Engineering the acyltransferase substrate specificity of assembly line polyketide synthases

Journal of the Royal Society Interface

Volumn 10, Issue 85, 2013, Pages

  Dunn, Briana J ^a   Khosla, Chaitan ^a,b  

^a Stanford University   (United States)

^b STANFORD UNIVERSITY   (United States)

Author keywords

Acyltransferase; Antibiotics; Enzyme engineering; Polyketide

Indexed keywords

ANTIBIOTICS; ASSEMBLY; ASSEMBLY MACHINES; ENGINEERING; KETONES;

ACYLTRANSFERASE; DOMAIN ENGINEERING; ENGINEERING APPROACHES; ENZYME ENGINEERING; POLYKETIDE SYNTHASES; POLYKETIDES; STRUCTURAL DIVERSITY; SUBSTRATE SPECIFICITY;

PLANTS (BOTANY);

ACYLTRANSFERASE; ERYTHROMYCIN; GELDANAMYCIN; POLYKETIDE SYNTHASE; RAPAMYCIN; THIOL ESTER HYDROLASE; ANTIBIOTIC AGENT; POLYKETIDE;

BIOSYNTHESIS; CARBOXY TERMINAL SEQUENCE; CARBOXYLATION; CRYSTAL STRUCTURE; CYCLIZATION; ENZYME ENGINEERING; ENZYME SPECIFICITY; ENZYME STRUCTURE; ESCHERICHIA COLI; EVOLUTION; GENE SEQUENCE; MOLECULAR DYNAMICS; NONHUMAN; PROTEIN PROTEIN INTERACTION; QUANTUM MECHANICS; REVIEW; RHIZOBIUM TRIFOLII; SACCHAROPOLYSPORA; SITE DIRECTED MUTAGENESIS; STREPTOMYCES COELICOLOR; CHEMISTRY; GENETICS; PROCEDURES; PROTEIN ENGINEERING; METHODOLOGY;

ACYLTRANSFERASES; POLYKETIDE SYNTHASES; PROTEIN ENGINEERING; SUBSTRATE SPECIFICITY;

ACYLTRANSFERASE; ANTIBIOTICS; ENZYME ENGINEERING; POLYKETIDE;

EID: 84891396350     PISSN: 17425689     EISSN: 17425662     Source Type: Journal    
DOI: 10.1098/rsif.2013.0297     Document Type: Review

References (127)

