、T411S、A443F、H468A、Q491K;A159V、T411S、A443F、H468A、Q491R;A159V、T411S、A443F、H468A、Q491E;A159V、T411S、A443F、H468K、Q491K;A159V、T411S、A443F、H468K、Q491R;A159V、T411S、A443F、H468K、Q491E;A159V、T411S、A443F、H468G、Q491K;A159V、T411S、A443F、H468G、Q491R;A159V、T411S、A443F、H468G、Q491E;A159V、T411S、A443F、H468S、Q491K;A159V、T411S、A443F、H468S、Q491R;A159V、T411S、A443F、H468S、Q491E;A159V、T411S、A443M、H468R、Q491K;A159V、T411S、A443M、H468R、Q491R;A159V、T411S、A443M、H468R、Q491E;A159V、T411S、A443M、H468A、Q491K;A159V、T411S、A443M、H468A、Q491R;A159V、T411S、A443M、H468A、Q491E;A159V、T411S、A443M、H468K、Q491K;A159V、T411S、A443M、H468K、Q491R;A159V、T411S、A443M、H468K、Q491E;A159V、T411S、A443M、H468G、Q491K;A159V、T411S、A443M、H468G、Q491R;A159V、T411S、A443M、H468G、Q491E;A159V、T411S、A443M、H468S、Q491K;A159V、T411S、A443M、H468S、Q491R;A159V、T411S、A443M、H468S、Q491E;A159V、T411S、A443Y、H468R、Q491K;A159V、T411S、A443Y、H468R、Q491R;A159V、T411S、A443Y、H468R、Q491E;A159V、T411S、A443Y、H468A、Q491K;A159V、T411S、A443Y、H468A、Q491R;A159V、T411S、A443Y、H468A、Q491E;A159V、T411S、A443Y、H468K、Q491K;A159V、T411S、A443Y、H468K、Q491R;A159V、T411S、A443Y、H468K、Q491E;A159V、T411S、A443Y、H468G、Q491K;A159V、T411S、A443Y、H468G、Q491R;A159V、T411S、A443Y、H468G、Q491E;A159V、T411S、A443Y、H468S、Q491K;A159V、T411S、A443Y、H468S、Q491R;A159V、T411S、A443Y、H468S、Q491E;A159V、T411S、A443V、H468R、Q491K;A159V、T411S、A443V、H468R、Q491R;A159V、T411S、A443V、H468R、Q491E;A159V、T411S、A443V、H468A、Q491K;A159V、T411S、A443V、H468A、Q491R;A159V、T411S、A443V、H468A、Q491E;A159V、T411S、A443V、H468K、Q491K;A159V、T411S、A443V、H468K、Q491R;A159V、T411S、A443V、H468K、Q491E;A159V、T411S、A443V、H468G、Q491K;A159V、T411S、A443V、H468G、Q491R;A159V、T411S、A443V、H468G、Q491E;A159V、T411S、A443V、H468S、Q491K;A159V、T411S、A443V、H468S、Q491R;A159V、T411S、A443V、H468S、Q491E;A159V、T411A、A443I、H468R、Q491K;A159V、T411A、A443I、H468R、Q491R;A159V、T411A、A443I、H468R、Q491E;A159V、T411A、A443I、H468A、Q491K;A159V、T411A、A443I、H468A、Q491R;A159V、T411A、A443I、H468A、Q491E;A159V、T411A、A443I、H468K、Q491K;A159V、T411A、A443I、H468K、Q491R;A159V、T411A、A443I、H468K、Q491E;A159V、T411A、A443I、H468G、Q491K;A159V、T411A、A443I、H468G、Q491R;A159V、T411A、A443I、H468G、Q491E;A159V、T411A、A443I、H468S、Q491K;A159V、T411A、A443I、H468S、Q491R;A159V、T411A、A443I、H468S、Q491E;A159V、T411A、A443L、H468R、Q491K;A159V、T411A、A443L、H468R、Q491R;A159V、T411A、A443L、H468R、Q491E;A159V、T411A、A443L、H468A、Q491K;A159V、T411A、A443L、H468A、Q491R;A159V、T411A、A443L、H468A、Q491E;A159V、T411A、A443L、H468K、Q491K;A159V、T411A、A443L、H468K、Q491R;A159V、T411A、A443L、H468K、Q491E;A159V、T411A、A443L、H468G、Q491K;A159V、T411A、A443L、H468G、Q491R;A159V、T411A、A443L、H468G、Q491E;A159V、T411A、A443L、H468S、Q491K;A159V、T411A、A443L、H468S、Q491R;A159V、T411A、A443L、H468S、Q491E;A159V、T411A、A443F、H468R、Q491K;A159V、T411A、A443F、H468R、Q491R;A159V、T411A、A443F、H468R、Q491E;A159V、T411A、A443F、H468A、Q491K;A159V、T411A、A443F、H468A、Q491R;A159V、T411A、A443F、H468A、Q491E;A159V、T411A、A443F、H468K、Q491K;A159V、T411A、A443F、H468K、Q491R;A159V、T411A、A443F、H468K、Q491E;A159V、T411A、A443F、H468G、Q491K;A159V、T411A、A443F、H468G、Q491R;A159V、T411A、A443F、H468G、Q491E;A159V、T411A、A443F、H468S、Q491K;A159V、T411A、A443F、H468S、Q491R;A159V、T411A、A443F、H468S、Q491E;A159V、T411A、A443M、H468R、Q491K;A159V、T411A、A443M、H468R、Q491R;A159V、T411A、A443M、H468R、Q491E;A159V、T411A、A443M、H468A、Q491K;A159V、T411A、A443M、H468A、Q491R;A159V、T411A、A443M、H468A、Q491E;A159V、T411A、A443M、H468K、Q491K;A159V、T411A、A443M、H468K、Q491R;A159V、T411A、A443M、H468K、Q491E;A159V、T411A、A443M、H468G、Q491K;A159V、T411A、A443M、H468G、Q491R;A159V、T411A、A443M、H468G、Q491E;A159V、T411A、A443M、H468S、Q491K;A159V、T411A、A443M、H468S、Q491R;A159V、T411A、A443M、H468S、Q491E;A159V、T411A、A443Y、H468R、Q491K;A159V、T411A、A443Y、H468R、Q491R;A159V、T411A、A443Y、H468R、Q491E;A159V、T411A、A443Y、H468A、Q491K;A159V、T411A、A443Y、H468A、Q491R;A159V、T411A、A443Y、H468A、Q491E;A159V、T411A、A443Y、H468K、Q491K;A159V、T411A、A443Y、H468K、Q491R;A159V、T411A、A443Y、H468K、Q491E;A159V、T411A、A443Y、H468G、Q491K;A159V、T411A、A443Y、H468G、Q491R;A159V、T411A、A443Y、H468G、Q491E;A159V、T411A、A443Y、H468S、Q491K;A159V、T411A、A443Y、H468S、Q491R;A159V、T411A、A443Y、H468S、Q491E;A159V、T411A、A443V、H468R、Q491K;A159V、T411A、A443V、H468R、Q491R;A159V、T411A、A443V、H468R、Q491E;A159V、T411A、A443V、H468A、Q491K;A159V、T411A、A443V、H468A、Q491R;A159V、T411A、A443V、H468A、Q491E;A159V、T411A、A443V、H468K、Q491K;A159V、T411A、A443V、H468K、Q491R;A159V、T411A、A443V、H468K、Q491E;A159V、T411A、A443V、H468G、Q491K;A159V、T411A、A443V、H468G、Q491R;A159V、T411A、A443V、H468G、Q491E;A159V、T411A、A443V、H468S、Q491K;A159V、T411A、A443V、H468S、Q491R;A159V、T411A、A443V、H468S、Q491E;A159V、T411Q、A443I、H468R、Q491K;A159V、T411Q、A443I、H468R、Q491R;A159V、T411Q、A443I、H468R、Q491E;A159V、T411Q、A443I、H468A、Q491K;A159V、T411Q、A443I、H468A、Q491R;A159V、T411Q、A443I、H468A、Q491E;A159V、T411Q、A443I、H468K、Q491K;A159V、T411Q、A443I、H468K、Q491R;A159V、T411Q、A443I、H468K、Q491E;A159V、T411Q、A443I、H468G、Q491K;A159V、T411Q、A443I、H468G、Q491R;A159V、T411Q、A443I、H468G、Q491E;A159V、T411Q、A443I、H468S、Q491K;A159V、T411Q、A443I、H468S、Q491R;A159V、T411Q、A443I、H468S、Q491E;A159V、T411Q、A443L、H468R、Q491K;A159V、T411Q、A443L、H468R、Q491R;A159V、T411Q、A443L、H468R、Q491E;A159V、T411Q、A443L、H468A、Q491K;A159V、T411Q、A443L、H468A、Q491R;A159V、T411Q、A443L、H468A、Q491E;A159V、T411Q、A443L、H468K、Q491K;A159V、T411Q、A443L、H468K、Q491R;A159V、T411Q、A443L、H468K、Q491E;A159V、T411Q、A443L、H468G、Q491K;A159V、T411Q、A443L、H468G、Q491R;A159V、T411Q、A443L、H468G、Q491E;A159V、T411Q、A443L、H468S、Q491K;A159V、T411Q、A443L、H468S、Q491R;A159V、T411Q、A443L、H468S、Q491E;A159V、T411Q、A443F、H468R、Q491K;A159V、T411Q、A443F、H468R、Q491R;A159V、T411Q、A443F、H468R、Q491E;A159V、T411Q、A443F、H468A、Q491K;A159V、T411Q、A443F、H468A、Q491R;A159V、T411Q、A443F、H468A、Q491E;A159V、T411Q、A443F、H468K、Q491K;A159V、T411Q、A443F、H468K、Q491R;A159V、T411Q、A443F、H468K、Q491E;A159V、T411Q、A443F、H468G、Q491K;A159V、T411Q、A443F、H468G、Q491R;A159V、T411Q、A443F、H468G、Q491E;A159V、T411Q、A443F、H468S、Q491K;A159V、T411Q、A443F、H468S、Q491R;A159V、T411Q、A443F、H468S、Q491E;A159V、T411Q、A443M、H468R、Q491K;A159V、T411Q、A443M、H468R、Q491R;A159V、T411Q、A443M、H468R、Q491E;A159V、T411Q、A443M、H468A、Q491K;A159V、T411Q、A443M、H468A、Q491R;A159V、T411Q、A443M、H468A、Q491E;A159V、T411Q、A443M、H468K、Q491K;A159V、T411Q、A443M、H468K、Q491R;A159V、T411Q、A443M、H468K、Q491E;A159V、T411Q、A443M、H468G、Q491K;A159V、T411Q、A443M、H468G、Q491R;A159V、T411Q、A443M、H468G、Q491E;A159V、T411Q、A443M、H468S、Q491K;A159V、T411Q、A443M、H468S、Q491R;A159V、T411Q、A443M、H468S、Q491E;A159V、T411Q、A443Y、H468R、Q491K;A159V、T411Q、A443Y、H468R、Q491R;A159V、T411Q、A443Y、H468R、Q491E;A159V、T411Q、A443Y、H468A、Q491K;A159V、T411Q、A443Y、H468A、Q491R;A159V、T411Q、A443Y、H468A、Q491E;A159V、T411Q、A443Y、H468K、Q491K;A159V、T411Q、A443Y、H468K、Q491R;A159V、T411Q、A443Y、H468K、Q491E;A159V、T411Q、A443Y、H468G、Q491K;A159V、T411Q、A443Y、H468G、Q491R;A159V、T411Q、A443Y、H468G、Q491E;A159V、T411Q、A443Y、H468S、Q491K;A159V、T411Q、A443Y、H468S、Q491R;A159V、T411Q、A443Y、H468S、Q491E;A159V、T411Q、A443V、H468R、Q491K;A159V、T411Q、A443V、H468R、Q491R;A159V、T411Q、A443V、H468R、Q491E;A159V、T411Q、A443V、H468A、Q491K;A159V、T411Q、A443V、H468A、Q491R;A159V、T411Q、A443V、H468A、Q491E;A159V、T411Q、A443V、H468K、Q491K;A159V、T411Q、A443V、H468K、Q491R;A159V、T411Q、A443V、H468K、Q491E;A159V、T411Q、A443V、H468G、Q491K;A159V、T411Q、A443V、H468G、Q491R;A159V、T411Q、A443V、H468G、Q491E;A159V、T411Q、A443V、H468S、Q491K;A159V、T411Q、A443V、H468S、Q491R;A159V、T411Q、A443V、H468S、Q491E;A159V、T411E、A443I、H468R、Q491K;A159V、T411E、A443I、H468R、Q491R;A159V、T411E、A443I、H468R、Q491E;A159V、T411E、A443I、H468A、Q491K;A159V、T411E、A443I、H468A、Q491R;A159V、T411E、A443I、H468A、Q491E;A159V、T411E、A443I、H468K、Q491K;A159V、T411E、A443I、H468K、Q491R;A159V、T411E、A443I、H468K、Q491E;A159V、T411E、A443I、H468G、Q491K;A159V、T411E、A443I、H468G、Q491R;A159V、T411E、A443I、H468G、Q491E;A159V、T411E、A443I、H468S、Q491K;A159V、T411E、A443I、H468S、Q491R;A159V、T411E、A443I、H468S、Q491E;A159V、T411E、A443L、H468R、Q491K;A159V、T411E、A443L、H468R、Q491R;A159V、T411E、A443L、H468R、Q491E;A159V、T411E、A443L、H468A、Q491K;A159V、T411E、A443L、H468A、Q491R;A159V、T411E、A443L、H468A、Q491E;A159V、T411E、A443L、H468K、Q491K;A159V、T411E、A443L、H468K、Q491R;A159V、T411E、A443L、H468K、Q491E;A159V、T411E、A443L、H468G、Q491K;A159V、T411E、A443L、H468G、Q491R;A159V、T411E、A443L、H468G、Q491E;A159V、T411E、A443L、H468S、Q491K;A159V、T411E、A443L、H468S、Q491R;A159V、T411E、A443L、H468S、Q491E;A159V、T411E、A443F、H468R、Q491K;A159V、T411E、A443F、H468R、Q491R;A159V、T411E、A443F、H468R、Q491E;A159V、T411E、A443F、H468A、Q491K;A159V、T411E、A443F、H468A、Q491R;A159V、T411E、A443F、H468A、Q491E;A159V、T411E、A443F、H468K、Q491K;A159V、T411E、A443F、H468K、Q491R;A159V、T411E、A443F、H468K、Q491E;A159V、T411E、A443F、H468G、Q491K;A159V、T411E、A443F、H468G、Q491R;A159V、T411E、A443F、H468G、Q491E;A159V、T411E、A443F、H468S、Q491K;A159V、T411E、A443F、H468S、Q491R;A159V、T411E、A443F、H468S、Q491E;A159V、T411E、A443M、H468R、Q491K;A159V、T411E、A443M、H468R、Q491R;A159V、T411E、A443M、H468R、Q491E;A159V、T411E、A443M、H468A、Q491K;A159V、T411E、A443M、H468A、Q491R;A159V、T411E、A443M、H468A、Q491E;A159V、T411E、A443M、H468K、Q491K;A159V、T411E、A443M、H468K、Q491R;A159V、T411E、A443M、H468K、Q491E;A159V、T411E、A443M、H468G、Q491K;A159V、T411E、A443M、H468G、Q491R;A159V、T411E、A443M、H468G、Q491E;A159V、T411E、A443M、H468S、Q491K;A159V、T411E、A443M、H468S、Q491R;A159V、T411E、A443M、H468S、Q491E;A159V、T411E、A443Y、H468R、Q491K;A159V、T411E、A443Y、H468R、Q491R;A159V、T411E、A443Y、H468R、Q491E;A159V、T411E、A443Y、H468A、Q491K;A159V、T411E、A443Y、H468A、Q491R;A159V、T411E、A443Y、H468A、Q491E;A159V、T411E、A443Y、H468K、Q491K;A159V、T411E、A443Y、H468K、Q491R;A159V、T411E、A443Y、H468K、Q491E;A159V、T411E、A443Y、H468G、Q491K;A159V、T411E、A443Y、H468G、Q491R;A159V、T411E、A443Y、H468G、Q491E;A159V、T411E、A443Y、H468S、Q491K;A159V、T411E、A443Y、H468S、Q491R;A159V、T411E、A443Y、H468S、Q491E;A159V、T411E、A443V、H468R、Q491K;A159V、T411E、A443V、H468R、Q491R;A159V、T411E、A443V、H468R、Q491E;A159V、T411E、A443V、H468A、Q491K;A159V、T411E、A443V、H468A、Q491R;A159V、T411E、A443V、H468A、Q491E;A159V、T411E、A443V、H468K、Q491K;A159V、T411E、A443V、H468K、Q491R;A159V、T411E、A443V、H468K、Q491E;A159V、T411E、A443V、H468G、Q491K;A159V、T411E、A443V、H468G、Q491R;A159V、T411E、A443V、H468G、Q491E;A159V、T411E、A443V、H468S、Q491K;A159V、T411E、A443V、H468S、Q491R;A159V、T411E、A443V、H468S、Q491E;A159V、T411K、A443I、H468R、Q491K;A159V、T411K、A443I、H468R、Q491R;A159V、T411K、A443I、H468R、Q491E;A159V、T411K、A443I、H468A、Q491K;A159V、T411K、A443I、H468A、Q491R;A159V、T411K、A443I、H468A、Q491E;A159V、T411K、A443I、H468K、Q491K;A159V、T411K、A443I、H468K、Q491R;A159V、T411K、A443I、H468K、Q491E;A159V、T411K、A443I、H468G、Q491K;A159V、T411K、A443I、H468G、Q491R;A159V、T411K、A443I、H468G、Q491E;A159V、T411K、A443I、H468S、Q491K;A159V、T411K、A443I、H468S、Q491R;A159V、T411K、A443I、H468S、Q491E;A159V、T411K、A443L、H468R、Q491K;A159V、T411K、A443L、H468R、Q491R;A159V、T411K、A443L、H468R、Q491E;A159V、T411K、A443L、H468A、Q491K;A159V、T411K、A443L、H468A、Q491R;A159V、T411K、A443L、H468A、Q491E;A159V、T411K、A443L、H468K、Q491K;A159V、T411K、A443L、H468K、Q491R;A159V、T411K、A443L、H468K、Q491E;A159V、T411K、A443L、H468G、Q491K;A159V、T411K、A443L、H468G、Q491R;A159V、T411K、A443L、H468G、Q491E;A159V、T411K、A443L、H468S、Q491K;A159V、T411K、A443L、H468S、Q491R;A159V、T411K、A443L、H468S、Q491E;A159V、T411K、A443F、H468R、Q491K;A159V、T411K、A443F、H468R、Q491R;A159V、T411K、A443F、H468R、Q491E;A159V、T411K、A443F、H468A、Q491K;A159V、T411K、A443F、H468A、Q491R;A159V、T411K、A443F、H468A、Q491E;A159V、T411K、A443F、H468K、Q491K;A159V、T411K、A443F、H468K、Q491R;A159V、T411K、A443F、H468K、Q491E;A159V、T411K、A443F、H468G、Q491K;A159V、T411K、A443F、H468G、Q491R;A159V、T411K、A443F、H468G、Q491E;A159V、T411K、A443F、H468S、Q491K;A159V、T411K、A443F、H468S、Q491R;A159V、T411K、A443F、H468S、Q491E;A159V、T411K、A443M、H468R、Q491K;A159V、T411K、A443M、H468R、Q491R;A159V、T411K、A443M、H468R、Q491E;A159V、T411K、A443M、H468A、Q491K;A159V、T411K、A443M、H468A、Q491R;A159V、T411K、A443M、H468A、Q491E;A159V、T411K、A443M、H468K、Q491K;A159V、T411K、A443M、H468K、Q491R;A159V、T411K、A443M、H468K、Q491E;A159V、T411K、A443M、H468G、Q491K;A159V、T411K、A443M、H468G、Q491R;A159V、T411K、A443M、H468G、Q491E;A159V、T411K、A443M、H468S、Q491K;A159V、T411K、A443M、H468S、Q491R;A159V、T411K、A443M、H468S、Q491E;A159V、T411K、A443Y、H468R、Q491K;A159V、T411K、A443Y、H468R、Q491R;A159V、T411K、A443Y、H468R、Q491E;A159V、T411K、A443Y、H468A、Q491K;A159V、T411K、A443Y、H468A、Q491R;A159V、T411K、A443Y、H468A、Q491E;A159V、T411K、A443Y、H468K、Q491K;A159V、T411K、A443Y、H468K、Q491R;A159V、T411K、A443Y、H468K、Q491E;A159V、T411K、A443Y、H468G、Q491K;A159V、T411K、A443Y、H468G、Q491R;A159V、T411K、A443Y、H468G、Q491E;A159V、T411K、A443Y、H468S、Q491K;A159V、T411K、A443Y、H468S、Q491R;A159V、T411K、A443Y、H468S、Q491E;A159V、T411K、A443V、H468R、Q491K;A159V、T411K、A443V、H468R、Q491R;A159V、T411K、A443V、H468R、Q491E;A159V、T411K、A443V、H468A、Q491K;A159V、T411K、A443V、H468A、Q491R;A159V、T411K、A443V、H468A、Q491E;A159V、T411K、A443V、H468K、Q491K;A159V、T411K、A443V、H468K、Q491R;A159V、T411K、A443V、H468K、Q491E;A159V、T411K、A443V、H468G、Q491K;A159V、T411K、A443V、H468G、Q491R;A159V、T411K、A443V、H468G、Q491E;A159V、T411K、A443V、H468S、Q491K;A159V、T411K、A443V、H468S、Q491R;A159V、T411K、A443V、H468S、Q491E;A159S、T411V、A443I、H468R、Q491K;A159S、T411V、A443I、H468R、Q491R;A159S、T411V、A443I、H468R、Q491E;A159S、T411V、A443I、H468A、Q491K;A159S、T411V、A443I、H468A、Q491R;A159S、T411V、A443I、H468A、Q491E;A159S、T411V、A443I、H468K、Q491K;A159S、T411V、A443I、H468K、Q491R;A159S、T411V、A443I、H468K、Q491E;A159S、T411V、A443I、H468G、Q491K;A159S、T411V、A443I、H468G、Q491R;A159S、T411V、A443I、H468G、Q491E;A159S、T411V、A443I、H468S、Q491K;A159S、T411V、A443I、H468S、Q491R;A159S、T411V、A443I、H468S、Q491E;A159S、T411V、A443L、H468R、Q491K;A159S、T411V、A443L、H468R、Q491R;A159S、T411V、A443L、H468R、Q491E;A159S、T411V、A443L、H468A、Q491K;A159S、T411V、A443L、H468A、Q491R;A159S、T411V、A443L、H468A、Q491E;A159S、T411V、A443L、H468K、Q491K;A159S、T411V、A443L、H468K、Q491R;A159S、T411V、A443L、H468K、Q491E;A159S、T411V、A443L、H468G、Q491K;A159S、T411V、A443L、H468G、Q491R;A159S、T411V、A443L、H468G、Q491E;A159S、T411V、A443L、H468S、Q491K;A159S、T411V、A443L、H468S、Q491R;A159S、T411V、A443L、H468S、Q491E;A159S、T411V、A443F、H468R、Q491K;A159S、T411V、A443F、H468R、Q491R;A159S、T411V、A443F、H468R、Q491E;A159S、T411V、A443F、H468A、Q491K;A159S、T411V、A443F、H468A、Q491R;A159S、T411V、A443F、H468A、Q491E;A159S、T411V、A443F、H468K、Q491K;A159S、T411V、A443F、H468K、Q491R;A159S、T411V、A443F、H468K、Q491E;A159S、T411V、A443F、H468G、Q491K;A159S、T411V、A443F、H468G、Q491R;A159S、T411V、A443F、H468G、Q491E;A159S、T411V、A443F、H468S、Q491K;A159S、T411V、A443F、H468S、Q491R;A159S、T411V、A443F、H468S、Q491E;A159S、T411V、A443M、H468R、Q491K;A159S、T411V、A443M、H468R、Q491R;A159S、T411V、A443M、H468R、Q491E;A159S、T411V、A443M、H468A、Q491K;A159S、T411V、A443M、H468A、Q491R;A159S、T411V、A443M、H468A、Q491E;A159S、T411V、A443M、H468K、Q491K;A159S、T411V、A443M、H468K、Q491R;A159S、T411V、A443M、H468K、Q491E;A159S、T411V、A443M、H468G、Q491K;A159S、T411V、A443M、H468G、Q491R;A159S、T411V、A443M、H468G、Q491E;A159S、T411V、A443M、H468S、Q491K;A159S、T411V、A443M、H468S、Q491R;A159S、T411V、A443M、H468S、Q491E;A159S、T411V、A443Y、H468R、Q491K;A159S、T411V、A443Y、H468R、Q491R;A159S、T411V、A443Y、H468R、Q491E;A159S、T411V、A443Y、H468A、Q491K;A159S、T411V、A443Y、H468A、Q491R;A159S、T411V、A443Y、H468A、Q491E;A159S、T411V、A443Y、H468K、Q491K;A159S、T411V、A443Y、H468K、Q491R;A159S、T411V、A443Y、H468K、Q491E;A159S、T411V、A443Y、H468G、Q491K;A159S、T411V、A443Y、H468G、Q491R;A159S、T411V、A443Y、H468G、Q491E;A159S、T411V、A443Y、H468S、Q491K;A159S、T411V、A443Y、H468S、Q491R;A159S、T411V、A443Y、H468S、Q491E;A159S、T411V、A443V、H468R、Q491K;A159S、T411V、A443V、H468R、Q491R;A159S、T411V、A443V、H468R、Q491E;A159S、T411V、A443V、H468A、Q491K;A159S、T411V、A443V、H468A、Q491R;A159S、T411V、A443V、H468A、Q491E;A159S、T411V、A443V、H468K、Q491K;A159S、T411V、A443V、H468K、Q491R;A159S、T411V、A443V、H468K、Q491E;A159S、T411V、A443V、H468G、Q491K;A159S、T411V、A443V、H468G、Q491R;A159S、T411V、A443V、H468G、Q491E;A159S、T411V、A443V、H468S、Q491K;A159S、T411V、A443V、H468S、Q491R;A159S、T411V、A443V、H468S、Q491E;A159S、T411S、A443I、H468R、Q491K;A159S、T411S、A443I、H468R、Q491R;A159S、T411S、A443I、H468R、Q491E;A159S、T411S、A443I、H468A、Q491K;A159S、T411S、A443I、H468A、Q491R;A159S、T411S、A443I、H468A、Q491E;A159S、T411S、A443I、H468K、Q491K;A159S、T411S、A443I、H468K、Q491R;A159S、T411S、A443I、H468K、Q491E;A159S、T411S、A443I、H468G、Q491K;A159S、T411S、A443I、H468G、Q491R;A159S、T411S、A443I、H468G、Q491E;A159S、T411S、A443I、H468S、Q491K;A159S、T411S、A443I、H468S、Q491R;A159S、T411S、A443I、H468S、Q491E;A159S、T411S、A443L、H468R、Q491K;A159S、T411S、A443L、H468R、Q491R;A159S、T411S、A443L、H468R、Q491E;A159S、T411S、A443L、H468A、Q491K;A159S、T411S、A443L、H468A、Q491R;A159S、T411S、A443L、H468A、Q491E;A159S、T411S、A443L、H468K、Q491K;A159S、T411S、A443L、H468K、Q491R;A159S、T411S、A443L、H468K、Q491E;A159S、T411S、A443L、H468G、Q491K;A159S、T411S、A443L、H468G、Q491R;A159S、T411S、A443L、H468G、Q491E;A159S、T411S、A443L、H468S、Q491K;A159S、T411S、A443L、H468S、Q491R;A159S、T411S、A443L、H468S、Q491E;A159S、T411S、A443F、H468R、Q491K;A159S、T411S、A443F、H468R、Q491R;A159S、T411S、A443F、H468R、Q491E;A159S、T411S、A443F、H468A、Q491K;A159S、T411S、A443F、H468A、Q491R;A159S、T411S、A443F、H468A、Q491E;A159S、T411S、A443F、H468K、Q491K;A159S、T411S、A443F、H468K、Q491R;A159S、T411S、A443F、H468K、Q491E;A159S、T411S、A443F、H468G、Q491K;A159S、T411S、A443F、H468G、Q491R;A159S、T411S、A443F、H468G、Q491E;A159S、T411S、A443F、H468S、Q491K;A159S、T411S、A443F、H468S、Q491R;A159S、T411S、A443F、H468S、Q491E;A159S、T411S、A443M、H468R、Q491K;A159S、T411S、A443M、H468R、Q491R;A159S、T411S、A443M、H468R、Q491E;A159S、T411S、A443M、H468A、Q491K;A159S、T411S、A443M、H468A、Q491R;A159S、T411S、A443M、H468A、Q491E;A159S、T411S、A443M、H468K、Q491K;A159S、T411S、A443M、H468K、Q491R;A159S、T411S、A443M、H468K、Q491E;A159S、T411S、A443M、H468G、Q491K;A159S、T411S、A443M、H468G、Q491R;A159S、T411S、A443M、H468G、Q491E;A159S、T411S、A443M、H468S、Q491K;A159S、T411S、A443M、H468S、Q491R;A159S、T411S、A443M、H468S、Q491E;A159S、T411S、A443Y、H468R、Q491K;A159S、T411S、A443Y、H468R、Q491R;A159S、T411S、A443Y、H468R、Q491E;A159S、T411S、A443Y、H468A、Q491K;A159S、T411S、A443Y、H468A、Q491R;A159S、T411S、A443Y、H468A、Q491E;A159S、T411S、A443Y、H468K、Q491K;A159S、T411S、A443Y、H468K、Q491R;A159S、T411S、A443Y、H468K、Q491E;A159S、T411S、A443Y、H468G、Q491K;A159S、T411S、A443Y、H468G、Q491R;A159S、T411S、A443Y、H468G、Q491E;A159S、T411S、A443Y、H468S、Q491K;A159S、T411S、A443Y、H468S、Q491R;A159S、T411S、A443Y、H468S、Q491E;A159S、T411S、A443V、H468R、Q491K;A159S、T411S、A443V、H468R、Q491R;A159S、T411S、A443V、H468R、Q491E;A159S、T411S、A443V、H468A、Q491K;A159S、T411S、A443V、H468A、Q491R;A159S、T411S、A443V、H468A、Q491E;A159S、T411S、A443V、H468K、Q491K;A159S、T411S、A443V、H468K、Q491R;A159S、T411S、A443V、H468K、Q491E;A159S、T411S、A443V、H468G、Q491K;A159S、T411S、A443V、H468G、Q491R;A159S、T411S、A443V、H468G、Q491E;A159S、T411S、A443V、H468S、Q491K;A159S、T411S、A443V、H468S、Q491R;A159S、T411S、A443V、H468S、Q491E;A159S、T411A、A443I、H468R、Q491K;A159S、T411A、A443I、H468R、Q491R;A159S、T411A、A443I、H468R、Q491E;A159S、T411A、A443I、H468A、Q491K;A159S、T411A、A443I、H468A、Q491R;A159S、T411A、A443I、H468A、Q491E;A159S、T411A、A443I、H468K、Q491K;A159S、T411A、A443I、H468K、Q491R;A159S、T411A、A443I、H468K、Q491E;A159S、T411A、A443I、H468G、Q491K;A159S、T411A、A443I、H468G、Q491R;A159S、T411A、A443I、H468G、Q491E;A159S、T411A、A443I、H468S、Q491K;A159S、T411A、A443I、H468S、Q491R;A159S、T411A、A443I、H468S、Q491E;A159S、T411A、A443L、H468R、Q491K;A159S、T411A、A443L、H468R、Q491R;A159S、T411A、A443L、H468R、Q491E;A159S、T411A、A443L、H468A、Q491K;A159S、T411A、A443L、H468A、Q491R;A159S、T411A、A443L、H468A、Q491E;A159S、T411A、A443L、H468K、Q491K;A159S、T411A、A443L、H468K、Q491R;A159S、T411A、A443L、H468K、Q491E;A159S、T411A、A443L、H468G、Q491K;A159S、T411A、A443L、H468G、Q491R;A159S、T411A、A443L、H468G、Q491E;A159S、T411A、A443L、H468S、Q491K;A159S、T411A、A443L、H468S、Q491R;A159S、T411A、A443L、H468S、Q491E;A159S、T411A、A443F、H468R、Q491K;A159S、T411A、A443F、H468R、Q491R;A159S、T411A、A443F、H468R、Q491E;A159S、T411A、A443F、H468A、Q491K;A159S、T411A、A443F、H468A、Q491R;A159S、T411A、A443F、H468A、Q491E;A159S、T411A、A443F、H468K、Q491K;A159S、T411A、A443F、H468K、Q491R;A159S、T411A、A443F、H468K、Q491E;A159S、T411A、A443F、H468G、Q491K;A159S、T411A、A443F、H468G、Q491R;A159S、T411A、A443F、H468G、Q491E;A159S、T411A、A443F、H468S、Q491K;A159S、T411A、A443F、H468S、Q491R;A159S、T411A、A443F、H468S、Q491E;A159S、T411A、A443M、H468R、Q491K;A159S、T411A、A443M、H468R、Q491R;A159S、T411A、A443M、H468R、Q491E;A159S、T411A、A443M、H468A、Q491K;A159S、T411A、A443M、H468A、Q491R;A159S、T411A、A443M、H468A、Q491E;A159S、T411A、A443M、H468K、Q491K;A159S、T411A、A443M、H468K、Q491R;A159S、T411A、A443M、H468K、Q491E;A159S、T411A、A443M、H468G、Q491K;A159S、T411A、A443M、H468G、Q491R;A159S、T411A、A443M、H468G、Q491E;A159S、T411A、A443M、H468S、Q491K;A159S、T411A、A443M、H468S、Q491R;A159S、T411A、A443M、H468S、Q491E;A159S、T411A、A443Y、H468R、Q491K;A159S、T411A、A443Y、H468R、Q491R;A159S、T411A、A443Y、H468R、Q491E;A159S、T411A、A443Y、H468A、Q491K;A159S、T411A、A443Y、H468A、Q491R;A159S、T411A、A443Y、H468A、Q491E;A159S、T411A、A443Y、H468K、Q491K;A159S、T411A、A443Y、H468K、Q491R;A159S、T411A、A443Y、H468K、Q491E;A159S、T411A、A443Y、H468G、Q491K;A159S、T411A、A443Y、H468G、Q491R;A159S、T411A、A443Y、H468G、Q491E;A159S、T411A、A443Y、H468S、Q491K;A159S、T411A、A443Y、H468S、Q491R;A159S、T411A、A443Y、H468S、Q491E;A159S、T411A、A443V、H468R、Q491K;A159S、T411A、A443V、H468R、Q491R;A159S、T411A、A443V、H468R、Q491E;A159S、T411A、A443V、H468A、Q491K;A159S、T411A、A443V、H468A、Q491R;A159S、T411A、A443V、H468A、Q491E;A159S、T411A、A443V、H468K、Q491K;A159S、T411A、A443V、H468K、Q491R;A159S、T411A、A443V、H468K、Q491E;A159S、T411A、A443V、H468G、Q491K;A159S、T411A、A443V、H468G、Q491R;A159S、T411A、A443V、H468G、Q491E;A159S、T411A、A443V、H468S、Q491K;A159S、T411A、A443V、H468S、Q491R;A159S、T411A、A443V、H468S、Q491E;A159S、T411Q、A443I、H468R、Q491K;A159S、T411Q、A443I、H468R、Q491R;A159S、T411Q、A443I、H468R、Q491E;A159S、T411Q、A443I、H468A、Q491K;A159S、T411Q、A443I、H468A、Q491R;A159S、T411Q、A443I、H468A、Q491E;A159S、T411Q、A443I、H468K、Q491K;A159S、T411Q、A443I、H468K、Q491R;A159S、T411Q、A443I、H468K、Q491E;A159S、T411Q、A443I、H468G、Q491K;A159S、T411Q、A443I、H468G、Q491R;A159S、T411Q、A443I、H468G、Q491E;A159S、T411Q、A443I、H468S、Q491K;A159S、T411Q、A443I、H468S、Q491R;A159S、T411Q、A443I、H468S、Q491E;A159S、T411Q、A443L、H468R、Q491K;A159S、T411Q、A443L、H468R、Q491R;A159S、T411Q、A443L、H468R、Q491E;A159S、T411Q、A443L、H468A、Q491K;A159S、T411Q、A443L、H468A、Q491R;A159S、T411Q、A443L、H468A、Q491E;A159S、T411Q、A443L、H468K、Q491K;A159S、T411Q、A443L、H468K、Q491R;A159S、T411Q、A443L、H468K、Q491E;A159S、T411Q、A443L、H468G、Q491K;A159S、T411Q、A443L、H468G、Q491R;A159S、T411Q、A443L、H468G、Q491E;A159S、T411Q、A443L、H468S、Q491K;A159S、T411Q、A443L、H468S、Q491R;A159S、T411Q、A443L、H468S、Q491E;A159S、T411Q、A443F、H468R、Q491K;A159S、T411Q、A443F、H468R、Q491R;A159S、T411Q、A443F、H468R、Q491E;A159S、T411Q、A443F、H468A、Q491K;A159S、T411Q、A443F、H468A、Q491R;A159S、T411Q、A443F、H468A、Q491E;A159S、T411Q、A443F、H468K、Q491K;A159S、T411Q、A443F、H468K、Q491R;A159S、T411Q、A443F、H468K、Q491E;A159S、T411Q、A443F、H468G、Q491K;A159S、T411Q、A443F、H468G、Q491R;A159S、T411Q、A443F、H468G、Q491E;A159S、T411Q、A443F、H468S、Q491K;A159S、T411Q、A443F、H468S、Q491R;A159S、T411Q、A443F、H468S、Q491E;A159S、T411Q、A443M、H468R、Q491K;A159S、T411Q、A443M、H468R、Q491R;A159S、T411Q、A443M、H468R、Q491E;A159S、T411Q、A443M、H468A、Q491K;A159S、T411Q、A443M、H468A、Q491R;A159S、T411Q、A443M、H468A、Q491E;A159S、T411Q、A443M、H468K、Q491K;A159S、T411Q、A443M、H468K、Q491R;A159S、T411Q、A443M、H468K、Q491E;A159S、T411Q、A443M、H468G、Q491K;A159S、T411Q、A443M、H468G、Q491R;A159S、T411Q、A443M、H468G、Q491E;A159S、T411Q、A443M、H468S、Q491K;A159S、T411Q、A443M、H468S、Q491R;A159S、T411Q、A443M、H468S、Q491E;A159S、T411Q、A443Y、H468R、Q491K;A159S、T411Q、A443Y、H468R、Q491R;A159S、T411Q、A443Y、H468R、Q491E;A159S、T411Q、A443Y、H468A、Q491K;A159S、T411Q、A443Y、H468A、Q491R;A159S、T411Q、A443Y、H468A、Q491E;A159S、T411Q、A443Y、H468K、Q491K;A159S、T411Q、A443Y、H468K、Q491R;A159S、T411Q、A443Y、H468K、Q491E;A159S、T411Q、A443Y、H468G、Q491K;A159S、T411Q、A443Y、H468G、Q491R;A159S、T411Q、A443Y、H468G、Q491E;A159S、T411Q、A443Y、H468S、Q491K;A159S、T411Q、A443Y、H468S、Q491R;A159S、T411Q、A443Y、H468S、Q491E;A159S、T411Q、A443V、H468R、Q491K;A159S、T411Q、A443V、H468R、Q491R;A159S、T411Q、A443V、H468R、Q491E;A159S、T411Q、A443V、H468A、Q491K;A159S、T411Q、A443V、H468A、Q491R;A159S、T411Q、A443V、H468A、Q491E;A159S、T411Q、A443V、H468K、Q491K;A159S、T411Q、A443V、H468K、Q491R;A159S、T411Q、A443V、H468K、Q491E;A159S、T411Q、A443V、H468G、Q491K;A159S、T411Q、A443V、H468G、Q491R;A159S、T411Q、A443V、H468G、Q491E;A159S、T411Q、A443V、H468S、Q491K;A159S、T411Q、A443V、H468S、Q491R;A159S、T411Q、A443V、H468S、Q491E;A159S、T411E、A443I、H468R、Q491K;A159S、T411E、A443I、H468R、Q491R;A159S、T411E、A443I、H468R、Q491E;A159S、T411E、A443I、H468A、Q491K;A159S、T411E、A443I、H468A、Q491R;A159S、T411E、A443I、H468A、Q491E;A159S、T411E、A443I、H468K、Q491K;A159S、T411E、A443I、H468K、Q491R;A159S、T411E、A443I、H468K、Q491E;A159S、T411E、A443I、H468G、Q491K;A159S、T411E、A443I、H468G、Q491R;A159S、T411E、A443I、H468G、Q491E;A159S、T411E、A443I、H468S、Q491K;A159S、T411E、A443I、H468S、Q491R;A159S、T411E、A443I、H468S、Q491E;A159S、T411E、A443L、H468R、Q491K;A159S、T411E、A443L、H468R、Q491R;A159S、T411E、A443L、H468R、Q491E;A159S、T411E、A443L、H468A、Q491K;A159S、T411E、A443L、H468A、Q491R;A159S、T411E、A443L、H468A、Q491E;A159S、T411E、A443L、H468K、Q491K;A159S、T411E、A443L、H468K、Q491R;A159S、T411E、A443L、H468K、Q491E;A159S、T411E、A443L、H468G、Q491K;A159S、T411E、A443L、H468G、Q491R;A159S、T411E、A443L、H468G、Q491E;A159S、T411E、A443L、H468S、Q491K;A159S、T411E、A443L、H468S、Q491R;A159S、T411E、A443L、H468S、Q491E;A159S、T411E、A443F、H468R、Q491K;A159S、T411E、A443F、H468R、Q491R;A159S、T411E、A443F、H468R、Q491E;A159S、T411E、A443F、H468A、Q491K;A159S、T411E、A443F、H468A、Q491R;A159S、T411E、A443F、H468A、Q491E;A159S、T411E、A443F、H468K、Q491K;A159S、T411E、A443F、H468K、Q491R;A159S、T411E、A443F、H468K、Q491E;A159S、T411E、A443F、H468G、Q491K;A159S、T411E、A443F、H468G、Q491R;A159S、T411E、A443F、H468G、Q491E;A159S、T411E、A443F、H468S、Q491K;A159S、T411E、A443F、H468S、Q491R;A159S、T411E、A443F、H468S、Q491E;A159S、T411E、A443M、H468R、Q491K;A159S、T411E、A443M、H468R、Q491R;A159S、T411E、A443M、H468R、Q491E;A159S、T411E、A443M、H468A、Q491K;A159S、T411E、A443M、H468A、Q491R;A159S、T411E、A443M、H468A、Q491E;A159S、T411E、A443M、H468K、Q491K;A159S、T411E、A443M、H468K、Q491R;A159S、T411E、A443M、H468K、Q491E;A159S、T411E、A443M、H468G、Q491K;A159S、T411E、A443M、H468G、Q491R;A159S、T411E、A443M、H468G、Q491E;A159S、T411E、A443M、H468S、Q491K;A159S、T411E、A443M、H468S、Q491R;A159S、T411E、A443M、H468S、Q491E;A159S、T411E、A443Y、H468R、Q491K;A159S、T411E、A443Y、H468R、Q491R;A159S、T411E、A443Y、H468R、Q491E;A159S、T411E、A443Y、H468A、Q491K;A159S、T411E、A443Y、H468A、Q491R;A159S、T411E、A443Y、H468A、Q491E;A159S、T411E、A443Y、H468K、Q491K;A159S、T411E、A443Y、H468K、Q491R;A159S、T411E、A443Y、H468K、Q491E;A159S、T411E、A443Y、H468G、Q491K;A159S、T411E、A443Y、H468G、Q491R;A159S、T411E、A443Y、H468G、Q491E;A159S、T411E、A443Y、H468S、Q491K;A159S、T411E、A443Y、H468S、Q491R;A159S、T411E、A443Y、H468S、Q491E;A159S、T411E、A443V、H468R、Q491K;A159S、T411E、A443V、H468R、Q491R;A159S、T411E、A443V、H468R、Q491E;A159S、T411E、A443V、H468A、Q491K;A159S、T411E、A443V、H468A、Q491R;A159S、T411E、A443V、H468A、Q491E;A159S、T411E、A443V、H468K、Q491K;A159S、T411E、A443V、H468K、Q491R;A159S、T411E、A443V、H468K、Q491E;A159S、T411E、A443V、H468G、Q491K;A159S、T411E、A443V、H468G、Q491R;A159S、T411E、A443V、H468G、Q491E;A159S、T411E、A443V、H468S、Q491K;A159S、T411E、A443V、H468S、Q491R;A159S、T411E、A443V、H468S、Q491E;A159S、T411K、A443I、H468R、Q491K;A159S、T411K、A443I、H468R、Q491R;A159S、T411K、A443I、H468R、Q491E;A159S、T411K、A443I、H468A、Q491K;A159S、T411K、A443I、H468A、Q491R;A159S、T411K、A443I、H468A、Q491E;A159S、T411K、A443I、H468K、Q491K;A159S、T411K、A443I、H468K、Q491R;A159S、T411K、A443I、H468K、Q491E;A159S、T411K、A443I、H468G、Q491K;A159S、T411K、A443I、H468G、Q491R;A159S、T411K、A443I、H468G、Q491E;A159S、T411K、A443I、H468S、Q491K;A159S、T411K、A443I、H468S、Q491R;A159S、T411K、A443I、H468S、Q491E;A159S、T411K、A443L、H468R、Q491K;A159S、T411K、A443L、H468R、Q491R;A159S、T411K、A443L、H468R、Q491E;A159S、T411K、A443L、H468A、Q491K;A159S、T411K、A443L、H468A、Q491R;A159S、T411K、A443L、H468A、Q491E;A159S、T411K、A443L、H468K、Q491K;A159S、T411K、A443L、H468K、Q491R;A159S、T411K、A443L、H468K、Q491E;A159S、T411K、A443L、H468G、Q491K;A159S、T411K、A443L、H468G、Q491R;A159S、T411K、A443L、H468G、Q491E;A159S、T411K、A443L、H468S、Q491K;A159S、T411K、A443L、H468S、Q491R;A159S、T411K、A443L、H468S、Q491E;A159S、T411K、A443F、H468R、Q491K;A159S、T411K、A443F、H468R、Q491R;A159S、T411K、A443F、H468R、Q491E;A159S、T411K、A443F、H468A、Q491K;A159S、T411K、A443F、H468A、Q491R;A159S、T411K、A443F、H468A、Q491E;A159S、T411K、A443F、H468K、Q491K;A159S、T411K、A443F、H468K、Q491R;A159S、T411K、A443F、H468K、Q491E;A159S、T411K、A443F、H468G、Q491K;A159S、T411K、A443F、H468G、Q491R;A159S、T411K、A443F、H468G、Q491E;A159S、T411K、A443F、H468S、Q491K;A159S、T411K、A443F、H468S、Q491R;A159S、T411K、A443F、H468S、Q491E;A159S、T411K、A443M、H468R、Q491K;A159S、T411K、A443M、H468R、Q491R;A159S、T411K、A443M、H468R、Q491E;A159S、T411K、A443M、H468A、Q491K;A159S、T411K、A443M、H468A、Q491R;A159S、T411K、A443M、H468A、Q491E;A159S、T411K、A443M、H468K、Q491K;A159S、T411K、A443M、H468K、Q491R;A159S、T411K、A443M、H468K、Q491E;A159S、T411K、A443M、H468G、Q491K;A159S、T411K、A443M、H468G、Q491R;A159S、T411K、A443M、H468G、Q491E;A159S、T411K、A443M、H468S、Q491K;A159S, T411K, A443M, H468S, Q491R; A159S, T411K, A443M, H468S, Q491E; A159S, T411K, A443Y, H468R, Q491K; A159S, T411K, A443Y, H468R, Q491R; A159S, T411K, A443Y, H468R, Q491E; A159S, T411K, A443Y, H468A, Q491K; A159S, T411K, A443Y, H468A, Q491R; A159S, T411K, A443Y, H468A, Q491E; A159S, T411K, A443Y, H468K, Q491K; A159S, T411K, A443Y, H468K, Q491R; A159S, T411K, A443Y, H468K, Q491E; A159S, T411K, A443Y, H468G, Q491K; A159S, T411K, A443Y, H468G, Q491R; A159S, T411K, A443Y, H468G, Q491E; A159S, T411K, A443Y, H468S, Q491K; A159S, T411K, A443Y, H468S, Q491R; A159S, T411K, A443Y, H468S, Q491E; A159S, T411K, A443V, H468R, Q491K; A159S, T411K, A443V, H468R, Q491R; A159S, T411K, A443V, H468R, Q491E; A159S, T411K, A443V, H468A, Q491K; A159S, T411K, A443V, H468A, Q491R; A159S, T411K, A443V, H468A, Q491E; A159S, T411K, A443V, H468K, Q491K; A159S, T411K, A443V, H468K, Q491R; A159S, T411K, A443V, H468K, Q491E; A159S, T411K, A443V, H468G, Q491K; A159S, T411K, A443V, H468G, Q491R; A159S, T411K, A443V, H468G, Q491E; A159S, T411K, A443V, H468S, Q491K; A159S, T411K, A443V, H468S, Q491R; or A159S, T411K, A443V, H468S, Q491E.;

