US2023108132A1PendingUtilityA1

Variant g6p g7p glucoamylase compositions and methods

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Assignee: FORNIA BIOSOLUTIONS INCPriority: Dec 21, 2018Filed: Jul 22, 2022Published: Apr 6, 2023
Est. expiryDec 21, 2038(~12.4 yrs left)· nominal 20-yr term from priority
Inventors:Xiyun ZhangJie YangGoutami BanerjeeKhin OoMarielle De Jesus PalatinoEric Lin HuImad N. SawayaTatsuya FukushimaJijiao ZengWenhua Lu
C12N 15/81C12N 1/16C12N 15/80Y02E50/10C12N 15/52C12N 1/20C12P 19/14C12Y 302/01003C12N 9/2428C12N 15/74C12N 1/14C12N 15/70
73
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Claims

Abstract

The invention is directed to novel variant glucoamylases.

Claims

exact text as granted — not AI-modified
1 . A composition comprising a variant glucoamylase enzyme, wherein the variant glucoamylase exhibits at least 95% identity to SEQ ID NO:15, wherein said variant glucoamylase enzyme has at least 1.1 fold better activity as compared to SEQ ID NO:25 under a condition selected from the group consisting of thermoactivity at about 30° C., thermoactivity at about 35° C., thermoactivity at about 40° C., thermoactivity at about 50° C., thermoactivity at about 60° C. and thermoactivity at about 70° C., wherein the variant glucoamylase enzyme does not include a starch binding domain; and wherein the variant glucoamylase enzyme is not naturally occurring. 
     
     
         2 . A composition comprising a variant glucoamylase enzyme, wherein the variant glucoamylase exhibits at least 95% identity to SEQ ID NO:15, wherein said variant glucoamylase enzyme has at least 1.1 fold better activity as compared to SEQ ID NO:25 under a condition selected from the group consisting of thermoactivity at about 30° C., thermoactivity at about 35° C., thermoactivity at about 40° C., thermoactivity at about 50° C., thermoactivity at about 60° C. and thermoactivity at about 70° C., wherein the variant glucoamylase enzyme consists of a catalytic domain; and wherein the variant glucoamylase enzyme is not naturally occurring. 
     
     
         3 . A composition comprising a variant glucoamylase enzyme comprising at least one amino acid substitution as compared to SEQ ID NO:15, wherein said amino acid substitution is at a position number selected from the group consisting of 5, 27, 36, 38, 39, 46, 47, 50, 65, 68, 79, 89, 98, 108, 121, 122, 124, 158, 161, 188, 192, 212, 215, 258, 262, 264, 298, 321, 400, 412, 419, 420, 422, 423, 457, 491, 497, 498, 503, 508, 509, 510, 7, 9, 11, 19, 26, 31, 42, 44, 49, 53, 55, 57, 69, 72, 73, 78, 85, 86, 88, 92, 93, 94, 97, 103, 106, 118, 119, 125, 141, 145, 149, 150, 153, 155, 168, 170, 171, 178, 179, 186, 195, 204, 205, 208, 209, 213, 214, 219, 220, 224, 227, 246, 247, 256, 261, 306, 307, 309, 311, 317, 342, 347, 348, 352, 353, 355, 362, 364, 370, 374, 381, 382, 388, 391, 394, 395, 399, 407, 418, 434, 436, 437, 440, 446, 452, 453, 460, 469, 470, 472, 475, 476, 478 and 492, wherein said variant enzyme is at least 95% identical to SEQ ID NO:15, wherein the variant glucoamylase enzyme does not include a starch binding domain; and wherein the variant glucoamylase enzyme is not naturally occurring. 
     