1. Li JW, Vederas JC. 2009 Drug discovery and natural products: end of an era or an endless frontier? Science 325, 161-165. (doi:10.1126/science.1168243)
2. Butler MS. 2004 The role of natural product chemistry in drug discovery. J. Nat. Prod. 67, 2141-2153. (doi:10.1021/np040106y)
3. Wright GD. 2012 Antibiotics: a new hope. Chem. Biol. 19, 3-10. (doi:10.1016/j.chembiol.2011.10.019)
4. Minowa Y, Araki M, Kanehisa M. 2007 Comprehensive analysis of distinctive polyketide and nonribosomal peptide structural motifs encoded in microbial genomes. J. Mol. Biol. 368, 1500-1517. (doi:10.1016/j.jmb.2007.02.099)
5. Donadio S, Staver MJ, McAlpine JB, Swanson SJ, Katz L. 1991 Modular organization of genes required for complex polyketide biosynthesis. Science 252, 675-679. (doi:10.1126/science.2024119)
6. Cortes J, Haydock SF, Roberts GA, Bevitt DJ, Leadlay PF. 1990 An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. Nature 348, 176-178. (doi:10.1038/348176a0)
7. Tsoi CJ, Khosla C. 1995 Combinatorial biosynthesis of 'unnatural' natural products: the polyketide example. Chem. Biol. 2, 355-362. (doi:10.1016/1074- 5521(95)90214-7)
8. Khosla C, Zawada RJ. 1996 Generation of polyketide libraries via combinatorial biosynthesis. Trends Biotechnol. 14, 335-341. (doi:10.1016/0167- 7799(96)10046-9)
9. Weissman KJ, Leadlay PF. 2005 Combinatorial biosynthesis of reduced polyketides. Nat. Rev. Microbiol. 3, 925-936. (doi:10.1038/nrmicro1287)
10. Khosla C, Gokhale RS, Jacobsen JR, Cane DE. 1999 Tolerance and specificity of polyketide synthases. Annu. Rev. Biochem. 68, 219-253. (doi:10.1146/annurev.biochem.68.1.219)
11. Wu N, Tsuji SY, Cane DE, Khosla C. 2001 Assessing the balance between protein-protein interactions and enzyme-substrate interactions in the channeling of intermediates between polyketide synthase modules. J. Am. Chem. Soc. 123, 6465-6474. (doi:10.1021/ja010219t)
12. Watanabe K, Wang CC, Boddy CN, Cane DE, Khosla C. 2003 Understanding substrate specificity of polyketide synthase modules by generating hybrid multimodular synthases. J. Biol. Chem. 278, 42 020-42 026. (doi:10.1074/jbc. M305339200)
13. Lau J, Cane DE, Khosla C. 2000 Substrate specificity of the loading didomain of the erythromycin polyketide synthase. Biochemistry 39, 10 514-10 520. (doi:10.1021/bi000602v)
14. Liou GF, Lau J, Cane DE, Khosla C. 2003 Quantitative analysis of loading and extender acyltransferases of modular polyketide synthases. Biochemistry 42, 200-207. (doi:10.1021/bi0268100)
15. Chen AY, Schnarr NA, Kim CY, Cane DE, Khosla C. 2006 Extender unit and acyl carrier protein specificity of ketosynthase domains of the 6-deoxyerythronolide B synthase. J. Am. Chem. Soc. 128, 3067-3074. (doi:10.1021/ja058093d)
16. Chan YA, Podevels AM, Kevany BM, Thomas MG. 2009 Biosynthesis of polyketide synthase extender units. Nat. Prod. Rep. 26, 90-114. (doi:10.1039/b801658p)
17. Rascher A, Hu Z, Viswanathan N, Schirmer A, Reid R, Nierman WC, Lewis M, Hutchinson CR. 2003 Cloning and characterization of a gene cluster for geldanamycin production in Streptomyces hygroscopicus NRRL 3602. FEMS Microbiol. Lett. 218, 223-230. (doi:10.1016/S0378-1097(02)01148-5)
18. Chan YA, Thomas MG. 2010 Recognition of (2S)-aminomalonyl-acyl carrier protein (ACP) and (2R)-hydroxymalonyl-ACP by acyltransferases in zwittermicin A biosynthesis. Biochemistry 49, 3667-3677. (doi:10.1021/bi100141n)