[0048] In some embodiments, the glucose oxidase variant (containing an amino acid substitution at any of positions 159, 411, 443, 468, and / or 491) contains a naturally occurring amino acid residue at position 92 that is different from D. In some embodiments, the glucose oxidase variant containing the substitution at position 92 may contain at least one additional substitution at any of positions 433, 440, and / or 503. In some embodiments, the glucose oxidase variant containing the substitution at position 92 may contain at least two additional substitutions at any of positions 433, 440, and / or 503. In some embodiments, the glucose oxidase variant containing the substitution at position 92 may contain substitutions at positions 433, 440, and 503. For example, glucose oxidase variants may contain one of the following amino acid residues at position 92: A (D92A), R (D92R), N (D92N), C (D92C), E (D92E), Q (D92Q), G (D92G), H (D92H), I (D92I), L (D92L), K (D92K), M (D92M), F (D92F), P (D92P), S (D92S), T (D92T), W (D92W), Y (D92Y), or V (D92V). For example, glucose oxidase variants may contain one of the following amino acid residues at position 92: A (D92A), R (D92R), E (D92E), Q (D92Q), K (D92K), S (D92S), or Y (D92Y). In another example, the glucose oxidase variant may contain one of the following amino acid residues at position 92: A (D92A), R (D92R), E (D92E), S (D92S), or Y (D92Y). In yet another example, the glucose oxidase variant may contain one of the following amino acid residues at position 92: E (D92E) or Q (D92Q). In yet another example, the glucose oxidase variant may contain E (D92E) at position 92. In some embodiments, the glucose oxidase variant does not contain Q (D92Q) at position 92. In some embodiments, the glucose oxidase variant does not contain K (D92K) at position 92. In some embodiments, the glucose oxidase variant does not contain Q (D92Q) or K (D92K) at position 992. Specific embodiments containing a substituted glucose oxidase at position 92 include, but are not limited to, polypeptides (including fragments thereof) containing the amino acid sequence of SEQ ID NO: 5 or variants thereof, which in some embodiments contain amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 5.