     
         4 . A composition comprising a variant glucoamylase enzyme comprising at least one amino acid substitution as compared to SEQ ID NO:15, wherein said amino acid substitution is at a position number selected from the group consisting of 5, 27, 36, 38, 39, 46, 47, 50, 65, 68, 79, 89, 98, 108, 121, 122, 124, 158, 161, 188, 192, 212, 215, 258, 262, 264, 298, 321, 400, 412, 419, 420, 422, 423, 457, 491, 497, 498, 503, 508, 509, 510, 7, 9, 11, 19, 26, 31, 42, 44, 49, 53, 55, 57, 69, 72, 73, 78, 85, 86, 88, 92, 93, 94, 97, 103, 106, 118, 119, 125, 141, 145, 149, 150, 153, 155, 168, 170, 171, 178, 179, 186, 195, 204, 205, 208, 209, 213, 214, 219, 220, 224, 227, 246, 247, 256, 261, 306, 307, 309, 311, 317, 342, 347, 348, 352, 353, 355, 362, 364, 370, 374, 381, 382, 388, 391, 394, 395, 399, 407, 418, 434, 436, 437, 440, 446, 452, 453, 460, 469, 470, 472, 475, 476, 478 and 492, wherein said variant glucoamylase enzyme has at least 1.1 fold better activity as compared to SEQ ID NO:15 under a condition selected from the group consisting of thermoactivity at about 30° C., thermoactivity at about 35° C., thermoactivity at about 40° C., thermoactivity at about 50° C., thermoactivity at about 60° C. and thermoactivity at about 70° C.; wherein said variant enzyme is at least 95% identical to SEQ ID NO:15, wherein the variant glucoamylase enzyme does not include a starch binding domain; and wherein the variant glucoamylase enzyme is not naturally occurring. 
     
     
         5 . The composition according to  claim 3 , wherein said variant glucoamylase enzyme exhibits at least 96% identity to SEQ ID NO:15. 
     
     
         6 . The composition according to  claim 3 , wherein said amino acid substitution(s) occur at at least two of said positions. 
     
     
         7 . The composition according to  claim 3 , wherein said amino acid substitution(s) is at position number(s) selected from the group consisting of 5, 68, 188, 321, 419, 422, 7, 11, 19, 26, 31, 42, 44, 49, 53, 55, 57, 69, 72, 73, 78, 79, 85, 86, 88, 89, 92, 93, 94, 97, 98, 103, 106, 118, 119, 125, 141, 145, 149, 150, 153, 155, 161, 168, 170, 171, 178, 179, 186, 195, 204, 205, 208, 209, 213, 214, 219, 220, 224, 227, 246, 247, 256, 261, 262, 306, 307, 309, 311, 317, 342, 347, 348, 352, 353, 355, 362, 364, 370, 374, 381, 382, 388, 391, 394, 395, 399, 400, 407, 412, 418, 434, 436, 437, 440, 446, 452, 453, 460, 469, 470, 472, 475, 476, 478, and 492. 
     
     
         8 . The composition according to  claim 3 , wherein said amino acid substitution(s) is selected from the group consisting of N27A, S36P, A38V, A39F, S46T, P47T, S50Q, V65I, E68N, L79F, T89N, T98S, A108S, P121S, F122M, G124P, G124S, G124T, G158S, Q161P, S188P, S188W, T192A, K212Y, S215A, T258S, A262S, H264M, I298V, Y321L, T400L, Y412F, L420K, A422G, P423G, P423R, P423V, G457S, A491V, K5P, K5S, K5T, K5Y, K5Q, K5N, K5H, E68K, E68Y, E68S, S188T, S188H, Y321F, Y321W, Q419P, A422S, R7C, E11S, L19I, C26N, T31N, V42I, I44V, R49H, D53N, Y55F, T57S, I69L, S72A, V73F, T78K, L79D, L79Y, E85Q, N86Q, V88I, T89S, A92T, Y93K, L94V, V97I, S103D, D106T, D118N, M119E, A125P, M141L, Y145A, L149I, N150D, A153S, T155A, N168S, V170I, A171T, G178T, Y179F, P186E, A195V, S204N, T205A, A208T, K209R, S213T, H214C, T219S, V220Q, I224V, Y227F, A246S, S247G, A256V, T261A, T261G, S306A, A307E, D309S, L311V, A317P, V342I, L347N, E348I, T352S, V353I, S355D, T362Q, L364I, T370V, A374N, E381N, S382D, T388Q, A391G, F394Y, V395L, Q399E, T400K, A407S, Q418T, S434T, T436S, E437A, D440Q, G446S, S452A, V453S, A460S, A469S, A470T, S472T, G475V, T476W, G478S, L492P, and L9P. 
     