19. Chan YA, Boyne 2nd MT, Podevels AM, Klimowicz AK, Handelsman J, Kelleher NL, Thomas MG. 2006 Hydroxymalonyl-acyl carrier protein (ACP) and aminomalonyl-ACP are two additional type I polyketide synthase extender units. Proc. Natl Acad. Sci. USA 103, 14 349-14 354. (doi:10.1073/pnas.0603748103)
20. Emmert EA, Klimowicz AK, Thomas MG, Handelsman J. 2004 Genetics of zwittermicin A production by Bacillus cereus. Appl. Environ. Microbiol. 70, 104-113. (doi:10.1128/AEM.70.1.104-113.2004)
21. Holmes TC et al. 2012 Molecular insights into the biosynthesis of guadinomine: a type III secretion system inhibitor. J. Am. Chem. Soc. 134, 17 797-17 806. (doi:10.1021/ja308622d)
22. Hughes AJ, Keatinge-Clay A. 2011 Enzymatic extender unit generation for in vitro polyketide synthase reactions: structural and functional showcasing of Streptomyces coelicolor MatB. Chem. Biol. 18, 165-176. (doi:10.1016/j.chembiol. 2010.12.014)
23. Lombo F, Pfeifer B, Leaf T, Ou S, Kim YS, Cane DE, Licari P, Khosla C. 2001 Enhancing the atom economy of polyketide biosynthetic processes through metabolic engineering. Biotechnol. Prog. 17, 612-617. (doi:10.1021/bp010045j)
24. Wilson MC, Moore BS. 2012 Beyond ethylmalonyl-CoA: the functional role of crotonyl-CoA carboxylase/reductase homologs in expanding polyketide diversity. Nat. Prod. Rep. 29, 72-86. (doi:10.1039/c1np00082a)
25. O'Hagan D, Rogers SV, Duffin GR, Reynolds KA. 1995 The biosynthesis of monensin-A: thymine, beta-aminoisobutyrate and methacrylate metabolism in Streptomyces cinnamonensis. J. Antibiot. (Tokyo) 48, 1280-1287. (doi:10.7164/antibiotics.48.1280)
26. Kim YS, Kang SW. 1994 Steady-state kinetics of malonyl-CoA synthetase from Bradyrhizobium japonicum and evidence for malonyl-AMP formation in the reaction. Biochem. J. 297, 327-333. (Pubitemid 24026426)
27. Kim YS, Chae HZ. 1991 Purification and properties of malonyl-CoA synthetase from Rhizobium japonicum. Biochem J. 273, 511-516.
28. Pohl NL, Hans M, Lee HY, Kim YS, Cane DE, Khosla C. 2001 Remarkably broad substrate tolerance of malonyl-CoA synthetase, an enzyme capable of intracellular synthesis of polyketide precursors. J. Am. Chem. Soc. 123, 5822-5823. (doi:10.1021/ja0028368)
29. Cane DE, Yang CC. 1987 Macrolide biosynthesis. IV. Intact incorporation of a chain-elongation intermediate into erythromycin. J. Am. Chem. Soc. 109, 1255-1257. (doi:10.1021/ja00238a051)
30. Pohl NL, Gokhale RS, Cane DE, Khosla C. 1998 Synthesis and incorporation of an N-acetylcysteamine analogue of methylmalonyl-CoA by a modular polyketide synthase. J. Am. Chem. Soc. 120, 11 206-11 207. (doi:10.1021/ja9830290)
31. Yue S, Duncan JS, Yamamoto Y, Hutchinson CR. 1987 Macrolide biosynthesis. Tylactone formation involves the processive addition of three carbon units. J. Am. Chem. Soc. 109, 1253-1255. (doi:10.1021/ja00238a050)
32. Xie X, Watanabe K, Wojcicki WA, Wang CC, Tang Y. 2006 Biosynthesis of lovastatin analogs with a broadly specific acyltransferase. Chem. Biol. 13, 1161-1169. (doi:10.1016/j.chembiol.2006.09.008)
33. Mo S et al. 2011 Biosynthesis of the allylmalonyl-CoA extender unit for the FK506 polyketide synthase proceeds through a dedicated polyketide synthase and facilitates the mutasynthesis of analogues. J. Am. Chem. Soc. 133, 976-985. (doi:10.1021/ja108399b)
34. Klopries S, Sundermann U, Schulz F. 2013 Quantification of N-acetylcysteamine activated methylmalonate incorporation into polyketide biosynthesis. Beilstein J. Org. Chem. 9, 664-674. (doi:10.3762/bjoc.9.75)