[0049] In some embodiments, the glucose oxidase variant (containing an amino acid substitution at any of positions 159, 411, 443, 468, and / or 491) contains a naturally occurring amino acid residue different from S at position 433. In some embodiments, the glucose oxidase variant containing the substitution at position 433 may contain at least one additional substitution at any of positions 92, 440, and / or 503. In some embodiments, the glucose oxidase variant containing the substitution at position 433 may contain at least two additional substitutions at any of positions 92, 440, and / or 503. In some embodiments, the glucose oxidase variant containing the substitution at position 433 may contain substitutions at positions 92, 440, and 503. For example, glucose oxidase variants may contain one of the following amino acid residues at position 433: A (S433A), R (S433R), N (S433N), D (S433D), C (S433C), E (S433E), Q (S433Q), G (S433G), H (S433H), I (S433I), L (S433L), K (S433K), M (S433M), F (S433F), P (S433P), T (S433T), W (S433W), Y (S433Y), or V (S433V). For example, glucose oxidase variants may contain one of the following amino acid residues at position 433: A (S433A), G (S433G), I (S433I), L (S433L), F (S433F), Y (S433Y), or V (S433V). In another example, the glucose oxidase variant may contain one of the following amino acid residues at position 433: G (S433G), I (S433I), L (S433L), F (S433F), Y (S433Y), or V (S433V). In yet another example, the glucose oxidase variant may contain one of the following amino acid residues at position 433: A (S433A) or V (S433V). In yet another example, the glucose oxidase variant may contain A (S433A) at position 433. In some embodiments, the glucose oxidase variant does not contain A (S433A) at position 433. Specific embodiments containing a substituted glucose oxidase at position 433 include, but are not limited to, polypeptides (including fragments thereof, in some embodiments, containing amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 5) comprising the amino acid sequence of SEQ ID NO: 5.

[0050] In some embodiments, the glucose oxidase variant (containing an amino acid substitution at any of positions 159, 411, 443, 468, and / or 491) contains a naturally occurring amino acid residue different from A at position 440. In some embodiments, the glucose oxidase variant containing the substitution at position 440 may contain at least one additional substitution at any of positions 92, 433, and / or 503. In some embodiments, the glucose oxidase variant containing the substitution at position 440 may contain at least two additional substitutions at any of positions 92, 433, and / or 503. In some embodiments, the glucose oxidase variant containing the substitution at position 440 may contain substitutions at positions 92, 433, and 503. For example, glucose oxidase variants may contain one of the following amino acid residues at position 440: R (A440R), N (A440N), D (A440D), C (A440C), E (A440E), Q (A440Q), G (A440G), H (A440H), I (A440I), L (A440L), K (A440K), M (A440M), F (A440F), P (A440P), S (A440S), T (A440T), W (A440W), Y (A440Y), or V (A440V). For example, glucose oxidase variants may contain one of the following amino acid residues at position 440: D (A440D), E (A440E), G (A440G), K (A440K), F (A440F), or S (A440S). In another example, the glucose oxidase variant may contain one of the following amino acid residues at position 440: D (A440D), E (A440E), G (A440G), F (A440F), or S (A440S). In yet another example, the glucose oxidase variant may contain one of the following amino acid residues at position 440: E (A440E) or G (A440G). In yet another example, the glucose oxidase variant may contain G (A440G) at position 440. In some embodiments, the glucose oxidase variant does not contain K (A440K) at position 440. Specific embodiments containing a substituted glucose oxidase at position 440 include, but are not limited to, polypeptides (including fragments thereof) containing the amino acid sequence of SEQ ID NO: 5 or a variant thereof, in some embodiments containing amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 5.

[0051] In embodiments where the glucose oxidase variant comprises A159L, the glucose oxidase variant does not contain one or a combination of the following amino acid substitutions: A114E, Y271L, and / or P530K. In embodiments where the glucose oxidase variant comprises A159L and Q491R, the glucose oxidase variant does not contain one or a combination of the following amino acid substitutions: Q164K, H388T, D462S, and / or Q475N. In further embodiments where the glucose oxidase variant comprises D92K, A159L, T411S, S433G, A440G, A443F, H468A, Q491R, and Q503A, the glucose oxidase variant does not contain one or a combination of the following amino acid substitutions: Q164K, K224D, P238Q, H242R, H388T, D462S, K463A, Q475N, and / or D514P.

[0052] In some embodiments, the glucose oxidase variant (containing an amino acid substitution at any of positions 159, 411, 443, 468, and / or 491) contains a naturally occurring amino acid residue at position 503 that is different from Q. In some embodiments, the glucose oxidase variant containing the substitution at position 503 may contain at least one additional substitution at any of positions 92, 433, and / or 440. In some embodiments, the glucose oxidase variant containing the substitution at position 503 may contain at least two additional substitutions at any of positions 92, 433, and / or 440. In some embodiments, the glucose oxidase variant containing the substitution at position 503 may contain substitutions at positions 92, 433, and 440. For example, glucose oxidase variants may contain one of the following amino acid residues at position 503: A (Q503A), R (Q503R), N (Q503N), D (Q503D), C (Q503C), E (Q503E), G (Q503G), H (Q503H), I (Q503I), L (Q503L), K (Q503K), M (Q503M), F (Q503F), P (Q503P), S (Q503S), T (Q503T), W (Q503W), Y (Q503Y), or V (Q503V). For example, glucose oxidase variants may contain one of the following amino acid residues at position 503: A (Q503A), R (Q503R), E (Q503E), K (Q503K), or S (Q503S). In another example, the glucose oxidase variant may contain one of the following amino acid residues at position 503: A (Q503A), R (Q503R), E (Q503E), or S (Q503S). In yet another example, the glucose oxidase variant may contain one of the following amino acid residues at position 503: A (Q503A) or K (Q503K). In yet another example, the glucose oxidase variant may contain K (Q503K) at position 503. In some embodiments, the glucose oxidase variant does not contain K (Q503K) at position 503. Specific embodiments containing a substituted glucose oxidase at position 503 include, but are not limited to, polypeptides (including fragments thereof) containing the amino acid sequence of SEQ ID NO: 5 or variants thereof, in some embodiments of which fragments contain amino acid residues from position 25 to position 605 of the amino acid sequence of SEQ ID NO: 5.