     
         9 . The composition according to  claim 3 , wherein said amino acid substitution(s) is selected from the group consisting of K5P, K5S, K5T, K5Y, K5Q, K5N, K5H, E68K, E68Y, E68S, S188T, S188H, Y321F, Y321W, Q419P, A422S, R7C, E11S, L19I, C26N, T31N, V42I, I44V, R49H, D53N, Y55F, T57S, I69L, S72A, V73F, T78K, L79D, L79Y, E85Q, N86Q, V88I, T89S, A92T, Y93K, L94V, V97I, T98S, S103D, D106T, D118N, M119E, A125P, M141L, Y145A, L149I, N150D, A153S, T155A, Q161P, N168S, V170I, A171T, G178T, Y179F, P186E, A195V, S204N, T205A, A208T, K209R, S213T, H214C, T219S, V220Q, I224V, Y227F, A246S, S247G, A256V, T261A, T261G, A262S, S306A, A307E, D309S, L311V, A317P, V342I, L347N, E348I, T352S, V353I, S355D, T362Q, L364I, T370V, A374N, E381N, S382D, T388Q, A391G, F394Y, V395L, Q399E, T400K, A407S, Y412F, Q418T, S434T, T436S, E437A, D440Q, G446S, S452A, V453S, A460S, A469S, A470T, S472T, G475V, T476W, G478S, and L492P. 
     
     
         10 - 14 . (canceled) 
     
     
         15 . A nucleic acid encoding said variant glucoamylase enzyme of  claim 3 . 
     
     
         16 . The nucleic acid of  claim 15 , wherein said nucleic acid is codon optimized for a host organism for expression of the variant glucoamylase enzyme in said organism. 
     
     
         17 . The nucleic acid of  claim 15  comprising the sequence of SEQ ID NO:16. 
     
     
         18 . An expression vector comprising the nucleic acid of  claim 15 . 
     
     
         19 . A host cell comprising the nucleic acid of  claim 15 . 
     
     
         20 . A host cell comprising the expression vector of  claim 18 . 
     
     
         21 . The host cell of  claim 19 , wherein said host cell is selected from the group consisting of a bacterial cell, a fungal cell, and a yeast cell. 
     
     
         22 . A method of making a variant glucoamylase enzyme comprising: a) culturing the host cell of  claim 19  under conditions wherein said variant glucoamylase enzyme is expressed; and b) recovering said variant glucoamylase enzyme. 
     
     
         23 - 42 . (canceled) 
     
     
         43 . A composition comprising a C-terminally truncated variant glucoamylase enzyme of SEQ ID NO:13, wherein said truncation position is at a position number selected from the group consisting of 493, 500, 502, 503, 506, 509, 510, 513, 514, 519, 520, 522, 524, 525, 544, 549, 550, 551, 556, 558, 560, 563, 564 and 569. 
     
     
         44 . A composition comprising a variant glucoamylase enzyme comprising at least one amino acid substitution as compared to SEQ ID NO:13, wherein said amino acid substitution is at a position selected from the group consisting of 5, 27, 36, 38, 46, 47, 50, 65, 68, 79, 89, 98, 108, 122, 124, 158, 161, 188, 192, 212, 215, 258, 262, 264, 298, 321, 400, 412, 420, 422, 457, 491, 497, 498, 503, 508, 509, 510, 516, 518, 521, 522, 526, 533, 534, 535, 540, 542, 544, 545, 549, 550, 551, 555, 556, 557, 559, 563, 564, 569, 570, 581584, 7, 9, 11, 19, 26, 31, 42, 53, 55, 57, 69, 72, 73, 78, 85, 86, 88, 92, 93, 94, 97, 103, 106, 118, 125, 141, 145, 149, 150, 153, 155, 168, 170, 171, 178, 179, 186, 195, 204, 205, 208, 209, 213, 214, 219, 220, 224, 227, 246, 247, 256, 261, 306, 307, 311, 317, 342, 347, 348, 352, 353, 355, 362, 364, 370, 374, 381, 382, 388, 391, 394, 395, 399, 407, 418, 434, 436, 437, 440, 446, 452, 453, 460, 469, 470, 472, 475, 476, 478 and 492, wherein said variant enzyme is at least 95% identical to SEQ ID NO:13, and wherein the variant glucoamylase enzyme is not naturally occurring. 
     