35. Meier JL, Burkart MD. 2009 Chapter 9. Synthetic probes for polyketide and nonribosomal peptide biosynthetic enzymes. Methods Enzymol. 458, 219-254. (doi:10.1016/S0076-6879(09)04809-5)
36. Koryakina I, Williams GJ. 2011 Mutant malonyl-CoA synthetases with altered specificity for polyketide synthase extender unit generation. Chembiochem 12, 2289-2293. (doi:10.1002/cbic.201100383)
37. Koryakina I, McArthur J, Randall S, Draelos MM, Musiol EM, Muddiman DC, Weber T, Williams GJ. 2013 Poly specific trans-acyltransferase machinery revealed via engineered acyl-CoA synthetases. ACS Chem. Biol. 8, 200-208. (doi:10.1021/cb3003489)
38. Khosla C, Tang Y, Chen AY, Schnarr NA, Cane DE. 2007 Structure and mechanism of the 6-deoxyerythronolide B synthase. Annu. Rev. Biochem. 76, 195-221. (doi:10.1146/annurev.biochem.76.053105.093515)
39. Dunn BJ, Cane DE, Khosla C. 2013 Mechanism and specificity of an acyltransferase domain from a modular polyketide synthase. Biochemistry 52, 1839-1841. (doi:10.1021/bi400185v)
40. Lau J, Fu H, Cane DE, Khosla C. 1999 Dissecting the role of acyltransferase domains of modular polyketide synthases in the choice and stereochemical fate of extender units. Biochemistry 38, 1643-1651. (doi:10.1021/bi9820311)
41. Bonnett SA, Rath CM, Shareef AR, Joels JR, Chemler JA, Hakansson K, Reynolds K, Sherman DH. 2011 Acyl-CoA subunit selectivity in the pikromycin polyketide synthase PikAIV: steady-state kinetics and active-site occupancy analysis by FTICR-MS. Chem. Biol. 18, 1075-1081. (doi:10.1016/j.chembiol.2011. 07.016)
42. Wong FT, Chen AY, Cane DE, Khosla C. 2010 Protein-protein recognition between acyltransferases and acyl carrier proteins in multimodular polyketide synthases. Biochemistry 49, 95-102. (doi:10.1021/bi901826g)
43. Wu N, Cane DE, Khosla C. 2002 Quantitative analysis of the relative contributions of donor acyl carrier proteins, acceptor ketosynthases, and linker regions to intermodular transfer of intermediates in hybrid polyketide synthases. Biochemistry 41, 5056-5066. (doi:10.1021/bi012086u)
44. Kapur S, Chen AY, Cane DE, Khosla C. 2010 Molecular recognition between ketosynthase and acyl carrier protein domains of the 6-deoxyerythronolide B synthase. Proc. Natl Acad. Sci. USA 107, 22 066-22 071. (doi:10.1073/pnas. 1014081107)
45. Charkoudian LK, Liu CW, Capone S, Kapur S, Cane DE, Togni A, Seebach D, Khosla C. 2011 Probing the interactions of an acyl carrier protein domain from the 6-deoxyerythronolide B synthase. Protein Sci. 20, 1244-1255. (doi:10.1002/pro.652)
46. Wong FT, Khosla C. 2012 Combinatorial biosynthesis of polyketides - a perspective. Curr. Opin. Chem. Biol. 16, 117-123. (doi:10.1016/j.cbpa.2012.01. 018)
47. Anand S, Prasad MV, Yadav G, Kumar N, Shehara J, Ansari MZ, Mohanty D. 2010 SBSPKS: structure based sequence analysis of polyketide synthases. Nucleic Acids Res. 38, W487-496. (doi:10.1093/nar/gkq340)
48. Yadav G, Gokhale RS, Mohanty D. 2003 Computational approach for prediction of domain organization and substrate specificity of modular polyketide synthases. J. Mol. Biol. 328, 335-363. (doi:10.1016/S0022-2836(03) 00232-8)
49. Jenke-Kodama H, Sandmann A, Muller R, Dittmann E. 2005 Evolutionary implications of bacterial polyketide synthases. Mol. Biol. Evol. 22, 2027-2039. (doi:10.1093/molbev/msi193)