[0053] Glucose oxidase variants having amino acid substitutions at positions 92, 433, 440, and / or 503 can be used in conjunction with embodiments of glucose oxidase variants having amino acid substitutions at positions 159, 411, 443, 468, and / or 491 as described herein, and include the following substitution combinations: D92E, S433A, A440G, Q503K; D92E, S433A, A440G, Q503A; D92E, S433A, A440G, Q503R; D92E, S433A, A440G, Q503S; D92E, S433A, A440G, Q503E; D92E, S433A, A440E, Q503K; D 92E, S433A, A440E, Q503A; D92E, S433A, A440E, Q503R; D92E, S433A, A440E , Q503S; D92E, S433A, A440E, Q503E; D92E, S433A, A440D, Q503K; D92E, S43 3A, A440D, Q503A; D92E, S433A, A440D, Q503R; D92E, S433A, A440D, Q503S; D92E, S433A, A440D, Q503E; D92E, S433A, A440S, Q503K; D92E, S433A, A440S , Q503A; D92E, S433A, A440S, Q503R; D92E, S433A, A440S, Q503S; D92E, S43 3A, A440S, Q503E; D92E, S433A, A440F, Q503K; D92E, S433A, A440F, Q503A; D92E, S433A, A440F, Q503R; D92E, S433A, A440F, Q503S; D92E, S433A, A440 F, Q503E; D92E, S433A, A440K, Q503K; D92E, S433A, A440K, Q503A; D92E, S43 3A, A440K, Q503R; D92E, S433A, A440K, Q503S; D92E, S433A, A440K, Q503E; D92E, S433V, A440G, Q503K; D92E, S433V, A440G, Q503A; D92E, S433V, A440 G, Q503R; D92E, S433V, A440G, Q503S; D92E, S433V, A440G, Q503E; D92E, S4 33V, A440E, Q503K; D92E, S433V, A440E, Q503A; D92E, S433V, A440E, Q503R;D92E、S433V、A440E、Q503S;D92E、S433V、A440E、Q503E;D92E、S433V、A440 D、Q503K;D92E、S433V、A440D、Q503A;D92E、S433V、A440D、Q503R;D92E、S43 3V、A440D、Q503S;D92E、S433V、A440D、Q503E;D92E、S433V、A440S、Q503K;D 92E、S433V、A440S、Q503A;D92E、S433V、A440S、Q503R;D92E、S433V、A440S、 Q503S;D92E、S433V、A440S、Q503E;D92E、S433V、A440F、Q503K;D92E、S433 V、A440F、Q503A;D92E、S433V、A440F、Q503R;D92E、S433V、A440F、Q503S;D9 2E, S433V, A440F, Q503E; D92E, S433V, A440K, Q503K; D92E, S433V, A440K, Q503A; D92E, S433V, A440K, Q503R; D92E, S433V, A440K, Q503S; D92E, S433V A440K, Q503E; D92E, S433L, A440G, Q503K; D92E, S433L, A440G, Q503A; D92E, S433L, A440G, Q503R; D92E, S433L, A440G, Q503S; D92E, S433L, A440G, Q5 03E; D92E, S433L, A440E, Q503K; D92E, S433L, A440E, Q503A; D92E, S433L, A440E, Q503R; D92E, S433L, A440E, Q503S; D92E, S433L, A440E, Q503E; D92E S433L, A440D, Q503K; D92E, S433L, A440D, Q503A; D92E, S433L, A440D, Q503R; D92E, S433L, A440D, Q503S; D92E, S433L, A440D, Q503E; D92E, S433L, A44 0S, Q503K; D92E, S433L, A440S, Q503A; D92E, S433L, A440S, Q503R; D92E, S433L, A440S, Q503S; D92E, S433L, A440S, Q503E; D92E, S433L, A440F, Q503K;D92E、S433L、A440F、Q503A;D92E、S433L、A440F、Q503R;D92E、S433L、A440F、Q503S;D92E、S433L、A440F、Q503E;D92E、S433L、A440K、Q503K;D92E、S433L、A440K、Q503A;D92E、S433L、A440K、Q503R;D92E、S433L、A440K、Q503S;D92E、S433L、A440K、Q503E;D92E、S433G、A440G、Q503K;D92E、S433G、A440G、Q503A;D92E、S433G、A440G、Q503R;D92E、S433G、A440G、Q503S;D92E、S433G、A440G、Q503E;D92E、S433G、A440E、Q503K;D92E、S433G、A440E、Q503A;D92E、S433G、A440E、Q503R;D92E、S433G、A440E、Q503S;D92E、S433G、A440E、Q503E;D92E、S433G、A440D、Q503K;D92E、S433G、A440D、Q503A;D92E、S433G、A440D、Q503R;D92E、S433G、A440D、Q503S;D92E、S433G、A440D、Q503E;D92E、S433G、A440S、Q503K;D92E、S433G、A440S、Q503A;D92E、S433G、A440S、Q503R;D92E、S433G、A440S、Q503S;D92E、S433G、A440S、Q503E;D92E、S433G、A440F、Q503K;D92E、S433G、A440F、Q503A;D92E、S433G、A440F、Q503R;D92E、S433G、A440F、Q503S;D92E、S433G、A440F、Q503E;D92E、S433G、A440K、Q503K;D92E、S433G、A440K、Q503A;D92E、S433G、A440K、Q503R;D92E、S433G、A440K、Q503S;D92E、S433G、A440K、Q503E;D92E、S433F、A440G、Q503K;D92E、S433F、A440G、Q503A;D92E、S433F、A440G、Q503R;D92E、S433F、A440G、Q503S;D92E, S433F, A440G, Q503E; D92E, S433F, A440E, Q503K; D92E, S433F, A440E, Q503A; D92E, S433F, A440E, Q503R; D92E, S433F, A440E, Q503S; D92E, S43 3F、A440E、Q503E;D92E、S433F、A440D、Q503K;D92E、S433F、A440D、Q503A;D 92E、S433F、A440D、Q503R;D92E、S433F、A440D、Q503S;D92E、S433F、A440D、 Q503E; D92E, S433F, A440S, Q503K; D92E, S433F, A440S, Q503A; D92E, S433F, A440S, Q503R; D92E, S433F, A440S, Q503S; D92E, S433F, A440S, Q503E; D9 2E, S433F, A440F, Q503K; D92E, S433F, A440F, Q503A; D92E, S433F, A440F, Q503R; D92E, S433F, A440F, Q503S; D92E, S433F, A440F, Q503E; D92E, S433F A440K、Q503K;D92E、S433F、A440K、Q503A;D92E、S433F、A440K、Q503R;D92 E、S433F、A440K、Q503S;D92E、S433F、A440K、Q503E;D92E、S433Y、A440G、Q5 03K; D92E, S433Y, A440G, Q503A; D92E, S433Y, A440G, Q503R; D92E, S433Y, A440G, Q503S; D92E, S433Y, A440G, Q503E; D92E, S433Y, A440E, Q503K; D92E S433Y, A440E, Q503A; D92E, S433Y, A440E, Q503R; D92E, S433Y, A440E, Q503S; D92E, S433Y, A440E, Q503E; D92E, S433Y, A440D, Q503K; D92E, S433Y, A44 0D, Q503A; D92E, S433Y, A440D, Q503R; D92E, S433Y, A440D, Q503S; D92E, S433Y, A440D, Q503E; D92E, S433Y, A440S, Q503K; D92E, S433Y, A440S, Q503A;D92E, S433Y, A440S, Q503R; D92E, S433Y, A440S, Q503S; D92E, S433Y, A440S, Q503E; D92E, S433Y, A440F, Q503K; D92E, S433Y, A440F, Q503A; D92E, S43 3Y、A440F、Q503R;D92E、S433Y、A440F、Q503S;D92E、S433Y、A440F、Q503E;D 92E、S433Y、A440K、Q503K;D92E、S433Y、A440K、Q503A;D92E、S433Y、A440K、 Q503R; D92E, S433Y, A440K, Q503S; D92E, S433Y, A440K, Q503E; D92E, S433I, A440G, Q503K; D92E, S433I, A440G, Q503A; D92E, S433I, A440G, Q503R; D9 2E, S433I, A440G, Q503S; D92E, S433I, A440G, Q503E; D92E, S433I, A440E, Q503K; D92E, S433I, A440E, Q503A; D92E, S433I, A440E, Q503R; D92E, S433I A440E, Q503S; D92E, S433I, A440E, Q503E; D92E, S433I, A440D, Q503K; D92E, S433I, A440D, Q503A; D92E, S433I, A440D, Q503R; D92E, S433I, A440D, Q5 03S; D92E, S433I, A440D, Q503E; D92E, S433I, A440S, Q503K; D92E, S433I, A440S, Q503A; D92E, S433I, A440S, Q503R; D92E, S433I, A440S, Q503S; D92E S433I, A440S, Q503E; D92E, S433I, A440F, Q503K; D92E, S433I, A440F, Q503A; D92E, S433I, A440F, Q503R; D92E, S433I, A440F, Q503S; D92E, S433I, A44 0F, Q503E; D92E, S433I, A440K, Q503K; D92E, S433I, A440K, Q503A; D92E, S433I, A440K, Q503R; D92E, S433I, A440K, Q503S; D92E, S433I, A440K, Q503E;D92Q, S433A, A440G, Q503K; D92Q, S433A, A440G, Q503A; D92Q, S433A, A440G, Q503R; D92Q, S433A, A440G, Q503S; D92Q, S433A, A440G, Q503E; D92Q, S43 3A, A440E, Q503K; D92Q, S433A, A440E, Q503A; D92Q, S433A, A440E, Q503R; D92Q, S433A, A440E, Q503S; D92Q, S433A, A440E, Q503E; D92Q, S433A, A440D Q503K; D92Q, S433A, A440D, Q503A; D92Q, S433A, A440D, Q503R; D92Q, S433A, A440D, Q503S; D92Q, S433A, A440D, Q503E; D92Q, S433A, A440S, Q503K; D9 2Q, S433A, A440S, Q503A; D92Q, S433A, A440S, Q503R; D92Q, S433A, A440S, Q503S; D92Q, S433A, A440S, Q503E; D92Q, S433A, A440F, Q503K; D92Q, S433A A440F, Q503A; D92Q, S433A, A440F, Q503R; D92Q, S433A, A440F, Q503S; D92Q, S433A, A440F, Q503E; D92Q, S433A, A440K, Q503K; D92Q, S433A, A440K, Q5 03A; D92Q, S433A, A440K, Q503R; D92Q, S433A, A440K, Q503S; D92Q, S433A, A440K, Q503E; D92Q, S433V, A440G, Q503K; D92Q, S433V, A440G, Q503A; D92Q S433V、A440G、Q503R;D92Q、S433V、A440G、Q503S;D92Q、S433V、A440G、Q503 E;D92Q、S433V、A440E、Q503K;D92Q、S433V、A440E、Q503A;D92Q、S433V、A44 0E、Q503R;D92Q、S433V、A440E、Q503S;D92Q、S433V、A440E、Q503E;D92Q、S4 33V、A440D、Q503K;D92Q、S433V、A440D、Q503A;D92Q、S433V、A440D、Q503R;D92Q、S433V、A440D、Q503S;D92Q、S433V、A440D、Q503E;D92Q、S433V、A440 S、Q503K;D92Q、S433V、A440S、Q503A;D92Q、S433V、A440S、Q503R;D92Q、S43 3V、A440S、Q503S;D92Q、S433V、A440S、Q503E;D92Q、S433V、A440F、Q503K;D 92Q、S433V、A440F、Q503A;D92Q、S433V、A440F、Q503R;D92Q、S433V、A440F、 Q503S;D92Q、S433V、A440F、Q503E;D92Q、S433V、A440K、Q503K;D92Q、S433 V、A440K、Q503A;D92Q、S433V、A440K、Q503R;D92Q、S433V、A440K、Q503S;D9 2Q, S433V, A440K, Q503E; D92Q, S433L, A440G, Q503K; D92Q, S433L, A440G, Q503A; D92Q, S433L, A440G, Q503R; D92Q, S433L, A440G, Q503S; D92Q, S433L A440G, Q503E; D92Q, S433L, A440E, Q503K; D92Q, S433L, A440E, Q503A; D92Q, S433L, A440E, Q503R; D92Q, S433L, A440E, Q503S; D92Q, S433L, A440E, Q5 03E; D92Q, S433L, A440D, Q503K; D92Q, S433L, A440D, Q503A; D92Q, S433L, A440D, Q503R; D92Q, S433L, A440D, Q503S; D92Q, S433L, A440D, Q503E; D92Q S433L, A440S, Q503K; D92Q, S433L, A440S, Q503A; D92Q, S433L, A440S, Q503R; D92Q, S433L, A440S, Q503S; D92Q, S433L, A440S, Q503E; D92Q, S433L, A44 0F, Q503K; D92Q, S433L, A440F, Q503A; D92Q, S433L, A440F, Q503R; D92Q, S433L, A440F, Q503S; D92Q, S433L, A440F, Q503E; D92Q, S433L, A440K, Q503K;D92Q、S433L、A440K、Q503A;D92Q、S433L、A440K、Q503R;D92Q、S433L、A440K、Q503S;D92Q、S433L、A440K、Q503E;D92Q、S433G、A440G、Q503K;D92Q、S433G、A440G、Q503A;D92Q、S433G、A440G、Q503R;D92Q、S433G、A440G、Q503S;D92Q、S433G、A440G、Q503E;D92Q、S433G、A440E、Q503K;D92Q、S433G、A440E、Q503A;D92Q、S433G、A440E、Q503R;D92Q、S433G、A440E、Q503S;D92Q、S433G、A440E、Q503E;D92Q、S433G、A440D、Q503K;D92Q、S433G、A440D、Q503A;D92Q、S433G、A440D、Q503R;D92Q、S433G、A440D、Q503S;D92Q、S433G、A440D、Q503E;D92Q、S433G、A440S、Q503K;D92Q、S433G、A440S、Q503A;D92Q、S433G、A440S、Q503R;D92Q、S433G、A440S、Q503S;D92Q、S433G、A440S、Q503E;D92Q、S433G、A440F、Q503K;D92Q、S433G、A440F、Q503A;D92Q、S433G、A440F、Q503R;D92Q、S433G、A440F、Q503S;D92Q、S433G、A440F、Q503E;D92Q、S433G、A440K、Q503K;D92Q、S433G、A440K、Q503A;D92Q、S433G、A440K、Q503R;D92Q、S433G、A440K、Q503S;D92Q、S433G、A440K、Q503E;D92Q、S433F、A440G、Q503K;D92Q、S433F、A440G、Q503A;D92Q、S433F、A440G、Q503R;D92Q、S433F、A440G、Q503S;D92Q、S433F、A440G、Q503E;D92Q、S433F、A440E、Q503K;D92Q、S433F、A440E、Q503A;D92Q、S433F、A440E、Q503R;D92Q、S433F、A440E、Q503S;D92Q, S433F, A440E, Q503E; D92Q, S433F, A440D, Q503K; D92Q, S433F, A440D, Q503A; D92Q, S433F, A440D, Q503R; D92Q, S433F, A440D, Q503S; D92Q, S43 3F, A440D, Q503E; D92Q, S433F, A440S, Q503K; D92Q, S433F, A440S, Q503A; D92Q, S433F, A440S, Q503R; D92Q, S433F, A440S, Q503S; D92Q, S433F, A440S Q503E; D92Q, S433F, A440F, Q503K; D92Q, S433F, A440F, Q503A; D92Q, S433F, A440F, Q503R; D92Q, S433F, A440F, Q503S; D92Q, S433F, A440F, Q503E; D9 2Q, S433F, A440K, Q503K; D92Q, S433F, A440K, Q503A; D92Q, S433F, A440K, Q503R; D92Q, S433F, A440K, Q503S; D92Q, S433F, A440K, Q503E; D92Q, S433Y A440G, Q503K; D92Q, S433Y, A440G, Q503A; D92Q, S433Y, A440G, Q503R; D92Q, S433Y, A440G, Q503S; D92Q, S433Y, A440G, Q503E; D92Q, S433Y, A440E, Q5 03K; D92Q, S433Y, A440E, Q503A; D92Q, S433Y, A440E, Q503R; D92Q, S433Y, A440E, Q503S; D92Q, S433Y, A440E, Q503E; D92Q, S433Y, A440D, Q503K; D92Q S433Y, A440D, Q503A; D92Q, S433Y, A440D, Q503R; D92Q, S433Y, A440D, Q503S; D92Q, S433Y, A440D, Q503E; D92Q, S433Y, A440S, Q503K; D92Q, S433Y, A44 0S, Q503A; D92Q, S433Y, A440S, Q503R; D92Q, S433Y, A440S, Q503S; D92Q, S433Y, A440S, Q503E; D92Q, S433Y, A440F, Q503K; D92Q, S433Y, A440F, Q503A;D92Q, S433Y, A440F, Q503R; D92Q, S433Y, A440F, Q503S; D92Q, S433Y, A440F, Q503E; D92Q, S433Y, A440K, Q503K; D92Q, S433Y, A440K, Q503A; D92Q, S43 3Y、A440K、Q503R;D92Q、S433Y、A440K、Q503S;D92Q、S433Y、A440K、Q503E;D 92Q、S433I、A440G、Q503K;D92Q、S433I、A440G、Q503A;D92Q、S433I、A440G、 Q503R; D92Q, S433I, A440G, Q503S; D92Q, S433I, A440G, Q503E; D92Q, S433I, A440E, Q503K; D92Q, S433I, A440E, Q503A; D92Q, S433I, A440E, Q503R; D9 2Q, S433I, A440E, Q503S; D92Q, S433I, A440E, Q503E; D92Q, S433I, A440D, Q503K; D92Q, S433I, A440D, Q503A; D92Q, S433I, A440D, Q503R; D92Q, S433I A440D, Q503S; D92Q, S433I, A440D, Q503E; D92Q, S433I, A440S, Q503K; D92Q, S433I, A440S, Q503A; D92Q, S433I, A440S, Q503R; D92Q, S433I, A440S, Q5 03S; D92Q, S433I, A440S, Q503E; D92Q, S433I, A440F, Q503K; D92Q, S433I, A440F, Q503A; D92Q, S433I, A440F, Q503R; D92Q, S433I, A440F, Q503S; D92Q S433I, A440F, Q503E; D92Q, S433I, A440K, Q503K; D92Q, S433I, A440K, Q503A; D92Q, S433I, A440K, Q503R; D92Q, S433I, A440K, Q503S; D92Q, S433I, A44 0K, Q503E; D92A, S433A, A440G, Q503K; D92A, S433A, A440G, Q503A; D92A, S433A, A440G, Q503R; D92A, S433A, A440G, Q503S; D92A, S433A, A440G, Q503E;D92A, S433A, A440E, Q503K; D92A, S433A, A440E, Q503A; D92A, S433A, A440E, Q503R; D92A, S433A, A440E, Q503S; D92A, S433A, A440E, Q503E; D92A, S43 3A, A440D, Q503K; D92A, S433A, A440D, Q503A; D92A, S433A, A440D, Q503R; D92A, S433A, A440D, Q503S; D92A, S433A, A440D, Q503E; D92A, S433A, A440S Q503K; D92A, S433A, A440S, Q503A; D92A, S433A, A440S, Q503R; D92A, S433A, A440S, Q503S; D92A, S433A, A440S, Q503E; D92A, S433A, A440F, Q503K; D9 2A, S433A, A440F, Q503A; D92A, S433A, A440F, Q503R; D92A, S433A, A440F, Q503S; D92A, S433A, A440F, Q503E; D92A, S433A, A440K, Q503K; D92A, S433A A440K, Q503A; D92A, S433A, A440K, Q503R; D92A, S433A, A440K, Q503S; D92A, S433A, A440K, Q503E; D92A, S433V, A440G, Q503K; D92A, S433V, A440G, Q5 03A; D92A, S433V, A440G, Q503R; D92A, S433V, A440G, Q503S; D92A, S433V, A440G, Q503E; D92A, S433V, A440E, Q503K; D92A, S433V, A440E, Q503A; D92A S433V, A440E, Q503R; D92A, S433V, A440E, Q503S; D92A, S433V, A440E, Q503E; D92A, S433V, A440D, Q503K; D92A, S433V, A440D, Q503A; D92A, S433V, A44 0D, Q503R; D92A, S433V, A440D, Q503S; D92A, S433V, A440D, Q503E; D92A, S433V, A440S, Q503K; D92A, S433V, A440S, Q503A; D92A, S433V, A440S, Q503R;D92A, S433V, A440S, Q503S; D92A, S433V, A440S, Q503E; D92A, S433V, A440F, Q503K; D92A, S433V, A440F, Q503A; D92A, S433V, A440F, Q503R; D92A, S43 3V、A440F、Q503S;D92A、S433V、A440F、Q503E;D92A、S433V、A440K、Q503K;D 92A、S433V、A440K、Q503A;D92A、S433V、A440K、Q503R;D92A、S433V、A440K、 Q503S; D92A, S433V, A440K, Q503E; D92A, S433L, A440G, Q503K; D92A, S433L, A440G, Q503A; D92A, S433L, A440G, Q503R; D92A, S433L, A440G, Q503S; D9 2A, S433L, A440G, Q503E; D92A, S433L, A440E, Q503K; D92A, S433L, A440E, Q503A; D92A, S433L, A440E, Q503R; D92A, S433L, A440E, Q503S; D92A, S433L A440E, Q503E; D92A, S433L, A440D, Q503K; D92A, S433L, A440D, Q503A; D92A, S433L, A440D, Q503R; D92A, S433L, A440D, Q503S; D92A, S433L, A440D, Q5 03E; D92A, S433L, A440S, Q503K; D92A, S433L, A440S, Q503A; D92A, S433L, A440S, Q503R; D92A, S433L, A440S, Q503S; D92A, S433L, A440S, Q503E; D92A S433L, A440F, Q503K; D92A, S433L, A440F, Q503A; D92A, S433L, A440F, Q503R; D92A, S433L, A440F, Q503S; D92A, S433L, A440F, Q503E; D92A, S433L, A44 0K, Q503K; D92A, S433L, A440K, Q503A; D92A, S433L, A440K, Q503R; D92A, S433L, A440K, Q503S; D92A, S433L, A440K, Q503E; D92A, S433G, A440G, Q503K;D92A, S433G, A440G, Q503A; D92A, S433G, A440G, Q503R; D92A, S433G, A440G, Q503S; D92A, S433G, A440G, Q503E; D92A, S433G, A440E, Q503K; D92A, S43 3G, A440E, Q503A; D92A, S433G, A440E, Q503R; D92A, S433G, A440E, Q503S; D92A, S433G, A440E, Q503E; D92A, S433G, A440D, Q503K; D92A, S433G, A440D Q503A; D92A, S433G, A440D, Q503R; D92A, S433G, A440D, Q503S; D92A, S433G, A440D, Q503E; D92A, S433G, A440S, Q503K; D92A, S433G, A440S, Q503A; D9 2A, S433G, A440S, Q503R; D92A, S433G, A440S, Q503S; D92A, S433G, A440S, Q503E; D92A, S433G, A440F, Q503K; D92A, S433G, A440F, Q503A; D92A, S433G A440F, Q503R; D92A, S433G, A440F, Q503S; D92A, S433G, A440F, Q503E; D92A, S433G, A440K, Q503K; D92A, S433G, A440K, Q503A; D92A, S433G, A440K, Q5 03R; D92A, S433G, A440K, Q503S; D92A, S433G, A440K, Q503E; D92A, S433F, A440G, Q503K; D92A, S433F, A440G, Q503A; D92A, S433F, A440G, Q503R; D92A S433F, A440G, Q503S; D92A, S433F, A440G, Q503E; D92A, S433F, A440E, Q503K; D92A, S433F, A440E, Q503A; D92A, S433F, A440E, Q503R; D92A, S433F, A44 0E, Q503S; D92A, S433F, A440E, Q503E; D92A, S433F, A440D, Q503K; D92A, S433F, A440D, Q503A; D92A, S433F, A440D, Q503R; D92A, S433F, A440D, Q503S;D92A, S433F, A440D, Q503E; D92A, S433F, A440S, Q503K; D92A, S433F, A440S, Q503A; D92A, S433F, A440S, Q503R; D92A, S433F, A440S, Q503S; D92A, S43 3F, A440S, Q503E; D92A, S433F, A440F, Q503K; D92A, S433F, A440F, Q503A; D92A, S433F, A440F, Q503R; D92A, S433F, A440F, Q503S; D92A, S433F, A440F Q503E; D92A, S433F, A440K, Q503K; D92A, S433F, A440K, Q503A; D92A, S433F, A440K, Q503R; D92A, S433F, A440K, Q503S; D92A, S433F, A440K, Q503E; D9 2A, S433Y, A440G, Q503K; D92A, S433Y, A440G, Q503A; D92A, S433Y, A440G, Q503R; D92A, S433Y, A440G, Q503S; D92A, S433Y, A440G, Q503E; D92A, S433Y A440E, Q503K; D92A, S433Y, A440E, Q503A; D92A, S433Y, A440E, Q503R; D92A, S433Y, A440E, Q503S; D92A, S433Y, A440E, Q503E; D92A, S433Y, A440D, Q5 03K; D92A, S433Y, A440D, Q503A; D92A, S433Y, A440D, Q503R; D92A, S433Y, A440D, Q503S; D92A, S433Y, A440D, Q503E; D92A, S433Y, A440S, Q503K; D92A S433Y, A440S, Q503A; D92A, S433Y, A440S, Q503R; D92A, S433Y, A440S, Q503S; D92A, S433Y, A440S, Q503E; D92A, S433Y, A440F, Q503K; D92A, S433Y, A44 0F, Q503A; D92A, S433Y, A440F, Q503R; D92A, S433Y, A440F, Q503S; D92A, S433Y, A440F, Q503E; D92A, S433Y, A440K, Q503K; D92A, S433Y, A440K, Q503A;D92A, S433Y, A440K, Q503R; D92A, S433Y, A440K, Q503S; D92A, S433Y, A440K, Q503E; D92A, S433I, A440G, Q503K; D92A, S433I, A440G, Q503A; D92A, S43 3I, A440G, Q503R; D92A, S433I, A440G, Q503S; D92A, S433I, A440G, Q503E; D92A, S433I, A440E, Q503K; D92A, S433I, A440E, Q503A; D92A, S433I, A440E Q503R; D92A, S433I, A440E, Q503S; D92A, S433I, A440E, Q503E; D92A, S433I, A440D, Q503K; D92A, S433I, A440D, Q503A; D92A, S433I, A440D, Q503R; D9 2A, S433I, A440D, Q503S; D92A, S433I, A440D, Q503E; D92A, S433I, A440S, Q503K; D92A, S433I, A440S, Q503A; D92A, S433I, A440S, Q503R; D92A, S433I A440S, Q503S; D92A, S433I, A440S, Q503E; D92A, S433I, A440F, Q503K; D92A, S433I, A440F, Q503A; D92A, S433I, A440F, Q503R; D92A, S433I, A440F, Q5 03S; D92A, S433I, A440F, Q503E; D92A, S433I, A440K, Q503K; D92A, S433I, A440K, Q503A; D92A, S433I, A440K, Q503R; D92A, S433I, A440K, Q503S; D92A S433I, A440K, Q503E; D92K, S433A, A440G, Q503K; D92K, S433A, A440G, Q503A; D92K, S433A, A440G, Q503R; D92K, S433A, A440G, Q503S; D92K, S433A, A44 0G, Q503E; D92K, S433A, A440E, Q503K; D92K, S433A, A440E, Q503A; D92K, S433A, A440E, Q503R; D92K, S433A, A440E, Q503S; D92K, S433A, A440E, Q503E;D92K, S433A, A440D, Q503K; D92K, S433A, A440D, Q503A; D92K, S433A, A440D, Q503R; D92K, S433A, A440D, Q503S; D92K, S433A, A440D, Q503E; D92K, S43 3A, A440S, Q503K; D92K, S433A, A440S, Q503A; D92K, S433A, A440S, Q503R; D92K, S433A, A440S, Q503S; D92K, S433A, A440S, Q503E; D92K, S433A, A440F Q503K; D92K, S433A, A440F, Q503A; D92K, S433A, A440F, Q503R; D92K, S433A, A440F, Q503S; D92K, S433A, A440F, Q503E; D92K, S433A, A440K, Q503K; D9 2K, S433A, A440K, Q503A; D92K, S433A, A440K, Q503R; D92K, S433A, A440K, Q503S; D92K, S433A, A440K, Q503E; D92K, S433V, A440G, Q503K; D92K, S433V A440G、Q503A;D92K、S433V、A440G、Q503R;D92K、S433V、A440G、Q503S;D92 K、S433V、A440G、Q503E;D92K、S433V、A440E、Q503K;D92K、S433V、A440E、Q5 03A; D92K, S433V, A440E, Q503R; D92K, S433V, A440E, Q503S; D92K, S433V, A440E, Q503E; D92K, S433V, A440D, Q503K; D92K, S433V, A440D, Q503A; D92K S433V、A440D、Q503R;D92K、S433V、A440D、Q503S;D92K、S433V、A440D、Q503 E;D92K、S433V、A440S、Q503K;D92K、S433V、A440S、Q503A;D92K、S433V、A44 0S、Q503R;D92K、S433V、A440S、Q503S;D92K、S433V、A440S、Q503E;D92K、S4 33V、A440F、Q503K;D92K、S433V、A440F、Q503A;D92K、S433V、A440F、Q503R;D92K、S433V、A440F、Q503S;D92K、S433V、A440F、Q503E;D92K、S433V、A440 K、Q503K;D92K、S433V、A440K、Q503A;D92K、S433V、A440K、Q503R;D92K、S43 3V、A440K、Q503S;D92K、S433V、A440K、Q503E;D92K、S433L、A440G、Q503K;D 92K、S433L、A440G、Q503A;D92K、S433L、A440G、Q503R;D92K、S433L、A440G、 Q503S; D92K, S433L, A440G, Q503E; D92K, S433L, A440E, Q503K; D92K, S433L, A440E, Q503A; D92K, S433L, A440E, Q503R; D92K, S433L, A440E, Q503S; D9 2K, S433L, A440E, Q503E; D92K, S433L, A440D, Q503K; D92K, S433L, A440D, Q503A; D92K, S433L, A440D, Q503R; D92K, S433L, A440D, Q503S; D92K, S433L A440D, Q503E; D92K, S433L, A440S, Q503K; D92K, S433L, A440S, Q503A; D92K, S433L, A440S, Q503R; D92K, S433L, A440S, Q503S; D92K, S433L, A440S, Q5 03E; D92K, S433L, A440F, Q503K; D92K, S433L, A440F, Q503A; D92K, S433L, A440F, Q503R; D92K, S433L, A440F, Q503S; D92K, S433L, A440F, Q503E; D92K S433L, A440K, Q503K; D92K, S433L, A440K, Q503A; D92K, S433L, A440K, Q503R; D92K, S433L, A440K, Q503S; D92K, S433L, A440K, Q503E; D92K, S433G, A44 0G、Q503K;D92K、S433G、A440G、Q503A;D92K、S433G、A440G、Q503R;D92K、S4 33G、A440G、Q503S;D92K、S433G、A440G、Q503E;D92K、S433G、A440E、Q503K;D92K、S433G、A440E、Q503A;D92K、S433G、A440E、Q503R;D92K、S433G、A440E、Q503S;D92K、S433G、A440E、Q503E;D92K、S433G、A440D、Q503K;D92K、S433G、A440D、Q503A;D92K、S433G、A440D、Q503R;D92K、S433G、A440D、Q503S;D92K、S433G、A440D、Q503E;D92K、S433G、A440S、Q503K;D92K、S433G、A440S、Q503A;D92K、S433G、A440S、Q503R;D92K、S433G、A440S、Q503S;D92K、S433G、A440S、Q503E;D92K、S433G、A440F、Q503K;D92K、S433G、A440F、Q503A;D92K、S433G、A440F、Q503R;D92K、S433G、A440F、Q503S;D92K、S433G、A440F、Q503E;D92K、S433G、A440K、Q503K;D92K、S433G、A440K、Q503A;D92K、S433G、A440K、Q503R;D92K、S433G、A440K、Q503S;D92K、S433G、A440K、Q503E;D92K、S433F、A440G、Q503K;D92K、S433F、A440G、Q503A;D92K、S433F、A440G、Q503R;D92K、S433F、A440G、Q503S;D92K、S433F、A440G、Q503E;D92K、S433F、A440E、Q503K;D92K、S433F、A440E、Q503A;D92K、S433F、A440E、Q503R;D92K、S433F、A440E、Q503S;D92K、S433F、A440E、Q503E;D92K、S433F、A440D、Q503K;D92K、S433F、A440D、Q503A;D92K、S433F、A440D、Q503R;D92K、S433F、A440D、Q503S;D92K、S433F、A440D、Q503E;D92K、S433F、A440S、Q503K;D92K、S433F、A440S、Q503A;D92K、S433F、A440S、Q503R;D92K、S433F、A440S、Q503S;D92K, S433F, A440S, Q503E; D92K, S433F, A440F, Q503K; D92K, S433F, A440F, Q503A; D92K, S433F, A440F, Q503R; D92K, S433F, A440F, Q503S; D92K, S43 3F、A440F、Q503E;D92K、S433F、A440K、Q503K;D92K、S433F、A440K、Q503A;D 92K、S433F、A440K、Q503R;D92K、S433F、A440K、Q503S;D92K、S433F、A440K、 Q503E; D92K, S433Y, A440G, Q503K; D92K, S433Y, A440G, Q503A; D92K, S433Y, A440G, Q503R; D92K, S433Y, A440G, Q503S; D92K, S433Y, A440G, Q503E; D9 2K, S433Y, A440E, Q503K; D92K, S433Y, A440E, Q503A; D92K, S433Y, A440E, Q503R; D92K, S433Y, A440E, Q503S; D92K, S433Y, A440E, Q503E; D92K, S433Y A440D, Q503K; D92K, S433Y, A440D, Q503A; D92K, S433Y, A440D, Q503R; D92K, S433Y, A440D, Q503S; D92K, S433Y, A440D, Q503E; D92K, S433Y, A440S, Q5 03K; D92K, S433Y, A440S, Q503A; D92K, S433Y, A440S, Q503R; D92K, S433Y, A440S, Q503S; D92K, S433Y, A440S, Q503E; D92K, S433Y, A440F, Q503K; D92K S433Y, A440F, Q503A; D92K, S433Y, A440F, Q503R; D92K, S433Y, A440F, Q503S; D92K, S433Y, A440F, Q503E; D92K, S433Y, A440K, Q503K; D92K, S433Y, A44 0K, Q503A; D92K, S433Y, A440K, Q503R; D92K, S433Y, A440K, Q503S; D92K, S433Y, A440K, Q503E; D92K, S433I, A440G, Q503K; D92K, S433I, A440G, Q503A;D92K, S433I, A440G, Q503R; D92K, S433I, A440G, Q503S; D92K, S433I, A440G, Q503E; D92K, S433I, A440E, Q503K; D92K, S433I, A440E, Q503A; D92K, S43 3I, A440E, Q503R; D92K, S433I, A440E, Q503S; D92K, S433I, A440E, Q503E; D92K, S433I, A440D, Q503K; D92K, S433I, A440D, Q503A; D92K, S433I, A440D Q503R; D92K, S433I, A440D, Q503S; D92K, S433I, A440D, Q503E; D92K, S433I, A440S, Q503K; D92K, S433I, A440S, Q503A; D92K, S433I, A440S, Q503R; D9 2K, S433I, A440S, Q503S; D92K, S433I, A440S, Q503E; D92K, S433I, A440F, Q503K; D92K, S433I, A440F, Q503A; D92K, S433I, A440F, Q503R; D92K, S433I A440F, Q503S; D92K, S433I, A440F, Q503E; D92K, S433I, A440K, Q503K; D92K, S433I, A440K, Q503A; D92K, S433I, A440K, Q503R; D92K, S433I, A440K, Q5 03S; D92K, S433I, A440K, Q503E; D92R, S433A, A440G, Q503K; D92R, S433A, A440G, Q503A; D92R, S433A, A440G, Q503R; D92R, S433A, A440G, Q503S; D92R S433A, A440G, Q503E; D92R, S433A, A440E, Q503K; D92R, S433A, A440E, Q503A; D92R, S433A, A440E, Q503R; D92R, S433A, A440E, Q503S; D92R, S433A, A44 0E, Q503E; D92R, S433A, A440D, Q503K; D92R, S433A, A440D, Q503A; D92R, S433A, A440D, Q503R; D92R, S433A, A440D, Q503S; D92R, S433A, A440D, Q503E;D92R, S433A, A440S, Q503K; D92R, S433A, A440S, Q503A; D92R, S433A, A440S, Q503R; D92R, S433A, A440S, Q503S; D92R, S433A, A440S, Q503E; D92R, S43 3A, A440F, Q503K; D92R, S433A, A440F, Q503A; D92R, S433A, A440F, Q503R; D92R, S433A, A440F, Q503S; D92R, S433A, A440F, Q503E; D92R, S433A, A440K Q503K; D92R, S433A, A440K, Q503A; D92R, S433A, A440K, Q503R; D92R, S433A, A440K, Q503S; D92R, S433A, A440K, Q503E; D92R, S433V, A440G, Q503K; D9 2R、S433V、A440G、Q503A;D92R、S433V、A440G、Q503R;D92R、S433V、A440G、Q 503S;D92R、S433V、A440G、Q503E;D92R、S433V、A440E、Q503K;D92R、S433V、 A440E、Q503A;D92R、S433V、A440E、Q503R;D92R、S433V、A440E、Q503S;D92 R、S433V、A440E、Q503E;D92R、S433V、A440D、Q503K;D92R、S433V、A440D、Q5 03A; D92R, S433V, A440D, Q503R; D92R, S433V, A440D, Q503S; D92R, S433V, A440D, Q503E; D92R, S433V, A440S, Q503K; D92R, S433V, A440S, Q503A; D92R S433V、A440S、Q503R;D92R、S433V、A440S、Q503S;D92R、S433V、A440S、Q503 E;D92R、S433V、A440F、Q503K;D92R、S433V、A440F、Q503A;D92R、S433V、A44 0F, Q503R; D92R, S433V, A440F, Q503S; D92R, S433V, A440F, Q503E; D92R, S433V, A440K, Q503K; D92R, S433V, A440K, Q503A; D92R, S433V, A440K, Q503R;D92R, S433V, A440K, Q503S; D92R, S433V, A440K, Q503E; D92R, S433L, A440G, Q503K; D92R, S433L, A440G, Q503A; D92R, S433L, A440G, Q503R; D92R, S43 3L, A440G, Q503S; D92R, S433L, A440G, Q503E; D92R, S433L, A440E, Q503K; D92R, S433L, A440E, Q503A; D92R, S433L, A440E, Q503R; D92R, S433L, A440E Q503S; D92R, S433L, A440E, Q503E; D92R, S433L, A440D, Q503K; D92R, S433L, A440D, Q503A; D92R, S433L, A440D, Q503R; D92R, S433L, A440D, Q503S; D9 2R, S433L, A440D, Q503E; D92R, S433L, A440S, Q503K; D92R, S433L, A440S, Q503A; D92R, S433L, A440S, Q503R; D92R, S433L, A440S, Q503S; D92R, S433L A440S, Q503E; D92R, S433L, A440F, Q503K; D92R, S433L, A440F, Q503A; D92R, S433L, A440F, Q503R; D92R, S433L, A440F, Q503S; D92R, S433L, A440F, Q5 03E; D92R, S433L, A440K, Q503K; D92R, S433L, A440K, Q503A; D92R, S433L, A440K, Q503R; D92R, S433L, A440K, Q503S; D92R, S433L, A440K, Q503E; D92R S433G、A440G、Q503K;D92R、S433G、A440G、Q503A;D92R、S433G、A440G、Q503 R;D92R、S433G、A440G、Q503S;D92R、S433G、A440G、Q503E;D92R、S433G、A44 0E、Q503K;D92R、S433G、A440E、Q503A;D92R、S433G、A440E、Q503R;D92R、S4 33G、A440E、Q503S;D92R、S433G、A440E、Q503E;D92R、S433G、A440D、Q503K;D92R、S433G、A440D、Q503A;D92R、S433G、A440D、Q503R;D92R、S433G、A440 D、Q503S;D92R、S433G、A440D、Q503E;D92R、S433G、A440S、Q503K;D92R、S43 3G, A440S, Q503A; D92R, S433G, A440S, Q503R; D92R, S433G, A440S, Q503S; D92R, S433G, A440S, Q503E; D92R, S433G, A440F, Q503K; D92R, S433G, A440F Q503A; D92R, S433G, A440F, Q503R; D92R, S433G, A440F, Q503S; D92R, S433G, A440F, Q503E; D92R, S433G, A440K, Q503K; D92R, S433G, A440K, Q503A; D9 2R, S433G, A440K, Q503R; D92R, S433G, A440K, Q503S; D92R, S433G, A440K, Q503E; D92R, S433F, A440G, Q503K; D92R, S433F, A440G, Q503A; D92R, S433F A440G、Q503R;D92R、S433F、A440G、Q503S;D92R、S433F、A440G、Q503E;D92 R、S433F、A440E、Q503K;D92R、S433F、A440E、Q503A;D92R、S433F、A440E、Q5 03R; D92R, S433F, A440E, Q503S; D92R, S433F, A440E, Q503E; D92R, S433F, A440D, Q503K; D92R, S433F, A440D, Q503A; D92R, S433F, A440D, Q503R; D92R S433F、A440D、Q503S;D92R、S433F、A440D、Q503E;D92R、S433F、A440S、Q503 K;D92R、S433F、A440S、Q503A;D92R、S433F、A440S、Q503R;D92R、S433F、A44 0S、Q503S;D92R、S433F、A440S、Q503E;D92R、S433F、A440F、Q503K;D92R、S4 33F、A440F、Q503A;D92R、S433F、A440F、Q503R;D92R、S433F、A440F、Q503S;D92R, S433F, A440F, Q503E; D92R, S433F, A440K, Q503K; D92R, S433F, A440K, Q503A; D92R, S433F, A440K, Q503R; D92R, S433F, A440K, Q503S; D92R, S43 3F, A440K, Q503E; D92R, S433Y, A440G, Q503K; D92R, S433Y, A440G, Q503A; D92R, S433Y, A440G, Q503R; D92R, S433Y, A440G, Q503S; D92R, S433Y, A440G Q503E; D92R, S433Y, A440E, Q503K; D92R, S433Y, A440E, Q503A; D92R, S433Y, A440E, Q503R; D92R, S433Y, A440E, Q503S; D92R, S433Y, A440E, Q503E; D9 2R, S433Y, A440D, Q503K; D92R, S433Y, A440D, Q503A; D92R, S433Y, A440D, Q503R; D92R, S433Y, A440D, Q503S; D92R, S433Y, A440D, Q503E; D92R, S433Y A440S, Q503K; D92R, S433Y, A440S, Q503A; D92R, S433Y, A440S, Q503R; D92R, S433Y, A440S, Q503S; D92R, S433Y, A440S, Q503E; D92R, S433Y, A440F, Q5 03K; D92R, S433Y, A440F, Q503A; D92R, S433Y, A440F, Q503R; D92R, S433Y, A440F, Q503S; D92R, S433Y, A440F, Q503E; D92R, S433Y, A440K, Q503K; D92R S433Y, A440K, Q503A; D92R, S433Y, A440K, Q503R; D92R, S433Y, A440K, Q503S; D92R, S433Y, A440K, Q503E; D92R, S433I, A440G, Q503K; D92R, S433I, A44 0G, Q503A; D92R, S433I, A440G, Q503R; D92R, S433I, A440G, Q503S; D92R, S433I, A440G, Q503E; D92R, S433I, A440E, Q503K; D92R, S433I, A440E, Q503A;D92R, S433I, A440E, Q503R; D92R, S433I, A440E, Q503S; D92R, S433I, A440E, Q503E; D92R, S433I, A440D, Q503K; D92R, S433I, A440D, Q503A; D92R, S43 3I, A440D, Q503R; D92R, S433I, A440D, Q503S; D92R, S433I, A440D, Q503E; D92R, S433I, A440S, Q503K; D92R, S433I, A440S, Q503A; D92R, S433I, A440S Q503R; D92R, S433I, A440S, Q503S; D92R, S433I, A440S, Q503E; D92R, S433I, A440F, Q503K; D92R, S433I, A440F, Q503A; D92R, S433I, A440F, Q503R; D9 2R, S433I, A440F, Q503S; D92R, S433I, A440F, Q503E; D92R, S433I, A440K, Q503K; D92R, S433I, A440K, Q503A; D92R, S433I, A440K, Q503R; D92R, S433I A440K, Q503S; D92R, S433I, A440K, Q503E; D92S, S433A, A440G, Q503K; D92S, S433A, A440G, Q503A; D92S, S433A, A440G, Q503R; D92S, S433A, A440G, Q5 03S; D92S, S433A, A440G, Q503E; D92S, S433A, A440E, Q503K; D92S, S433A, A440E, Q503A; D92S, S433A, A440E, Q503R; D92S, S433A, A440E, Q503S; D92S S433A, A440E, Q503E; D92S, S433A, A440D, Q503K; D92S, S433A, A440D, Q503A; D92S, S433A, A440D, Q503R; D92S, S433A, A440D, Q503S; D92S, S433A, A44 0D, Q503E; D92S, S433A, A440S, Q503K; D92S, S433A, A440S, Q503A; D92S, S433A, A440S, Q503R; D92S, S433A, A440S, Q503S; D92S, S433A, A440S, Q503E;D92S, S433A, A440F, Q503K; D92S, S433A, A440F, Q503A; D92S, S433A, A440F, Q503R; D92S, S433A, A440F, Q503S; D92S, S433A, A440F, Q503E; D92S, S43 3A, A440K, Q503K; D92S, S433A, A440K, Q503A; D92S, S433A, A440K, Q503R; D92S, S433A, A440K, Q503S; D92S, S433A, A440K, Q503E; D92S, S433V, A440G Q503K;D92S、S433V、A440G、Q503A;D92S、S433V、A440G、Q503R;D92S、S433 V、A440G、Q503S;D92S、S433V、A440G、Q503E;D92S、S433V、A440E、Q503K;D9 2S、S433V、A440E、Q503A;D92S、S433V、A440E、Q503R;D92S、S433V、A440E、Q 503S;D92S、S433V、A440E、Q503E;D92S、S433V、A440D、Q503K;D92S、S433V、 A440D、Q503A;D92S、S433V、A440D、Q503R;D92S、S433V、A440D、Q503S;D92 S、S433V、A440D、Q503E;D92S、S433V、A440S、Q503K;D92S、S433V、A440S、Q5 03A;D92S、S433V、A440S、Q503R;D92S、S433V、A440S、Q503S;D92S、S433V、A 440S、Q503E;D92S、S433V、A440F、Q503K;D92S、S433V、A440F、Q503A;D92S、 S433V、A440F、Q503R;D92S、S433V、A440F、Q503S;D92S、S433V、A440F、Q503 E;D92S、S433V、A440K、Q503K;D92S、S433V、A440K、Q503A;D92S、S433V、A44 0K, Q503R; D92S, S433V, A440K, Q503S; D92S, S433V, A440K, Q503E; D92S, S433L, A440G, Q503K; D92S, S433L, A440G, Q503A; D92S, S433L, A440G, Q503R;D92S, S433L, A440G, Q503S; D92S, S433L, A440G, Q503E; D92S, S433L, A440E, Q503K; D92S, S433L, A440E, Q503A; D92S, S433L, A440E, Q503R; D92S, S43 3L, A440E, Q503S; D92S, S433L, A440E, Q503E; D92S, S433L, A440D, Q503K; D92S, S433L, A440D, Q503A; D92S, S433L, A440D, Q503R; D92S, S433L, A440D Q503S; D92S, S433L, A440D, Q503E; D92S, S433L, A440S, Q503K; D92S, S433L, A440S, Q503A; D92S, S433L, A440S, Q503R; D92S, S433L, A440S, Q503S; D9 2S, S433L, A440S, Q503E; D92S, S433L, A440F, Q503K; D92S, S433L, A440F, Q503A; D92S, S433L, A440F, Q503R; D92S, S433L, A440F, Q503S; D92S, S433L A440F, Q503E; D92S, S433L, A440K, Q503K; D92S, S433L, A440K, Q503A; D92S, S433L, A440K, Q503R; D92S, S433L, A440K, Q503S; D92S, S433L, A440K, Q5 03E;D92S、S433G、A440G、Q503K;D92S、S433G、A440G、Q503A;D92S、S433G、A 440G、Q503R;D92S、S433G、A440G、Q503S;D92S、S433G、A440G、Q503E;D92S、 S433G、A440E、Q503K;D92S、S433G、A440E、Q503A;D92S、S433G、A440E、Q503 R;D92S、S433G、A440E、Q503S;D92S、S433G、A440E、Q503E;D92S、S433G、A44 0D、Q503K;D92S、S433G、A440D、Q503A;D92S、S433G、A440D、Q503R;D92S、S4 33G、A440D、Q503S;D92S、S433G、A440D、Q503E;D92S、S433G、A440S、Q503K;D92S、S433G、A440S、Q503A;D92S、S433G、A440S、Q503R;D92S、S433G、A440S、Q503S;D92S、S433G、A440S、Q503E;D92S、S433G、A440F、Q503K;D92S、S433G、A440F、Q503A;D92S、S433G、A440F、Q503R;D92S、S433G、A440F、Q503S;D92S、S433G、A440F、Q503E;D92S、S433G、A440K、Q503K;D92S、S433G、A440K、Q503A;D92S、S433G、A440K、Q503R;D92S、S433G、A440K、Q503S;D92S、S433G、A440K、Q503E;D92S、S433F、A440G、Q503K;D92S、S433F、A440G、Q503A;D92S、S433F、A440G、Q503R;D92S、S433F、A440G、Q503S;D92S、S433F、A440G、Q503E;D92S、S433F、A440E、Q503K;D92S、S433F、A440E、Q503A;D92S、S433F、A440E、Q503R;D92S、S433F、A440E、Q503S;D92S、S433F、A440E、Q503E;D92S、S433F、A440D、Q503K;D92S、S433F、A440D、Q503A;D92S、S433F、A440D、Q503R;D92S、S433F、A440D、Q503S;D92S、S433F、A440D、Q503E;D92S、S433F、A440S、Q503K;D92S、S433F、A440S、Q503A;D92S、S433F、A440S、Q503R;D92S、S433F、A440S、Q503S;D92S、S433F、A440S、Q503E;D92S、S433F、A440F、Q503K;D92S、S433F、A440F、Q503A;D92S、S433F、A440F、Q503R;D92S、S433F、A440F、Q503S;D92S、S433F、A440F、Q503E;D92S、S433F、A440K、Q503K;D92S、S433F、A440K、Q503A;D92S、S433F、A440K、Q503R;D92S、S433F、A440K、Q503S;D92S, S433F, A440K, Q503E; D92S, S433Y, A440G, Q503K; D92S, S433Y, A440G, Q503A; D92S, S433Y, A440G, Q503R; D92S, S433Y, A440G, Q503S; D92S, S43 3Y、A440G、Q503E;D92S、S433Y、A440E、Q503K;D92S、S433Y、A440E、Q503A;D 92S、S433Y、A440E、Q503R;D92S、S433Y、A440E、Q503S;D92S、S433Y、A440E、 Q503E; D92S, S433Y, A440D, Q503K; D92S, S433Y, A440D, Q503A; D92S, S433Y, A440D, Q503R; D92S, S433Y, A440D, Q503S; D92S, S433Y, A440D, Q503E; D9 2S, S433Y, A440S, Q503K; D92S, S433Y, A440S, Q503A; D92S, S433Y, A440S, Q503R; D92S, S433Y, A440S, Q503S; D92S, S433Y, A440S, Q503E; D92S, S433Y A440F, Q503K; D92S, S433Y, A440F, Q503A; D92S, S433Y, A440F, Q503R; D92S, S433Y, A440F, Q503S; D92S, S433Y, A440F, Q503E; D92S, S433Y, A440K, Q5 03K; D92S, S433Y, A440K, Q503A; D92S, S433Y, A440K, Q503R; D92S, S433Y, A440K, Q503S; D92S, S433Y, A440K, Q503E; D92S, S433I, A440G, Q503K; D92S S433I, A440G, Q503A; D92S, S433I, A440G, Q503R; D92S, S433I, A440G, Q503S; D92S, S433I, A440G, Q503E; D92S, S433I, A440E, Q503K; D92S, S433I, A44 0E, Q503A; D92S, S433I, A440E, Q503R; D92S, S433I, A440E, Q503S; D92S, S433I, A440E, Q503E; D92S, S433I, A440D, Q503K; D92S, S433I, A440D, Q503A;D92S, S433I, A440D, Q503R; D92S, S433I, A440D, Q503S; D92S, S433I, A440D, Q503E; D92S, S433I, A440S, Q503K; D92S, S433I, A440S, Q503A; D92S, S43 3I, A440S, Q503R; D92S, S433I, A440S, Q503S; D92S, S433I, A440S, Q503E; D92S, S433I, A440F, Q503K; D92S, S433I, A440F, Q503A; D92S, S433I, A440F Q503R; D92S, S433I, A440F, Q503S; D92S, S433I, A440F, Q503E; D92S, S433I, A440K, Q503K; D92S, S433I, A440K, Q503A; D92S, S433I, A440K, Q503R; D9 2S, S433I, A440K, Q503S; D92S, S433I, A440K, Q503E; D92Y, S433A, A440G, Q503K; D92Y, S433A, A440G, Q503A; D92Y, S433A, A440G, Q503R; D92Y, S433A A440G, Q503S; D92Y, S433A, A440G, Q503E; D92Y, S433A, A440E, Q503K; D92Y, S433A, A440E, Q503A; D92Y, S433A, A440E, Q503R; D92Y, S433A, A440E, Q5 03S; D92Y, S433A, A440E, Q503E; D92Y, S433A, A440D, Q503K; D92Y, S433A, A440D, Q503A; D92Y, S433A, A440D, Q503R; D92Y, S433A, A440D, Q503S; D92Y S433A, A440D, Q503E; D92Y, S433A, A440S, Q503K; D92Y, S433A, A440S, Q503A; D92Y, S433A, A440S, Q503R; D92Y, S433A, A440S, Q503S; D92Y, S433A, A44 0S, Q503E; D92Y, S433A, A440F, Q503K; D92Y, S433A, A440F, Q503A; D92Y, S433A, A440F, Q503R; D92Y, S433A, A440F, Q503S; D92Y, S433A, A440F, Q503E;D92Y, S433A, A440K, Q503K; D92Y, S433A, A440K, Q503A; D92Y, S433A, A440K, Q503R; D92Y, S433A, A440K, Q503S; D92Y, S433A, A440K, Q503E; D92Y, S43 3V、A440G、Q503K;D92Y、S433V、A440G、Q503A;D92Y、S433V、A440G、Q503R;D 92Y、S433V、A440G、Q503S;D92Y、S433V、A440G、Q503E;D92Y、S433V、A440E、 Q503K; D92Y, S433V, A440E, Q503A; D92Y, S433V, A440E, Q503R; D92Y, S433V, A440E, Q503S; D92Y, S433V, A440E, Q503E; D92Y, S433V, A440D, Q503K; D9 2Y, S433V, A440D, Q503A; D92Y, S433V, A440D, Q503R; D92Y, S433V, A440D, Q503S; D92Y, S433V, A440D, Q503E; D92Y, S433V, A440S, Q503K; D92Y, S433V A440S、Q503A;D92Y、S433V、A440S、Q503R;D92Y、S433V、A440S、Q503S;D92 Y、S433V、A440S、Q503E;D92Y、S433V、A440F、Q503K;D92Y、S433V、A440F、Q5 03A; D92Y, S433V, A440F, Q503R; D92Y, S433V, A440F, Q503S; D92Y, S433V, A440F, Q503E; D92Y, S433V, A440K, Q503K; D92Y, S433V, A440K, Q503A; D92Y S433V, A440K, Q503R; D92Y, S433V, A440K, Q503S; D92Y, S433V, A440K, Q503E; D92Y, S433L, A440G, Q503K; D92Y, S433L, A440G, Q503A; D92Y, S433L, A44 0G, Q503R; D92Y, S433L, A440G, Q503S; D92Y, S433L, A440G, Q503E; D92Y, S433L, A440E, Q503K; D92Y, S433L, A440E, Q503A; D92Y, S433L, A440E, Q503R;D92Y, S433L, A440E, Q503S; D92Y, S433L, A440E, Q503E; D92Y, S433L, A440D, Q503K; D92Y, S433L, A440D, Q503A; D92Y, S433L, A440D, Q503R; D92Y, S43 3L, A440D, Q503S; D92Y, S433L, A440D, Q503E; D92Y, S433L, A440S, Q503K; D92Y, S433L, A440S, Q503A; D92Y, S433L, A440S, Q503R; D92Y, S433L, A440S Q503S; D92Y, S433L, A440S, Q503E; D92Y, S433L, A440F, Q503K; D92Y, S433L, A440F, Q503A; D92Y, S433L, A440F, Q503R; D92Y, S433L, A440F, Q503S; D9 2Y, S433L, A440F, Q503E; D92Y, S433L, A440K, Q503K; D92Y, S433L, A440K, Q503A; D92Y, S433L, A440K, Q503R; D92Y, S433L, A440K, Q503S; D92Y, S433L A440K、Q503E;D92Y、S433G、A440G、Q503K;D92Y、S433G、A440G、Q503A;D92 Y、S433G、A440G、Q503R;D92Y、S433G、A440G、Q503S;D92Y、S433G、A440G、Q5 03E; D92Y, S433G, A440E, Q503K; D92Y, S433G, A440E, Q503A; D92Y, S433G, A440E, Q503R; D92Y, S433G, A440E, Q503S; D92Y, S433G, A440E, Q503E; D92Y S433G、A440D、Q503K;D92Y、S433G、A440D、Q503A;D92Y、S433G、A440D、Q503 R;D92Y、S433G、A440D、Q503S;D92Y、S433G、A440D、Q503E;D92Y、S433G、A44 0S, Q503K; D92Y, S433G, A440S, Q503A; D92Y, S433G, A440S, Q503R; D92Y, S433G, A440S, Q503S; D92Y, S433G, A440S, Q503E; D92Y, S433G, A440F, Q503K;D92Y, S433G, A440F, Q503A; D92Y, S433G, A440F, Q503R; D92Y, S433G, A440F, Q503S; D92Y, S433G, A440F, Q503E; D92Y, S433G, A440K, Q503K; D92Y, S43 3G, A440K, Q503A; D92Y, S433G, A440K, Q503R; D92Y, S433G, A440K, Q503S; D92Y, S433G, A440K, Q503E; D92Y, S433F, A440G, Q503K; D92Y, S433F, A440G Q503A; D92Y, S433F, A440G, Q503R; D92Y, S433F, A440G, Q503S; D92Y, S433F, A440G, Q503E; D92Y, S433F, A440E, Q503K; D92Y, S433F, A440E, Q503A; D9 2Y, S433F, A440E, Q503R; D92Y, S433F, A440E, Q503S; D92Y, S433F, A440E, Q503E; D92Y, S433F, A440D, Q503K; D92Y, S433F, A440D, Q503A; D92Y, S433F A440D, Q503R; D92Y, S433F, A440D, Q503S; D92Y, S433F, A440D, Q503E; D92Y, S433F, A440S, Q503K; D92Y, S433F, A440S, Q503A; D92Y, S433F, A440S, Q5 03R; D92Y, S433F, A440S, Q503S; D92Y, S433F, A440S, Q503E; D92Y, S433F, A440F, Q503K; D92Y, S433F, A440F, Q503A; D92Y, S433F, A440F, Q503R; D92Y S433F, A440F, Q503S; D92Y, S433F, A440F, Q503E; D92Y, S433F, A440K, Q503K; D92Y, S433F, A440K, Q503A; D92Y, S433F, A440K, Q503R; D92Y, S433F, A44 0K, Q503S; D92Y, S433F, A440K, Q503E; D92Y, S433Y, A440G, Q503K; D92Y, S433Y, A440G, Q503A; D92Y, S433Y, A440G, Q503R; D92Y, S433Y, A440G, Q503S;D92Y, S433Y, A440G, Q503E; D92Y, S433Y, A440E, Q503K; D92Y, S433Y, A440E, Q503A; D92Y, S433Y, A440E, Q503R; D92Y, S433Y, A440E, Q503S; D92Y, S43 3Y、A440E、Q503E;D92Y、S433Y、A440D、Q503K;D92Y、S433Y、A440D、Q503A;D 92Y、S433Y、A440D、Q503R;D92Y、S433Y、A440D、Q503S;D92Y、S433Y、A440D、 Q503E; D92Y, S433Y, A440S, Q503K; D92Y, S433Y, A440S, Q503A; D92Y, S433Y, A440S, Q503R; D92Y, S433Y, A440S, Q503S; D92Y, S433Y, A440S, Q503E; D9 2Y, S433Y, A440F, Q503K; D92Y, S433Y, A440F, Q503A; D92Y, S433Y, A440F, Q503R; D92Y, S433Y, A440F, Q503S; D92Y, S433Y, A440F, Q503E; D92Y, S433Y A440K, Q503K; D92Y, S433Y, A440K, Q503A; D92Y, S433Y, A440K, Q503R; D92Y, S433Y, A440K, Q503S; D92Y, S433Y, A440K, Q503E; D92Y, S433I, A440G, Q5 03K; D92Y, S433I, A440G, Q503A; D92Y, S433I, A440G, Q503R; D92Y, S433I, A440G, Q503S; D92Y, S433I, A440G, Q503E; D92Y, S433I, A440E, Q503K; D92Y S433I, A440E, Q503A; D92Y, S433I, A440E, Q503R; D92Y, S433I, A440E, Q503S; D92Y, S433I, A440E, Q503E; D92Y, S433I, A440D, Q503K; D92Y, S433I, A44 0D, Q503A; D92Y, S433I, A440D, Q503R; D92Y, S433I, A440D, Q503S; D92Y, S433I, A440D, Q503E; D92Y, S433I, A440S, Q503K; D92Y, S433I, A440S, Q503A;D92Y, S433I, A440S, Q503R; D92Y, S433I, A440S, Q503S; D92Y, S433I, A440S, Q503E; D92Y, S 433I, A440F, Q503K; D92Y, S433I, A440F, Q503A; D92Y, S433I, A440F, Q503R; D92Y, S433I, A 440F, Q503S; D92Y, S433I, A440F, Q503E; D92Y, S433I, A440K, Q503K; D92Y, S433I, A440K, Q503A; D92Y, S433I, A440K, Q503R; D92Y, S433I, A440K, Q503S; or D92Y, S433I, A440K, Q503E.