     
         45 . A composition comprising a variant glucoamylase enzyme comprising at least one amino acid substitution as compared to SEQ ID NO:13, wherein said amino acid substitution is at a position selected from the group consisting of 5, 27, 36, 38, 46, 47, 50, 65, 68, 79, 89, 98, 108, 122, 124, 158, 161, 188, 192, 212, 215, 258, 262, 264, 298, 321, 400, 412, 420, 422, 457, 491, 497, 498, 503, 508, 509, 510, 516, 518, 521, 522, 526, 533, 534, 535, 540, 542, 544, 545, 549, 550, 551, 555, 556, 557, 559, 563, 564, 569, 570, 581584, 7, 9, 11, 19, 26, 31, 42, 53, 55, 57, 69, 72, 73, 78, 85, 86, 88, 92, 93, 94, 97, 103, 106, 118, 125, 141, 145, 149, 150, 153, 155, 168, 170, 171, 178, 179, 186, 195, 204, 205, 208, 209, 213, 214, 219, 220, 224, 227, 246, 247, 256, 261, 306, 307, 311, 317, 342, 347, 348, 352, 353, 355, 362, 364, 370, 374, 381, 382, 388, 391, 394, 395, 399, 407, 418, 434, 436, 437, 440, 446, 452, 453, 460, 469, 470, 472, 475, 476, 478 and 492, wherein said variant glucoamylase enzyme has at least 1.1 fold better activity as compared to SEQ ID NO:13 under a condition selected from the group consisting of thermoactivity at about 30° C., thermoactivity at about 35° C., thermoactivity at about 40° C., thermoactivity at about 50° C., thermoactivity at about 60° C. and thermoactivity at about 70° C.; wherein said variant enzyme is at least 95% identical to SEQ ID NO:13; and wherein the variant glucoamylase enzyme is not naturally occurring. 
     
     
         46 . The composition according to  claim 45 , wherein said variant enzyme is at least 96% identical to SEQ ID NO:13. 
     
     
         47 . The composition according to  claim 44 , wherein said amino acid substitution(s) occurs at at least two of said positions. 
     
     
         48 - 54 . (canceled) 
     
     
         55 . The composition according to  claim 44 , wherein said variant glucoamylase enzyme further comprises a C-terminal amino acid truncation at a position number selected from the group consisting of 493, 500, 502, 503, 506, 509, 510, 513, 514, 519, 520, 522, 524, 525, 544, 549, 550, 551, 556, 558, 560, 563, 564 and 569. 
     
     
         56 . A nucleic acid encoding said variant glucoamylase enzyme of  claim 44 . 
     
     
         57 . The nucleic acid of  claim 56 , wherein said nucleic acid is codon optimized for a host organism for expression of the variant glucoamylase enzyme in said organism. 
     
     
         58 . (canceled) 
     
     
         59 . An expression vector comprising the nucleic acid of  claim 56 . 
     
     
         60 . A host cell comprising the nucleic acid of  claim 56 . 
     
     
         61 . A host cell comprising the expression vector of  claim 59 . 
     
     
         62 . The host cell of  claim 60  or  claim 61 , wherein said host cell is selected from the group consisting of a bacterial cell, a fungal cell, and a yeast cell. 
     
     
         63 . A method of making a variant glucoamylase enzyme comprising: a) culturing the host cell of  claim 62  under conditions wherein said variant glucoamylase enzyme is expressed; and b) recovering said variant glucoamylase enzyme. 
     