50. Ridley CP, Lee HY, Khosla C. 2008 Evolution of polyketide synthases in bacteria. Proc. Natl Acad. Sci. USA 105, 4595-4600. (doi:10.1073/pnas. 0710107105)
51. Tang Y, Kim CY, Mathews II, Cane DE, Khosla C. 2006 The 2.7-Angstrom crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase. Proc. Natl Acad. Sci. USA 103, 11 124-11 129. (doi:10.1073/pnas. 0601924103)
52. Tang Y, Chen AY, Kim CY, Cane DE, Khosla C. 2007 Structural and mechanistic analysis of protein interactions in module 3 of the 6-deoxyerythronolide B synthase. Chem. Biol. 14, 931-943. (doi:10.1016/j. chembiol.2007.07.012)
53. Wong FT, Jin X, Mathews II, Cane DE, Khosla C. 2011 Structure and mechanism of the trans-acting acyltransferase from the disorazole synthase. Biochemistry 50, 6539-6548. (doi:10.1021/bi200632j)
54. Serre L, Verbree EC, Dauter Z, Stuitje AR, Derewenda ZS. 1995 The Escherichia coli malonyl-CoA:acyl carrier protein transacylase at 1.5-Å resolution. Crystal structure of a fatty acid synthase component. J. Biol. Chem. 270, 12 961-12 964. (doi:10.1074/jbc.270.22.12961)
55. Keatinge-Clay AT, Shelat AA, Savage DF, Tsai SC, Miercke LJ, O'Connell 3rd JD, Khosla C, Stroud RM. 2003 Catalysis, specificity, and ACP docking site of Streptomyces coelicolor malonyl-CoA:ACP transacylase. Structure 11, 147-154. (doi:10.1016/S0969-2126(03)00004-2)
56. Oefner C, Schulz H, D'Arcy A, Dale GE. 2006 Mapping the active site of Escherichia coli malonyl-CoA-acyl carrier protein transacylase (FabD) by protein crystallography. Acta Crystallogr. D Biol. Crystallogr. 62, 613-618. (doi:10.1107/S0907444906009474)
57. Haydock SF et al. 1995 Divergent sequence motifs correlated with the substrate specificity of (methyl)malonyl-CoA : acyl carrier protein transacylase domains in modular polyketide synthases. FEBS Lett. 374, 246-248. (doi:10.1016/0014-5793(95)01119-Y)
58. Reeves CD, Murli S, Ashley GW, Piagentini M, Hutchinson CR, McDaniel R. 2001 Alteration of the substrate specificity of a modular polyketide synthase acyltransferase domain through site-specific mutations. Biochemistry 40, 15 464-15 470. (doi:10.1021/bi015864r)
59. Del Vecchio F et al. 2003 Active-site residue, domain and module swaps in modular polyketide synthases. J. Ind. Microbiol. Biot. 30, 489-494. (Pubitemid 37214969)
60. Sundermann U, Bravo-Rodriguez K, Klopries S, Kushnir S, Gomez H, Sanchez-Garcia E, Schulz F. 2012 Enzyme-directed mutasynthesis: a combined experimental and theoretical approach to substrate recognition of a polyketide synthase. ACS Chem. Biol. 8, 443-450. (doi:10.1021/cb300505w)
61. Bergeret F et al. 2012 Biochemical and structural study of the atypical acyltransferase domain from the mycobacterial polyketide synthase Pks13. J. Biol. Chem. 287, 33 675-33 690. (doi:10.1074/jbc.M111.325639)
62. Keatinge-Clay AT. 2012 The structures of type I polyketide synthases. Nat. Prod. Rep. 29, 1050-1073. (doi:10.1039/c2np20019h)
63. Oliynyk M, Brown MJ, Cortes J, Staunton J, Leadlay PF. 1996 A hybrid modular polyketide synthase obtained by domain swapping. Chem. Biol. 3, 833-839. (doi:10.1016/S1074-5521(96)90069-1)
64. Ruan X et al. 1997 Acyltransferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives. J. Bacteriol. 179, 6416-6425. (Pubitemid 27443925)
65. McDaniel R, Thamchaipenet A, Gustafsson C, Fu H, Betlach M, Ashley G. 1999 Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel 'unnatural' natural products. Proc. Natl Acad. Sci. USA 96, 1846-1851. (doi:10.1073/pnas.96.5.1846)