[0054] The glucose oxidase variants disclosed herein contain conserved amino acid residues that, among other things, participate in substrate binding and catalytic activity, and preferably should not be substituted. Conserved amino acid residues involved in substrate binding include, but are not limited to, Y90, T132, N536, R534, H538, and H581 (all referenced to the amino acid sequence numbers in SEQ ID NO: 1). Therefore, the glucose oxidase variants disclosed herein include Y90, T132, N536, R534, H538, and H581 (represented by the amino acid sequence numbers in SEQ ID NO: 1). Conserved amino acid residues involved in catalytic activity include, but are not limited to, E434, H538, and H581 (represented by the amino acid sequence numbers in SEQ ID NO: 1). Therefore, the glucose oxidase variants disclosed herein include E434, H538, and H581 (represented by the amino acid sequence numbers in SEQ ID NO: 1). It has also been reported that certain amino acid residues (Y90, F346, and W448; amino acid sequence numbers relative to SEQ ID NO: 1) mutated to A result in an almost complete reduction in the glucose oxidation rate. Therefore, in some embodiments, the glucose oxidase variant of this disclosure does not contain A (relative to amino acid sequence numbers relative to SEQ ID NO: 1) at positions 90, 346, and 448. In some embodiments, the glucose variant of this disclosure contains the following amino acid residues: Y90, F346, and W448 (relative to amino acid sequence numbers relative to SEQ ID NO: 1).