     
         64 - 84 . (canceled) 
     
     
         85 . A composition comprising a variant glucoamylase enzyme comprising amino acid substitutions as compared to SEQ ID NO:13, wherein said amino acid substitutions are selected from the group consisting of S188H/Y321W/Q419P, T98S/Q161P/F516L, T98S/Q161P/N570P, T98S/Q161P, T550D/F555S, V65I/Y412F/Y503S/S518I, Y412F/Y503S/I564T, Y412F/Y503E, Y412F/Y503E/S518I, V65I/Y412F/Y503S, V65I/Y503E, Y503D/S518I/I564N, Y503E/S518L, V65I/Y503E/S544Q, V65I/Y503S, Y503E/S544E, V65I/Y503E/S544E/I564N, V65I/Y412F/Y503E, Y503E/S518I/S544Q, V65I/Y503E/S518M, Y412F/S518L, Y503E/S544Q, V65I/Y412F/Y503E/S544E/I564T/G569I, Y412F/Y503S, Y503E/I564T, S549D/F555D/G559N, S549D/F555R, K508T/L526N/S549D/G559N, K508T/G559N, F555D/I556P/G559N, S549D/F555R/I556P/G559N, F555R/I556P, L526I/F555R/I556P, F555R/I556P/G559N, K508T/I556P/G559N, F555D/I556P, K508T/L526N/A534T/S549D/I556P, K508T/L526I/S549D/G559N, K508N/L526I/S549E/F555L/G559N, L526N/S549D/F555D/I556P, L526I/F555D/G559N, A38V/F555R, A39F/T540N/T542N, L498T/T542N/T581N/T584N, T542N/T581N/T584N, S535Y/T542N, T540N/T584N, T540N/T542N/T581N/T584N, L498T/T581N/T584N, L498T/T584N, L498T/T542N/T581N, P121S/T542N/T584N, L498T/T542N, S535Y/T540N/T542N/T581N, Q419P/P423R, L79F/Q419P, Q419P/P423V, Q419P/P423R/T533R, S36P/Q419P, Q419P/P423G, S36P/T400L/Q419P/P423G, S50Q/Q419P/P423R, S50Q/Q419P/P423R/G457S/E497V/P521S, Y321F/A422S, S188H/Q419P, K5H/Y321W, K5N/Y321F, K5P/S188H, E68S/S188H/A422S, S188T/Y321F/Q419P/A422S, K5H/S188H/Y321F/A422S, S188H/Y321W/Q419P, S188H/A422S, S188H/A422S/V545A, K5Q/A422S, K5S/E68K/Y321W, K5H/Y321F/A422S, S188H/Y321W/Q419P, K5Y/A422S, Q419P/A422S, K5Y/S188H/A422S, K5T/A422S, K5T/Y321W, Y321W/A422S, Q419P/A422S, K5P/Y321F, K5H/S188H/Y321F/A422S, E68K/A422S, Y321F/A422S, K5H/Y321F, K5T/Y321F/Q419P/A422S, K5T/E68Y/S188T, K5S/E68Y/S188H, K5N/S188H, K5T/E68S/S188T, K5H/E68Y/S188P, K5P/E68Y/S188T, K5T/E68K/S188H, K5P/E68K/S188T, K5H/E68Y/S188T, K5T/S188H, K5T/E68N/S188T, K5Y/E68Y/S188T, K5S/E68Y/S188T, K5Q/E68K/S188H, K5P/E68N/S188H, K5P/E68N/S188T, K5P/E68Y/S188H, K5Y/E68Y/S188H, K5S/S188T, K5H/E68N/S188H, K5P/S188H, K5H/S46T/E68K/S188H, K5H/E68K/S188T, K5Q/E68Y/S188T, K5Y/E68N/S188H, V42I/S188H/A195V/Y412F/Q419P, L19I/V42I/E68Y/N168S/S188H/A195