[0055] It is also known that some residues of wild-type glucose oxidase are glycosylated or can be glycosylated and can play a role in the enzyme's thermostability. The N-linked glycosylated amino acid residues are presumed to include, but are not limited to, N65, N111, N183, N190, N377, N410, and N495 (amino acid sequence numbers relative to SEQ ID NO: 1). Therefore, in some embodiments, glucose oxidase variants of this disclosure may include N65, N111, N183, N190, N377, N410, and / or N495 (amino acid sequence numbers relative to SEQ ID NO: 1). In other embodiments, glucose oxidase variants of this disclosure may contain amino acid residues different from N, but which allow the enzyme to undergo N-glycosylation, at positions 65, 111, 183, 190, 377, 410, or 495 (amino acid sequence numbers relative to SEQ ID NO: 1). The presumed O-linked glycosylated amino acid residues include, but are not limited to, S185, T192, and T411 (amino acid sequence numbers relative to SEQ ID NO: 1). Therefore, in some embodiments, the glucose oxidase variants of this disclosure may include S185, T192, and / or T411 (amino acid sequence numbers relative to SEQ ID NO: 1). In other embodiments, the glucose oxidase variants of this disclosure may contain amino acid residues at positions 185, 192, or 411 (amino acid sequence numbers relative to SEQ ID NO: 1) that differ from S or T but allow for O-glycosylation of the enzyme.

[0056] The glucose oxidase variants disclosed herein may comprise one or any combination of the following additional conserved residues: D43, G48, G50, G53, A57, R59, L60, V68, E72, G74, G119, G123, G124, N129, R135, D142, W144, G149, W153, E166, G188, G191, G219, D225, G233, R247, R261, N263, L264, A286, G288, V289 A303, E306, V307, G312, P317, L320, S323, G324, G326, L331, I336, P343, V344, G345, N347, L348, D350, P452, R455, G456, D482, P512, T542, M545, V553, V554, D555, V560, G562, L566, R567, V568, D570, S572, P575 and / or I597. Alternatively, or in combination, the glucose oxidase variants of this disclosure may comprise one or any combination of the following additional conserved residues: T52, S73, L87, H100, S118, T126, P136, A140, S162, G227, Q351, T454, D46, A470, Y472, M546, A558, L591 and / or S594.

[0057] System for producing glucose oxidase variant

[0058] This disclosure provides recombinant microbial host cells for expressing one or more glucose oxidase variants described herein. The recombinant microbial host cells are obtained from microbial cells, which may be bacteria, yeast, or fungi. In one embodiment, the recombinant microbial host cell is obtained from a microbial cell, which is a bacterium. In some embodiments, the bacteria are Gram-positive bacteria. In other embodiments, the bacteria are Gram-negative bacteria. In one embodiment, the recombinant microbial host cell / microbial cell is derived from the genus *Actinomyces* (…). Actinoplanes In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Missouri actinomycetes* (sp). Actinoplanes In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Missouriensis*. Aeribacillus In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Bacillus pallida* (sp). Aeribacillus pallidusIn one embodiment, the recombinant microbial host cell / microbial cell is derived from the genus *Anoxybacillus*. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Pyrolytic Protein-Anaerobic Bacillus*. Anoxybacillus caldiproteolyticus In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus Bacillus ( ). Bacillus ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Bacillus acidophilus* (…). Bacillus acidopullulyticus In another embodiment, the recombinant microbial host cell / microbial cell is derived from Bacillus amyloliquefaciens (BAM). Bacillus amyloliquefaciens In another embodiment, the recombinant microbial host cell / microbial cell is derived from Bacillus licheniformis (B. licheniformis). Bacillus licheniformis In another embodiment, the recombinant microbial host cell / microbial cell is derived from Bacillus pumilus (…). Bacillus pumilus In another embodiment, the recombinant microbial host cell / microbial cell is derived from Bacillus subtilis (…). Bacillus subtilis In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Chlorobacterium* (…). Chryseobacterium ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Chlorobacterium chrysogenum* (… Chryseobacterium proteolyticum In one implementation, the recombinant microbial host cell / microbial cell is derived from Escherichia coli (Escherichia coli spp.). Escherichia ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Escherichia coli* (E. coli). Escherichia coli In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Geotrichum* (…). Geobacillus ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Bacillus steatophilus* (… Geobacillus stearothermophilus In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Lactobacillus* (…). Lactobacillus ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Lactobacillus fermentum ( Lactobacillus fermentum In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Lactococcus* (…). Lactococcus ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Lactococcus lactis ( Lactococcus lactis In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Macrococcus* (…). Macrococcus) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Macrococcus casei* ( Macrococcus caseolyticus In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Microbacterium* (…). Microbacterium ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from dendritic microbes ( Microbacterium arborescens In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Micrococcus* (…). Micrococcus ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Micrococcus lysate ( Micrococcus lysodeikticus In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Priscilla* (…). Priestia ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Priscilla curvilinearis* (… Priestia flexa In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus Streptomyces (…). Streptomyces ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Streptomyces mogulata* ( Streptomyces mobaraensis In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Streptomyces griseus* (…). Streptomyces murinus In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Streptomyces oliveii* (…). Streptomyces olivaceus In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Streptomyces olfactoryum* (…). Streptomyces olivochromogenes In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Streptomyces fumonis* (…). Streptomyces rubiginosus In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Streptomyces purpureus* (…). Streptomyces violaceoruber In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Pseudomonas* (…). Pseudomonas ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Pseudomonas fluorescens* (… Pseudomonas fluorescens In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Weizmannia* (…). Weizmannia ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Weizmannia coagulans* ( Weizmannia coagulans ).

[0059] In one embodiment, the recombinant microbial host cell is obtained from a microbial cell, which is yeast. In some embodiments, the yeast is a budding yeast. In other embodiments, the yeast is methyltrophic (e.g., yeast capable of utilizing methanol as its sole carbon and energy source). Embodiments of methyltrophic yeast include, but are not limited to, species of the genus *Hansenula* and species of *Hansenula*. Ogataea ) strain. In some embodiments, the yeast is an oil-producing yeast (e.g., a yeast capable of accumulating more than 20% of its stem cell weight in lipids or triglycerides).

[0060] In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Botrytis cinerea* (… Blastobotrys ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Botrytis cinerea* (adenine-budding yeast). Blastobotrys adeninivorans (Base name: *Adenine-sporum*) Trichosporon adeninivorans In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Candida* (…). Candida ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Candida albicans ( Candida albicans In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Astrocytes* (…). Cyberlindnera ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Gardinia star yeast* ( Cyberlindnera jadinii (Base name: Jardine yeast) Saccharomyces jadinii In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Debali* (…). Debaryomyces ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Hansophila bali* ( Debaryomyces hansenii In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Hansenula da Barry*. In one embodiment, the recombinant microbial host cell / microbial cell is derived from the genus *Hansenula sporeans* (…). Hanseniaspora ) strain (also known as Klerk yeast) Kloeckera (Strain). In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Hansenula polymorpha* (strain). Hanseniaspora guilliermondii In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Hansenula polymorpha* (a type of yeast). Hanseniaspora pseudoguilliermondii In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Saccharomyces* of Kazakhstan (…). Kazachstania ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Bledkazakhstan yeast* ( Kazachstania bulderi (Base name: Breed yeast) Saccharomyces bulderi In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Pasteurella multocida* (Kazakhstan yeast). Kazachstania barnettii (Base name: Pasteurella multocida) Saccharomyces barnettii In another embodiment, the recombinant microbial host cell / microbial cell is derived from oligosporous Kazakhstan yeast (…). Kazachstania exigua (Base name: Oligosaccharomyces cerevisiae) Saccharomyces exiguus In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Kluyveromyces* (…). Kluyveromyces ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Kluyveromyces lactis ( Kluyveromyces lactis (base name: Lactobacillus lactis) Torulaspora lactis In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Kluyveromyces martensii* (…). Kluyveromyces marxianus ), also known as Kluyveromyces brittle-wall ( Kluyveromyces fragilis (Base name: *Saccharomyces marxianus*). In one embodiment, the recombinant microbial host cell / microbial cell is derived from a species of the genus *Saccharomyces*. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces phaf.*. In one embodiment, the recombinant microbial host cell / microbial cell is derived from a species of the genus *Lintonia*. Limtongozyma ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Lintella cylindrica* ( Limtongozyma cylindracea (Base name: Candida columnare) Candida cylindracea In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Oleoma* (…). Lipomyces ) strain. In one embodiment, the recombinant microbial host cell / microbial cell is derived from the genus *Megiria* ( Metschnikowia ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces cerevisiae* (Sinopsaccharomyces cerevisiae). Metschnikowia sinensis In another implementation, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces cerevisiae* (fruit-derived *Saccharomyces cerevisiae*). Metschnikowia fructicola In another implementation, the recombinant microbial host cell / microbial cell is derived from *Megamiprid* (Saccharomyces cerevisiae). Metschnikowia pulcherrima In another embodiment, the recombinant microbial host cell / microbial cell is derived from Zobelmech yeast ( Metschnikowia zobellii In another implementation, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces cerevisiae* (Shanxi Meiqi yeast). Metschnikowia shanxiensis In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Onosacchari* (…). Ogataea ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces simonii* (…). Ogataea polymorpha (Base name: Hansenula polymorpha) Hansenula polymorpha In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces cerevisiae* (Methanol-Bacillus oryzae). Ogataea methanolica (Base name: Pichia pastoris) Pichia methanolica In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Pichia pastoris*. Pichia sp) (also known as Hansenula genus) Hansenula In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus Lassamycin (sp). Rasamsonia ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Eimersonella lasalina* ( Rasamsonia emersonii In one embodiment, the recombinant microbial host cell / microbial cell is derived from a yeast species. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces cerevisiae*. In yet another embodiment, the recombinant microbial host cell / microbial cell is derived from a *Saccharomyces cerevisiae* saccharified variant (…). Saccharomyces cerevisiae var. diastaticus In another implementation, the recombinant microbial host cell / microbial cell is derived from grape juice yeast (…). Saccharomyces uvarum In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces boulardii* (…). Saccharomyces boulardii In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Schaefflera* (…). Scheffersomyces ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces cerevisiae* (tree trunk *Saccharomyces cerevisiae*). Scheffersomyces stipitis (Base name: Pichia pastoris) Pichia stipitis In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Schwannium* (…). Schwanniomyces ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Schwanstein polymorpha* (… Schwanniomyces polymorphus (Base name: Pichia pastoris) Pichia polymorpha In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Schwanstein* (Western Schwann yeast). Schwanniomyces occidentalis In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Wickhamia* (…). Wickerhamomyces ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Saccharomyces cerevisiae* (Wickham yeast). Wickerhamomyces anomalus In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Yersinia* (…). Yarrowia ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Yersinia lipolytica ( Yarrowia lipolytica ).

[0061] In one embodiment, the recombinant microbial host cell is obtained from a microbial cell, which is a fungus. In some embodiments, the fungus is an ascomycete fungus. In another embodiment, the fungus is a basidiomycete fungus. In yet another embodiment, the fungus is an oil-producing fungus (e.g., a fungus capable of accumulating more than 20% of its stem cell weight in lipids or triglycerides). In one embodiment, the recombinant microbial host cell / microbial cell is derived from Aspergillus (…). Aspergillus ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Aspergillus acidophilus ( Aspergillus acidus In another embodiment, the recombinant microbial host cell / microbial cell is derived from Aspergillus feiziana ( ). Aspergillus fijiensis In another embodiment, the recombinant microbial host cell / microbial cell is derived from Aspergillus japonicus (…). Aspergillus japonicus In another embodiment, the recombinant microbial host cell / microbial cell is derived from Aspergillus ryukyu (…). Aspergillus luchuensis In another embodiment, the recombinant microbial host cell / microbial cell is derived from Aspergillus honeysuckle (…). Aspergillus melleus In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Aspergillus niger*. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Aspergillus oryzae*. Aspergillus oryzae In another embodiment, the recombinant microbial host cell / microbial cell is derived from Aspergillus flavus (…). Aspergillus flavus In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Brahma* (…). Blakeslea ) strain. In one embodiment, the recombinant microbial host cell / microbial cell is derived from the genus *Clostridium* ( Cunninghamella ) bacterial strain. In one embodiment, the recombinant microbial host cell / microbial cell is derived from the genus Cryptosporidium ( Cryphonectria ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Cryptozoa glomerata ( Cryphonectria parasitica In one implementation, the recombinant microbial host cell / microbial cell is derived from Cryptococcus spp. ( Cryptococcus) strain. In one embodiment, the recombinant microbial host cell / microbial cell is derived from the genus *Gnaphalium* (*Diplophora*). Disporotrichum ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Diplosporum dimorphosum (Dipsporium dimorphosum) Disporotrichum dimorphosporium In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus Fusarium (…). Fusarium ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Fusarium oxysporum (… Fusarium wilt In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Pythium* (…). Humicola ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from a specific humic mold ( Humicola insolens In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Morchella* (…). Mortierella ) strain. In one embodiment, the recombinant microbial host cell / microbial cell is derived from the genus *Mucor* ( I am sick. ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Mucor ( ) Mucor circinelloides In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Thermophilic Fungi* (…). Mycotherm ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from thermophilic fungi ( Mycothermus thermophiloides In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Penicillium* (…). Pencil ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Penicillium salmaria ( Penicillium camemberti In another embodiment, the recombinant microbial host cell / microbial cell is derived from Penicillium chrysogenum (…). Chrysogenian pencil In another embodiment, the recombinant microbial host cell / microbial cell is derived from Penicillium rubrum (…). Penicillium rubens In another implementation, the recombinant microbial host cell / microbial cell is derived from *Penicillium rochfellii* (…). Penicillium Roquefort In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Phaefflera* (…). Phaffia ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Phaeodactylum rubrum* ( Phaffia rhodozyma In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Mucor* (…). Phycomyces ) strain. In one embodiment, the recombinant microbial host cell / microbial cell is derived from the genus *Rhizopus* ( Rhizomucor) strain. In one embodiment, the recombinant microbial host cell / microbial cell is derived from *Rhizopus micranthum* ( Rhizomucor miehei In another implementation, the recombinant microbial host cell / microbial cell is derived from *Rhizopus microsporum* (…). Rhizomucor pusillus In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus Rhizopus ( ). Rhizopus ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from Rhizopus oligosporus ( Rhizopus arrhizus (also known as Rhizopus oryzae) Rhizopus rice In another embodiment, the recombinant microbial host cell / microbial cell is derived from Rhizopus delbrueckii (…). Rhizopus delemar In another embodiment, the recombinant microbial host cell / microbial cell is derived from Rhizopus spp. ( ). Rhizopus niveus In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Rhodotorula* (…). Rhododendron ) strain (also known as Rhodotorula spp.) Rhodosporidum (Strain). In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Fissionytomyces* (…). Schizosaccharomyces ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Schizosaccharomyces cerevisiae* (Schizosaccharomyces cerevisiae). Schizosaccharomyces pombe In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Basilella* (…). Talaromyces ) bacterial strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Basilella fragilis* (… Talaromyces funiculosus (also known as Penicillium cordifolium) Penicillium funiculosum In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Trichoderma*. Trichoderma ) strain. In another embodiment, the recombinant microbial host cell / microbial cell is derived from *Trichoderma reesei* ( Trichoderma reesei In one implementation, the recombinant microbial host cell / microbial cell is derived from the genus *Hylocereus* (…). Trichosporon sp).

[0062] The recombinant microbial host cell of this disclosure comprises a heterologous nucleic acid molecule encoding at least one glucose oxidase variant. In some embodiments, the recombinant microbial host cell of this disclosure comprises multiple heterologous nucleic acid molecules, each encoding the same glucose oxidase variant. For example, the recombinant microbial host cell may comprise at least one copy of a heterologous nucleic acid molecule encoding a glucose oxidase variant having the amino acid sequence (or a variant / fragment thereof) of SEQ ID NO: 5. In this example, the recombinant microbial host cell may comprise one or more copies of a heterologous nucleic acid molecule having the nucleic acid sequence of SEQ ID NO: 6, or a degenerate nucleic acid sequence encoding a glucose oxidase variant having the amino acid sequence (or a variant / fragment thereof) of SEQ ID NO: 5. In another example, the recombinant microbial host cell may comprise at least one copy of a heterologous nucleic acid molecule encoding a glucose oxidase variant having the amino acid sequence (or a variant / fragment thereof) of SEQ ID NO: 7. In another example, the recombinant microbial host cell may contain one or more copies of a heterologous nucleic acid molecule having the nucleic acid sequence of SEQ ID NO: 8, or a degenerate nucleic acid sequence encoding a glucose oxidase variant having the amino acid sequence of SEQ ID NO: 7 (or a variant / fragment thereof). In some embodiments, the recombinant microbial host cell of this disclosure contains a plurality of heterologous nucleic acid molecules, each encoding a different glucose oxidase variant. In yet another embodiment, the recombinant microbial host cell of this disclosure contains at least two heterologous nucleic acid molecules, each encoding a different glucose oxidase variant. In yet another example, the recombinant yeast host cell of this disclosure may contain at least one copy of a first heterologous nucleic acid molecule and at least one copy of a second heterologous nucleic acid molecule, the first heterologous nucleic acid molecule encoding a glucose oxidase variant having the amino acid sequence of SEQ ID NO: 5 (or a variant / fragment thereof), and the second heterologous nucleic acid molecule encoding a glucose oxidase variant having the amino acid sequence of SEQ ID NO: 7 (or a variant / fragment thereof). In this additional example, the recombinant microbial host cell may contain one or more copies of the following heterologous nucleic acid molecules: these heterologous nucleic acid molecules have the nucleic acid sequence of SEQ ID NO: 6, or a degenerate nucleic acid sequence encoding a glucose oxidase variant having the amino acid sequence of SEQ ID NO: 5 (or a variant / fragment thereof); and one or more copies of the following heterologous nucleic acid molecules: these heterologous nucleic acid molecules have the nucleic acid sequence of SEQ ID NO: 8, or a degenerate nucleic acid sequence encoding a glucose oxidase variant having the amino acid sequence of SEQ ID NO: 7 (or a variant / fragment thereof).

[0063] As used herein, the term "heterologous" when referring to nucleic acid molecules (such as promoters, terminators, or coding sequences) or polypeptides means a nucleic acid molecule or polypeptide that is not naturally present in the recombinant microbial host cell. "Heterologous" also includes the introduction of natural coding regions / promoters / terminators, or portions thereof, from the source organism in a form different from the corresponding natural gene and / or at a location different from the corresponding natural gene (e.g., not a natural location in its genome). One or more heterologous nucleic acid molecules are intentionally introduced into the recombinant microbial host cell. For example, heterologous nucleic acid elements may be derived from host cells of different strains or from organisms of different taxa (e.g., different domains, kingdoms, phyla, classes, orders, families, genera, or species, or any subgroup of one of these taxa).

[0064] One or more heterologous nucleic acid molecules encoding a glucose oxidase variant are introduced into a recombinant microbial host cell to enable it to express the enzyme. Expression of the heterologous peptide or control peptide can be constitutive or inducible. Expression of the glucose oxidase variant derived from one or more heterologous nucleic acid molecules can occur during the growth and / or stationary phases of the recombinant microbial host cell.

[0065] In some implementations, one or more nucleic acid molecules encoding glucose oxidase variants are introduced into a recombinant microbial host cell and codon-optimized relative to the intended recipient recombinant microbial host cell. As used herein, the term "codon-optimized coding region" refers to a nucleic acid coding region adapted for expression in the cells of a given organism by replacing at least one or more codons with one or more codons that are more frequently used in the genes of that organism. Generally, highly expressed genes in an organism are biased toward codons recognized by the most abundant tRNA species in that organism. One measure of this bias is the "codon fitness index" or "CAI," which measures the degree to which the codons encoding each amino acid in a particular gene are those that occur most frequently in a reference set of highly expressed genes from the organism. The CAI of the codon-optimized heteronucleic acid molecules described herein corresponds to between about 0.8 and 1.0, between about 0.8 and 0.9, or about 1.0.

[0066] The heterologous nucleic acid molecules disclosed herein contain coding regions for glucose oxidase variants. A DNA or RNA “coding region” is a DNA or RNA molecule that, when placed under the control of appropriate regulatory sequences, is transcribed and / or translated into a polypeptide in vitro or in vivo. An “appropriate regulatory region” refers to a nucleic acid region located upstream (5' non-coding sequence), inside, or downstream (3' non-coding sequence) of the coding region and influencing the transcription, RNA processing, or stability, or translation of the associated coding region. Regulatory regions may include promoters, translation leader sequences, RNA processing sites, effector binding sites, and stem-loop structures. The boundaries of the coding region are defined by a 5' (amino)-terminal start codon and a 3' (carboxyl)-terminal translation stop codon. The coding region may include, but is not limited to, prokaryotic regions, cDNA derived from mRNA, genomic DNA molecules, synthetic DNA molecules, or RNA molecules. If the coding region is intended for expression in eukaryotic cells, the polyadenylation signal and transcription termination sequence will typically be located at the 3' end of the coding region. In one embodiment, the coding region may be referred to as an open reading frame. An "open reading frame" is abbreviated as ORF and refers to a segment of nucleotides (DNA, cDNA, or RNA) that contains a translation start signal or start codon (such as ATG or AUG) and a stop codon and can potentially be translated into a polypeptide sequence.

[0067] The heterologous nucleic acid molecules described in this article may contain transcriptional and / or translational control regions. "Transcriptional and translational control regions" are DNA regulatory regions that provide for the expression of coding regions in host cells, such as promoters, enhancers, and terminators. In eukaryotic cells, polyadenylation signals are the control region.

[0068] Heterogeneous nucleic acid molecules can be introduced into recombinant microbial host cells using vectors. A “vector,” such as a “plasmid,” “gravel,” or “artificial chromosome” (e.g., a yeast artificial chromosome), refers to an extrachromosomal element and is typically in the form of a circular double-stranded DNA molecule. Such vectors can be derived from autonomously replicating sequences, genome-integrated sequences, bacteriophages, or nucleotide sequences from any source, or linear, circular, or supercoiled single-stranded or double-stranded DNA or RNA, in which multiple nucleotide sequences have been linked or recombined into a unique construct.

[0069] In the heterologous nucleic acid molecules described herein, the promoter and the nucleic acid molecule encoding a glucose oxidase variant are operatively linked to each other. In the context of this disclosure, the expression "operatively linked" or "operatively associated" means that the promoter physically binds to the nucleic acid molecule encoding the polypeptide in a manner that allows expression of the polypeptide from the nucleic acid molecule under certain conditions. In one embodiment, the promoter may be located upstream (5') of the nucleic acid sequence encoding the heterologous polypeptide. In the context of this disclosure, a nucleic acid molecule may contain one or more promoters. When a nucleic acid molecule contains more than one promoter, each promoter is operatively linked to the nucleic acid sequence encoding the polypeptide. With respect to the nucleic acid molecule encoding the polypeptide, the promoter may be located upstream, downstream, or both upstream and downstream.

[0070] A “promoter” is a segment of DNA that controls the expression of a coding sequence or functional RNA. As used herein, the term “expression” refers to the transcription and stable accumulation of meaningful (mRNA) from a heterologous nucleic acid molecule described herein. Expression can also refer to the translation of mRNA into a polypeptide. Promoters can be entirely derived from natural genes, or consist of different elements derived from different promoters found in nature, or even contain synthetic DNA segments. Those skilled in the art will understand that different promoters can direct expression at different developmental stages or in response to different environmental or physiological conditions. Promoters that cause genes to be expressed at substantially similar levels in most cells most of the time are generally referred to as “constitutive promoters.” It is further recognized that DNA segments of different lengths may have the same promoter activity because the exact boundaries of the regulatory sequence are not fully determined in most cases. Promoters are typically bounded at their 3' end by the transcription start site and extend upstream (in the 5' direction) to contain the minimum number of bases or elements necessary to initiate transcription at a detectable level above the background. Within the promoter, a transcription start site (e.g., conveniently defined by mapping with nuclease S1) and a polypeptide-binding domain (a common sequence) responsible for polymerase binding will be found.

[0071] The promoter can be heterologous to the nucleic acid molecule encoding the heterologous polypeptide. The promoter can be heterologous or derived from a strain of the same genus or species as the recombinant microbial host cell. In one embodiment, the promoter is derived from the same genus or species as the recombinant microbial host cell, while the polypeptide is derived from a different genus than the recombinant microbial host cell. One or more promoters can be used to allow the polypeptide to be expressed in the recombinant yeast host cell.

[0072] In some embodiments, the heteronucleotide molecule may contain one or more terminators to terminate the translation of the glucose oxidase variant. In some embodiments, the one or more terminators used are terminators derived from genes found in yeasts (such as, for example, *Saccharomyces* or *Cotyledon*). In some embodiments, the terminator contains terminators derived from: the dit1 gene (dit1t, its functional variant or functional fragment), the idp1 gene (idp1t, its functional variant or functional fragment), the gpm1 gene (gpm1t, its functional variant or functional fragment), the pma1 gene (pam1t, its functional variant or functional fragment), the tdh3 gene (tdh3t, its functional variant or functional fragment), the hxt2 gene (its functional variant or functional fragment), and the adh3 gene (adh... 3t, its functional variants or functional fragments), ira2 gene (ira2t, its functional variants or functional fragments), rpl3 gene (rpl3t, its functional variants or functional fragments), bna4 gene (bna4t, its functional variants or functional fragments), pgk1 gene (pgk1t, its functional variants or functional fragments), fur4 gene (fur4t, its functional variants or functional fragments), mig2 gene (mig2t, its functional variants or functional fragments), icy2 gene (i cy2t, its functional variants or functional fragments thereof), gic1 gene (gic1t, its functional variants or functional fragments thereof), aox1 gene (aox1t, its functional variants or functional fragments thereof), gap1 gene (gap1t, its functional variants or functional fragments thereof), gapdh gene (gapdht, its functional variants or functional fragments thereof), dhas gene (dhast, its functional variants or functional fragments thereof), fdh gene (fdht, its functional variants or functional fragments thereof), fld gene The gene includes (fldt, its functional variant or functional fragment), act (actt, its functional variant or functional fragment), arg4 (arg4t, its functional variant or functional fragment), icl1 (icl1t, its functional variant or functional fragment), prm9 (prm9t, its functional variant or functional fragment), vps13 (vps13t, its functional variant or functional fragment), and / or lac4 (lac4t, its functional variant or functional fragment).

[0073] In some embodiments, the promoter or combination of promoters present in the heterologous nucleic acid allows expression of glucose oxidase variants during the growth phase of the recombinant microbial host cell. In some embodiments, the promoter also allows expression of peptides during the stationary phase of the recombinant microbial host cell.

[0074] Promoters that can be included in heterologous nucleic acid molecules can be constitutive or inducible promoters. In some embodiments, the promoter is derived from promoters present in Saccharomyces cerevisiae. Inducible promoters include, but are not limited to, glucose-regulated promoters (e.g., the promoter of the hxt7 gene (referred to as hxt7p), its functional variants or functional fragments; the promoter of the ctt1 gene (referred to as ctt1p), its functional variants or functional fragments; the promoter of the glo1 gene (referred to as glo1p), its functional variants or functional fragments; the promoter of the ygp1 gene (referred to as ygp1p), its functional variants or functional fragments; the promoter of the gsy2 gene (referred to as gsy2p), its functional variants or functional fragments; the promoter of the gpm1 gene (referred to as gpm1p), its functional variants or functional fragments; p Promoters of the gk1 gene (called pgk1p); molasses-regulated promoters (e.g., promoters of the mol1 gene (called mol1p), their functional variants or functional fragments); promoters of heat shock regulation (e.g., promoters of the glo1 gene (called glo1p), their functional variants or functional fragments; promoters of the sti1 gene (called sti1p), their functional variants or functional fragments; promoters of the ygp1 gene (called ygp1p), their functional variants or functional fragments; promoters of the gsy2 gene (called gsy2p), their functional variants or functional fragments); promoters of oxidative stress response (e.g., The promoter of the cup1 gene (called cup1p), its functional variants or functional segments; the promoter of the ctt1 gene (called ctt1p), its functional variants or functional segments; the promoter of the trx2 gene (called trx2p), its functional variants or functional segments; the promoter of the gpd1 gene (called gpd1p), its functional variants or functional segments; the promoter of the hsp12 gene (called hsp12p), its functional variants or functional segments; the promoter of the hsp150 gene (called hsp150p), its functional variants or functional segments; the promoter of the ssc1 gene (called ssc1p), its functional variants or functional segments; Functional variants or functional fragments); osmotic stress response promoters (e.g., the promoter of the ctt1 gene (called ctt1p), its functional variants or functional fragments; the promoter of the glo1 gene (called glo1p), its functional variants or functional fragments; the promoter of the gpd1 gene (called gpd1p), its functional variants or functional fragments; the promoter of the ygp1 gene (called ygp1p), its functional variants or functional fragments; the promoter of the hor7 gene (called hor7p), its functional variants or functional fragments; the promoter of the stl1 gene (called stl1p), its functional variants or functional fragments).Nitrogen-regulated promoters (e.g., the promoter of the ygp1 gene (called ygp1p), its functional variants, or functional fragments); anaerobic-regulated promoters (e.g., the promoter from the aox1 gene (called aox1p), its functional variants, or functional fragments; the promoter of the tir1 gene (called tir1p), its functional variants, or functional fragments; the promoter of the pau5 gene (called pau5p), its functional variants, or functional fragments; the promoter of the dan1 gene (called dan1p); the promoter of the tdh1 gene (called tdh1p), its functional variants, or functional fragments; the promoter of the spi1 gene (called spi1p), its functional variants, or functional fragments; hx The promoter of the k1 gene (called hxk1p), its functional variants or functional segments; the promoter of the anb1 gene (called anb1p), its functional variants or functional segments; the promoter of the hxt6 gene (called hxt6p), its functional variants or functional segments; the promoter of the trx1 gene (called trx1p), its functional variants or functional segments; the promoter of the aac3 gene (called aac3p), its functional variants or functional segments; the promoter of the hor7 gene (called hor7p), its functional variants or functional segments; the promoter of the adh1 gene (called adh1p), its functional variants or functional segments; the promoter of the tdh2 gene (called tdh2... p), its functional variants or functional segments; the promoter of the tdh3 gene (called tdh3p), its functional variants or functional segments; the promoter of the gpd1 gene (called gpd1p), its functional variants or functional segments; the promoter of the cdc19 gene (called cdc19p), its functional variants or functional segments; the promoter of the eno2 gene (called eno2p), its functional variants or functional segments; the promoter of the pdc1 gene (called pdc1p), its functional variants or functional segments; the promoter of the hxt3 gene (called hxt3p), its functional variants or functional segments; or the promoter of the tpi1 gene (called tpi1p)); ethanol-regulated promoters Promoters (including ethanol-responsive promoters); redox-regulated promoters (e.g., including but not limited to the gpd2 gene promoter (referred to as gpd2p), its functional variants or functional fragments); sulfite-regulated promoters (e.g., including but not limited to the fzf1 gene promoter (referred to as fzf1p), its functional variants or functional fragments; the ssu1 gene promoter (referred to as ssu1p), its functional variants or functional fragments; and the ssu1-r gene promoter (referred to as ssu1-rp), its functional variants or functional fragments); and stress-responsive promoters (e.g., including but not limited to the yap1 gene promoter (referred to as yap1p), its functional variants or functional fragments);The promoter of the ssa3 gene (referred to as ssa3p), its functional variants or functional fragments; and the promoter of the hsp104 gene (referred to as hsp104p), its functional variants or functional fragments. Constitutive promoters include, but are not limited to; tef2 The promoter of a gene (called tef2p) cwp2 The promoter of a gene (called cwp2p) ssa1 The promoter of a gene (called ssa1p) eno1 The promoter of a gene (called eno1p) hxk1 The promoter of the gene (called hxk1p) pgk1 The promoter of a gene (called pgk1p) adh1 The promoter of a gene (called adh1p) rev1 The promoter of a gene (called rev1p) cycle1 The promoter of the gene (called cyc1p) and this5 Gene promoters (called ste5p), and their functional variants or functional segments.