V/Y412F, E11S/V42I/T57S/D118N/N168S/S188H/A195V/L311V, E11S/V42I/D53N/E68Y/N168S/S188H/A195V/L311V/Y412F, E11S/L19I/V42I/I69L/Y321W/Y412F/Q419P, E11S/L19I/V42I/E68Y/D118N/S188H/A195V/L311V/Y412F, E11S/L19I/T57S/M119E/S188H/A195V/L311V/Y412F, E11S/V42I/A317P/Y412F/Q419P, L19I/T57S/I69L/D118N/N168S/S188H/A195V/L311V/A317P/Y321F/Y412F/Q419P, E11S/E68Y/S188H/A195V/L311V/Y412F, E11S/L19I/V42I/E68Y/I69L/D118N/N168S/S188H/A195V/L311V/Y412F, E11S/L19I/V42I/S188H/A195V/L311V/Y321W/Y412F/Q419P, E11S/L19I/N168S/S188H/A195V/L311V/A317P/Y321F/Y412F, E11S/V42I/E68Y/Y412F, E11S/L19I/V42I/E68Y/Y412F, E11S/V42I/E68Y/S188H/A195V/Y412F, E11S/L19I/V42I/T57S/I69L/S188H/A195V/L311V/Y321W/Y412F, E11S/L19I/D53N/E68Y/S188H/A195V/L311V/Y412F, E11S/V42I/E68Y/S188H/A195V/L311V/Y321W/Y412F, E11S/V42I/E68Y/S188H/L311V/Y412F/Q419P, E11S/L19I/V42I/E68Y/S188H/A195V/L311V/A317P/Y321W/Y412F/Q419P, E11S/L19I/D53N/I69L/S188H/A195V/L311V/Q419P, E11S/V42I/E68Y/N168S/L311V/A317P/Y321W/Y412F, E11S/E68Y/I69L/S188H/A195V/L311V/A317P/Y321F/Y412F, E11S/V42I/T57S/E68Y/I69L/S188H/A195V/L311V/A317P/Y321F, E11S/D53N/T57S/L311V/Y321F/Y412F/Q419P, E11S/L19I/S188H/A195V/L311V/A317P/Y321W/Y412F/Q419P, E11S/L19I/I69L/S188H/A195V/L311V/A317P, E11S/V42I/I69L/N168S/S188H/A195V/L311V/A317P/Y412F/Q419P, E11S/V42I/E68Y/S188H/A195V/L311V/Y412F, E11S/V42I/I69L/S188H/A195V/L311V/A317P/Y321F/Y412F, E11S/Y412F, E11S/L19I/V42I/E68Y/I69L/S188H/A195V/Y412F, E11S/L19I/V42I/D53N/T57S/S188H/A195V/L311V/Y321W/Y412F, V42I/E68Y/Y412F, E11S/L19I/V42I/D53N/T57S/E68Y/I69L/N168S/S188H/A195V/L311V/A317P/Y321F, E11S/L19I/V42I/D53N/T57S/I69L/S188H/A195V/L311V/A317P/Y321W/Y412F, E11S/V42I/A317P/Y321F, E11S/V42I/T57S/E68Y/D118N/S188H/A195V/L311V/Y412F, E11S/L19I/V42I/E68Y/I69L/D118N/N168S/S188H/A195V/L311V/Y412F/Q419P, E11S/V42I/D53N/E68Y/S188H/A195V/L311V/Y412F, E11S/I69L/D118N/S188H/A195V/L311V/Y412F, V42I/D53N/T57S/E68Y/M141L/N168S/T261A/Y321W/E381N/Y412F, E11S/V42I/S188H/L347N/Y412F/S434T, D53N/T57S/E68Y/D118N/M119E/L311V/E348I/Y412F, D118N/N168S/S188H/L347N/E348I/S382D/T388Q/V395L, E68Y/I69L/N168S/S188H/A195V/L311V/A317P/Y321W/Y412F/Q419P, E11S/E68Y/V88I/A317P/Y321F/S355D, D53N/I69L/L79Y/M119E/T261A/L311V/L347N/E348I/Q419P, V42I/E68Y/I69L/D118N/M119E/M141L/L311V/A317P/Y321F/L347N, E11S/L19I/E68Y/I69L/L79Y/M141L/N168