[0075] In some embodiments, the promoter can be obtained or derived from natural promoters present in *Phaeodactylum phragmites*. Inducible promoters include, but are not limited to, glucose-regulated promoters, fructose-regulated promoters, glycerol-regulated promoters, heat shock-regulated promoters, oxidative stress-responsive promoters, osmotic stress-responsive promoters, nitrogen-regulated promoters, and ethanol-regulated promoters. In one embodiment, ethanol-regulated promoters include, but are not limited to, promoters derived from… adh2 The promoter of a gene, also known as adh3 Gene (called adh2p). Constitutive promoters include, but are not limited to, those from... spi1 The gene promoter (called spi1p). In one implementation, the parental promoter is derived from... gap1 The gene promoter (called gap1p). In one implementation, the parental promoter is derived from... hgt1 The gene promoter (called hgt1p). In one implementation, the parental promoter is derived from... glc3 The gene promoter (called glc3p). In one implementation, the parental promoter is derived from... acb2 The gene promoter (called acb2p). In one implementation, the parental promoter is derived from... pex8 The gene promoter (called pex8p). In one implementation, the parental promoter is derived from... urc1 The gene promoter (called urc1p). In one implementation, the parental promoter is derived from... tpo3The gene promoter (called top3p). In one implementation, the parental promoter is derived from... bio2 The gene promoter (called bio2p). In one implementation, the parental promoter is derived from... gut1 The gene promoter (called gut1p). In one implementation, the parental promoter is derived from... cat1 The gene promoter (called cat1p). In one implementation, the parental promoter is derived from... icl1 The gene promoter (called icl1p). In one implementation, the parental promoter is derived from... gcw14 The promoter of the gene (called gcw14p).

[0076] In some implementations, the promoter may be obtained from or derived from natural promoters present in *Onosacchari polymorpha*. In one implementation, the promoter is derived from... sister1 The promoter of the gene (called sor1p) comes from the methanol oxidase of Hansenula polymorpha. soon1 The gene promoter (called mox1p) comes from gap1 The polymorphic Hansenula polymorpha promoter (called OpGAP1p) is derived from... gapdh The polymorphic Hansenula polymorpha promoter (called OpGAPDHp) is derived from... gcw14 The polymorphic Hansenula yeast promoter (called OpGCW14p) is derived from adh1 The polymorphic Hansenula polymorpha promoter (called OpADH1p) is derived from... icl1 The polymorphic Hansenula polymorpha promoter (called OpICL1p) or derived from tef1 The polymorphic Hansenula yeast promoter (called OpTEF1p).

[0077] In one specific embodiment, the heterologous nucleic acid molecule encoding a glucose oxidase variant comprises at least one of the adh2 and / or spi1 variant promoters described in U.S. Patent Application No. 18 / 740,964, filed June 12, 2023, which is incorporated herein by reference. In yet another specific embodiment, the heterologous nucleic acid molecule encoding a glucose oxidase variant comprises the nucleic acid sequence of SEQ ID NO: 11, a variant thereof, or a fragment thereof.

[0078] Promoters that may be included in the heterologous nucleic acid molecules disclosed herein include, but are not limited to, tdh1 The promoter of a gene (called tdh1p, a functional variant or functional segment). hour7 The promoter of a gene (called hor7p, its functional variants or functional segments), hsp150 The promoter of a gene (called hsp150p, a functional variant or functional segment). hxt7 The promoter of a gene (called hxt7p, a functional variant or functional fragment), gpm1 The promoter of a gene (called gpm1p, its functional variants or functional segments), pgk1 The promoter of a gene (called pgk1p, a functional variant or functional segment). stl1 The promoter of a gene (called stl1p, a functional variant or functional segment). tef2 The promoter of a gene (called tef2p, a functional variant or functional segment). tdh3 The promoter of a gene (called tdh3p, a functional variant or fragment thereof). fba1 The promoter of a gene (called fba1p, a functional variant or fragment thereof). eno2 The promoter of the gene (called eno2p, a functional variant or fragment thereof), and / or hypo2 The promoter of the gene (called a hyp2p, a functional variant or fragment thereof). In some specific implementations, the heterologous nucleic acid contains a constitutive promoter, such as, for example, from... tef2 A promoter of a gene containing the nucleic acid sequence SEQ ID NO: 12, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises from... tdh3 A promoter of the gene containing the nucleic acid sequence of SEQ ID NO: 13, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises a promoter of the fba1 gene containing the nucleic acid sequence of SEQ ID NO: 14, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises a promoter of the fba1 gene containing the nucleic acid sequence of SEQ ID NO: 14, or a functional variant / fragment thereof. tdh3 The promoter of a gene containing the nucleic acid sequence of SEQ ID NO: 13, or a functional variant / fragment thereof, and from fba1 A promoter of a gene containing the nucleic acid sequence of SEQ ID NO: 14, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises from... eno2 A promoter of a gene containing the nucleic acid sequence of SEQ ID NO: 15, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises from... hypo2 A promoter of a gene containing the nucleic acid sequence SEQ ID NO: 16, or a functional variant / fragment thereof. In some specific embodiments, the heterologous nucleic acid comprises from... eno2 The promoter of a gene containing the nucleic acid sequence of SEQ ID NO: 15, or a functional variant / fragment thereof, and from hypo2 A promoter of a gene containing the nucleic acid sequence of SEQ ID NO: 16, or a functional variant / fragment thereof.

[0079] In the context of this disclosure, the term "functional fragment of a promoter" refers to a nucleic acid sequence that is shorter than the natural promoter but retains the ability to control the expression of a nucleic acid sequence encoding a glucose oxidase variant. Typically, a functional fragment is a segment obtained by truncating one or more nucleic acid residues from the 5' and / or 3' ends of the nucleic acid sequence of a natural promoter. In the context of this disclosure, the term "functional variant of a promoter" refers to a nucleic acid sequence that differs from the natural promoter at at least one position but still retains the ability to control the expression of a nucleic acid sequence encoding a glucose oxidase variant.

[0080] In some embodiments, the heterologous nucleic acid molecule contains one or more terminator sequences to terminate transcription of a glucose oxidase variant. The terminator may be native or heterologous to the nucleic acid sequence encoding the heterologous polypeptide. In some embodiments, one or more terminators may be used. In some embodiments, the terminator comprises a terminator derived from the following genes: say1 Gene (dit1t, its functional variants or functional segments), idp1 Gene (idp1t, its functional variants or functional segments), gpm1 Gene (gpm1t, its functional variants or functional segments), pma1 Gene (pam1t, its functional variants or functional segments), tdh3 Gene (tdh3t, its functional variants or functional segments), hxt2 Genes (their functional variants or functional segments), adh3 Gene (adh3t, its functional variants or functional fragments), and / or ira2 The gene (ira2t, its functional variants or functional fragments). In one implementation, the terminator contains or is derived from... dit1 Gene (dit1t, its functional variant or functional fragment). In another embodiment, the terminator contains or is derived from... adh3t and / or idp1t .

[0081] In the context of this disclosure, the term "functional variant of a terminator" refers to a nucleic acid sequence in which at least one nucleic acid position is substituted compared to the natural terminator, but the ability to terminate the expression of a nucleic acid sequence encoding a glucose oxidase variant is retained. In the context of this disclosure, the term "functional fragment of a terminator" refers to a nucleic acid sequence that is shorter than the natural terminator, but retains the ability to terminate the expression of a nucleic acid sequence encoding a glucose oxidase variant.

[0082] The glucose oxidase variant disclosed herein can also be obtained in a cell-free system using the heterologous nucleic acid molecules described herein.

[0083] Method for preparing compositions containing glucose oxidase variants

[0084] This disclosure provides methods for preparing glucose oxidase variants and compositions comprising glucose oxidase variants. In some embodiments, a cell-free system is used to express a glucose oxidase variant encoded by one or more heterologous nucleic acid molecules. In other embodiments, these methods include using one or more recombinant microbial host cells to express glucose oxidase. In such methods, recombinant microbial host cells containing one or more heterologous nucleic acid molecules (directly or indirectly) encoding glucose oxidase variants can be cultured or propagated to allow for the expression and accumulation of the glucose oxidase variant. Growth phases and stationary phases can be carried out in a culture medium that allows the recombinant microbial host cells to grow and divide, under conditions (stirring, temperature, oxygen concentration, etc.) favorable to the expression and accumulation of the glucose oxidase variant and optionally its secretion. In some embodiments, during or after the growth phase, the recombinant microbial cells can be placed in the presence of an inducer, which will allow for the expression of the glucose oxidase variant.

[0085] During the growth phase, the recombinant microbial host cell is contacted with a metabolizable carbon source. When the recombinant microbial host cell is *Saccharomyces phagnum* or *Saccharomyces cerevisiae*, the metabolizable carbon source is a C1-C6 carbon source. In some embodiments, the metabolizable carbon source may include a C2 carbon source, including but not limited to ethanol. Alternatively, or in combination, the metabolizable carbon source may include, but is not limited to, glucose, sucrose, fructose, glycerol, or combinations thereof. In one specific embodiment, during the growth phase, the recombinant microbial host cell is contacted with glucose as the sole metabolizable carbohydrate source. In another specific embodiment, during the growth phase, the recombinant microbial host cell is contacted with glycerol as the sole metabolizable carbohydrate source. In yet another embodiment, during the growth phase, the recombinant microbial host cell is contacted with fructose as the sole metabolizable carbohydrate source. In yet another embodiment, during the growth phase, the recombinant microbial host cell is contacted with sucrose as the sole metabolizable carbohydrate source. In some embodiments, the growth phase is carried out as a continuous fermentation. In another alternative embodiment, the growth phase is carried out as a batch fermentation. In another implementation scheme, the growth phase is carried out as a fed-batch fermentation. The expression step can be carried out at least partially under aerobic conditions.

[0086] In some embodiments, the method may further include a step of purifying a glucose oxidase variant from recombinant microbial host cells (at least partially). The purification step refers to the step of physically dissociating the expressed glucose oxidase variant from the components of the recombinant microbial host cell that expressed the variant, at least partially. The expression "substantially purified form" means the fact that the expressed glucose oxidase variant has been physically dissociated from some (and in some embodiments, most) of the components of the recombinant microbial host cell that expressed the polypeptide. In one embodiment, the composition comprising the substantially purified form of the expressed glucose oxidase variant is at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% pure. In some embodiments, the composition comprising the expressed glucose oxidase variant lacks a detectable amount of deoxyribonucleic acid from the recombinant microbial host cell used to express the variant. The purification step may include, but is not limited to, filtration, centrifugation, dialysis, precipitation, affinity capture, chromatography, etc.

[0087] In embodiments intended for intracellular expression of glucose oxidase variants, the method may include (after the expression step) a cell permeation step and / or a cell lysis step. Those skilled in the art will recognize that there are various methods for permeating and / or lysing recombinant microbial host cells. For example, cells may be homogenized (e.g., using bead-milling, bead-beating, or high-pressure homogenization techniques), and therefore, the method may include a homogenization step. In another example, cells may be treated with an enzyme, and therefore, the method may include an enzyme treatment step. In yet another embodiment of the method disclosed herein, the recombinant microbial host cells may be treated under alkaline or acidic conditions, and therefore, the method may include a pH treatment step. In other embodiments of the method disclosed herein, osmotic pressure may be applied to the recombinant microbial host cells, and therefore, the method may include a salt treatment step. In still other embodiments of the method disclosed herein, the recombinant microbial host cells may be subjected to thermo-pressure, and therefore, the method may include a cold treatment or heat treatment step.

[0088] In some embodiments, autolysis (optionally in the presence of an additional exogenous enzyme) can be used to lyse multiplied recombinant microbial host cells. For example, multiplied recombinant yeast host cells can be subjected to a combination of heat and pH treatment for a specific duration (e.g., 6, 12, 18, 24, 36, 48 hours or longer) to induce autolysis of the multiplied recombinant yeast host cells, thereby providing lysed recombinant yeast host cells. For example, multiplied recombinant yeast host cells can be subjected to temperatures between about 40°C and about 70°C or between about 50°C and about 60°C. Temperatures of at least approximately 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, or 70°C can be applied to the propagated recombinant yeast host cells. Alternatively or in combination, the propagated recombinant yeast host cells may be subjected to temperatures not exceeding about 70°C, 69°C, 68°C, 67°C, 66°C, 65°C, 64°C, 63°C, 62°C, 61°C, 60°C, 59°C, 58°C, 57°C, 56°C, 55°C, 54°C, 53°C, 52°C, 51°C, 50°C, 49°C, 48°C, 47°C, 46°C, 45°C, 44°C, 43°C, 42°C, 41°C, or 40°C. In another example, the propagated recombinant yeast host cells may be subjected to a pH between about 3.5 and 8.5, between about 5.0 and 7.5, or between about 5.0 and 6.0. The recombinant yeast host cells that have been propagated can be subjected to a pH of at least about 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5.Alternatively or in combination, the recombinant yeas...

Claims

1. A glucose oxidase variant, said glucose oxidase variant: (i) having at least 90% identity with the amino acid sequence of SEQ ID NO: 1, and (ii) comprising an amino acid substitution at any one of positions 159, 411, 443, 468 and / or 491.

2. The glucose oxidase variant according to claim 1, wherein the glucose oxidase variant comprises an amino acid substitution at position 159.

3. The glucose oxidase variant according to claim 2, wherein the glucose oxidase variant comprises amino acid substitutions of A159F, A159L, A159K, A159R, A159Y, A159T, A159V, or A159S.

4. The glucose oxidase variant according to any one of claims 1 to 3, wherein the glucose oxidase variant comprises an amino acid substitution at position 411.

5. The glucose oxidase variant of claim 4, wherein the glucose oxidase variant comprises amino acid substitutions of T411V, T411S, T411A, T411Q, T411E, or T411K.

6. The glucose oxidase variant according to any one of claims 1 to 5, wherein the glucose oxidase variant comprises an amino acid substitution at position 443.

7. The glucose oxidase variant of claim 6, wherein the glucose oxidase variant comprises amino acid substitutions of A443I, A443L, A443F, A443M, A443Y, or A443V.

8. The glucose oxidase variant according to any one of claims 1 to 7, wherein the glucose oxidase variant comprises an amino acid substitution at position 468.

9. The glucose oxidase variant of claim 8, wherein the glucose oxidase variant comprises amino acid substitutions of H468R, H468A, H468K, H468G, or H468S.

10. The glucose oxidase variant according to any one of claims 1 to 9, wherein the glucose oxidase variant comprises an amino acid substitution at position 491.

11. The glucose oxidase variant of claim 10, wherein the glucose oxidase variant comprises an amino acid substitution of Q491K, Q491R, or Q491E.

12. The glucose oxidase variant of claim 1, wherein the glucose oxidase variant further comprises one or more additional amino acid substitutions at any of positions 92, 433, 440 and / or 503.

13. The glucose oxidase variant of claim 12, wherein the glucose oxidase variant comprises an amino acid substitution at position 92.

14. The glucose oxidase variant of claim 13, wherein the glucose oxidase variant comprises amino acid substitutions of D92E, D92Q, D92A, D92K, D92R, D92S, or D92Y.

15. The glucose oxidase variant according to any one of claims 12 to 14, wherein the glucose oxidase variant comprises an amino acid substitution at position 433.

16. The glucose oxidase variant of claim 15, wherein the glucose oxidase variant comprises amino acid substitutions of S433A, S433V, S433L, S433G, S433F, S433Y, or S433I.

17. The glucose oxidase variant according to any one of claims 12 to 16, wherein the glucose oxidase variant comprises an amino acid substitution at position 440.

18. The glucose oxidase according to claim 17, wherein the glucose oxidase comprises amino acid substitutions of A440G, A440E, A440D, A440S, A440F or A440K.

19. The glucose oxidase variant according to any one of claims 12 to 17, wherein the glucose oxidase variant comprises an amino acid substitution at position 503.

20. The glucose oxidase variant of claim 19, wherein the glucose oxidase variant comprises amino acid substitutions of Q503K, Q503A, Q503R, Q503S, or Q503E.

21. A heterologous nucleic acid molecule comprising an open reading frame encoding an open reading frame encoding a glucose oxidase variant according to any one of claims 1 to 20.

22. The heterologous nucleic acid molecule of claim 21, wherein the heterologous nucleic acid molecule further comprises at least one promoter operatively associated with the open reading frame.

23. A vector comprising the heterologous nucleic acid molecule of claim 21 or 22.

24. An expression cassette comprising the heterologous nucleic acid molecule of claim 21 or 22.

25. A recombinant microbial host cell expressing a glucose oxidase variant as described in any one of claims 1 to 20.

26. The recombinant microbial host cell according to claim 25, wherein the recombinant microbial host cell comprises the heterologous nucleic acid molecule according to claim 21 or 22, the vector according to claim 23, or the expression cassette according to claim 24.

27. The recombinant microbial host cell according to claim 25 or 26, wherein the recombinant microbial host cell is yeast.

28. The recombinant microbial host cell according to claim 27, wherein the recombinant microbial host cell is derived from a yeast species.

29. The recombinant microbial host cell according to claim 28, wherein the recombinant microbial host cell is derived from Saccharomyces cerevisiae.

30. The recombinant microbial host cell according to claim 27, wherein the recombinant microbial host cell is derived from a species of the genus *Saccharomyces*.

31. The recombinant microbial host cell according to claim 30, wherein the recombinant microbial host cell is derived from *Phaeodactylum fafesumi*.

32. A method for preparing a glucose oxidase variant according to any one of claims 1 to 20, the method comprising (i) expressing the heterologous nucleic acid molecule of claim 21 or 22, the vector of claim 23, or the expression cassette of claim 24 in a recombinant microbial host cell according to any one of claims 25 to 29.

33. The method of claim 32, wherein the glucose oxidase variant is an intracellular polypeptide or a secreted polypeptide.

34. The method of claim 33, wherein the secreted polypeptide is in free form or bound to the surface of the recombinant microbial host cell.

35. The method of claim 34, wherein the polypeptide bound to the surface of the recombinant yeast host cell is a tethering polypeptide.

36. The method according to any one of claims 32 to 35, the method further comprising, after step (i), (ii) substantially separating the glucose oxidase variant from the recombinant microbial host cell.

37. The method according to any one of claims 32 to 36, the method further comprising drying the glucose oxidase variant after step (i) or (ii).

38. A composition comprising a glucose oxidase variant according to any one of claims 1 to 20, and a carrier.

39. The composition of claim 38, wherein the glucose oxidase variant can be obtained by the method of any one of claims 32 to 37, or by the method of any one of claims 32 to 37.

40. The composition according to claim 38 or 39, wherein the composition further comprises another enzyme.

41. A method for preparing dough or a baked product prepared from said dough, said method comprising adding an effective amount of any one of claims 1 to 20 of a glucose oxidase variant to said dough, optionally in combination with a fermenting yeast.

42. The method of claim 41, further comprising proofing the dough before, during, and / or after the addition.

43. The method according to claim 41 or 42, the method further comprising baking the dough after the addition.

44. The method according to any one of claims 41 to 43, wherein the method is used to increase the softness and / or elasticity of the baked product.

45. The method according to any one of claims 41 to 44, wherein the method is used to increase the strength of the dough.

46. ​​The method according to any one of claims 41 to 45, wherein the method is used to at least partially reduce the amount of chemical dough enhancer in the dough.

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