S/T261A/A317P/Y321W/L347N, E11S/V42I/E68Y/I69L/L311V/Y321W/S434T, E11S/V42I/D53N/N168S/L311V/A317P/Y321W, E11S/E68Y/I69L/D118N/N168S/Y321F/Y412F, V42I/D53N/T57S/L311V/Y321W/S355D/Y412F/Q419P, V42I/E68Y/L311V/L347N/L364I/Y412F, E11S/D118N/M119E/M141L/L311V/Y321W/L347N, V42I/D53N/T57S/M119E/M141L/A317P/Y321F/Q419P, T57S/I69L/T89S/S188H/A195V/T261A/L311V/A317P/Y321W/F394Y/Y412F, Y321F/Y412F, V42I/T57S/E68Y/I69L/T89S/M119E/T261A/A317P/Y412F/S434T, E11S/V42I/E68Y/L311V/A317P/S434T, V42I/D53N/T57S/E68Y/I69L/S434T, V42I/E68Y/Y321W, L311V/L347N/E348I/S355D/L364I/S434T, E11S/D53N/T57S/E68Y/V88I/T89S/M119E/A317P/Y321W, D53N/E68Y/I69L/T89S/L311V/A317P/S355D/Q419P, V42I/E68Y/A317P/Y321F/Y412F, L19I/I69L/T89S/L311V/A317P/Y321F/S355D/L364I/Y412F, V42I/D53N/T57S/E68Y/I69L/M141L/S188H/A195V/L311V/A317P/Y321F/Y412F/S434T, T57S/V88I/A317P/Y321W/Q419P, E11S/L19I/V42I/D53N/E68Y/L311V/A317P/Y321W/Y412F, E11S/V42I/D53N/E68Y/I69L/S188H/A195V/E348I, L19I/V42I/T57S/I69L/V88I/M119E/T261A/A317P/Y321F/Y412F, D53N/E68Y/D118N/M119E/M141L/T261A/L347N/E348I/S355D/L364I/S434T, E11S/T261A/L347N/E348I/S355D/S434T, M119E/S188H/E348I, E11S/A317P/Y321F/L347N, E11S/E68Y/I69L/T261A/L364I, D118N/M119E/N168S/S188H/A195V/L311V/Y321W/L347N/F394Y, E11S/L311V/Y321W/E348I/S355D/L364I/Y412F, V42I/D53N/T57S/I69L/V88I/L347N/E348I/F394Y/V395L/S434T, E11S/D53N/T89S/N168S/S188H/T261A/L311V/A317P/Y321W/S355D/Y412F, L19I/V42I/D53N/L79Y/T89S/N168S/T261A/L311V/Y321W/Y412F/Q419P/S434T, L79Y/V88I/D118N/M119E/T261A/Y321F/L364I/Y412F, V42I/E68Y/T89S/M141L/T261A/L311V/Y321F/E348I/L364I, V42I/E68Y/D118N/S188H/T261A/Y412F/S434T, E11S/D53N/E68Y/I69L/T89S/Y321W/E348I/S355D, M119E/L311V/Y321F, L311V/L347N/E348I, E11S/V42I/A317P/Y321F/L347N/Y412F, E11S/L19I/V42I/E68Y/A317P/Y321F/L364I/Y412F, D53N/E68Y/T89S/T261A, I69L/S188H/A195V/L311V/A317P/Y321W/V395L/Y412F, V42I/D53N/E68Y/V88I/T89S/D118N/L311V/Y412F/S434T, E11S/V42I/E68Y/I69L/L311V/E348I, V42I/Y321W, E68Y/T261A/L311V/L347N/E348I/S434T, E11S/E68Y/I69L/L79Y, V42I/D53N/E68Y/S188H/A195V/T261A/L311V/Y321F/S355D/S434T, L19I/V42I/S188H/A195V/S382D/V395L/Q419P, E11S/L19I/V42I/D53N/T57S/M119E/L311V/Y321W/L347N/F394Y/Y412F, L9P/E11S/D53N/T57S/E68Y/M119E/M141L/E348I/Y412F and L19I/V42I/I69L/L311V/Y321W/L347N.

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