66. Liu L, Thamchaipenet A, Fu H, Betlach M, Ashley G. 1997 Biosynthesis of 2-nor-6-deoxyerythronolide B by rationally designed domain substitution. J. Am. Chem. Soc. 119, 10 553-10 554. (doi:10.1021/ja972451y)
67. Ranganathan A et al. 1999 Knowledge-based design of bimodular and trimodular polyketide synthases based on domain and module swaps: a route to simple statin analogues. Chem. Biol. 6, 731-741. (doi:10.1016/S1074-5521(00) 80020-4)
68. Stassi DL et al. 1998 Ethyl-substituted erythromycin derivatives produced by directed metabolic engineering. Proc. Natl Acad. Sci. USA 95, 7305-7309. (doi:10.1073/pnas.95.13.7305)
69. Kato Y, Bai L, Xue Q, Revill WP, Yu TW, Floss HG. 2002 Functional expression of genes involved in the biosynthesis of the novel polyketide chain extension unit, methoxymalonyl-acyl carrier protein, and engineered biosynthesis of 2-desmethyl-2-methoxy-6-deoxyerythronolide B. J. Am. Chem. Soc. 124, 5268-5269. (doi:10.1021/ja0127483)
70. Patel K, Piagentini M, Rascher A, Tian ZQ, Buchanan GO, Regentin R, Hu Z, Hutchinson CR, McDaniel R. 2004 Engineered biosynthesis of geldanamycin analogs for Hsp90 inhibition. Chem. Biol. 11, 1625-1633. (doi:10.1016/j.chembiol.2004. 09.012)
71. Petkovic H et al. 2008 Substrate specificity of the acyl transferase domains of EpoC from the epothilone polyketide synthase. Org. Biomol. Chem. 6, 500-506. (doi:10.1039/b714804f)
72. Liou GF, Khosla C. 2003 Building-block selectivity of polyketide synthases. Curr. Opin. Chem. Biol. 7, 279-284. (doi:10.1016/S1367-5931(03)00016- 4)
73. Hans M, Hornung A, Dziarnowski A, Cane DE, Khosla C. 2003 Mechanistic analysis of acyl transferase domain exchange in polyketide synthase modules. J. Am. Chem. Soc. 125, 5366-5374. (doi:10.1021/ja029539i)
74. Kapur S, Lowry B, Yuzawa S, Kenthirapalan S, Chen AY, Cane DE, Khosla C. 2012 Reprogramming a module of the 6-deoxyerythronolide B synthase for iterative chain elongation. Proc. Natl Acad. Sci. USA 109, 4110-4115. (doi:10.1073/pnas.1118734109)
75. Nguyen T et al. 2008 Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection. Nat. Biotechnol. 26, 225-233. (doi:10.1038/nbt1379)
76. Carvalho R, Reid R, Viswanathan N, Gramajo H, Julien B. 2005 The biosynthetic genes for disorazoles, potent cytotoxic compounds that disrupt microtubule formation. Gene 359, 91-98. (doi:10.1016/j.gene.2005.06.003)
77. Kopp M, Irschik H, Pradella S, Muller R. 2005 Production of the tubulin destabilizer disorazol in Sorangium cellulosum: biosynthetic machinery and regulatory genes. Chembiochem 6, 1277-1286. (doi:10.1002/cbic.200400459)
78. Weber T, Laiple KJ, Pross EK, Textor A, Grond S, Welzel K, Pelzer S, Vente A, Wohlleben W. 2008 Molecular analysis of the kirromycin biosynthetic gene cluster revealed beta-alanine as precursor of the pyridone moiety. Chem. Biol. 15, 175-188. (doi:10.1016/j.chembiol.2007.12.009)
79. Laiple KJ, Hartner T, Fiedler HP, Wohlleben W, Weber T. 2009 The kirromycin gene cluster of Streptomyces collinus Tu 365 codes for an aspartate-alphadecarboxylase, KirD, which is involved in the biosynthesis of the precursor beta-alanine. J. Antibiot. (Tokyo). 62, 465-468. (doi:10.1038/ja. 2009.67)
80. Musiol EM, Hartner T, Kulik A, Moldenhauer J, Piel J, Wohlleben W, Weber T. 2011 Supramolecular templating in kirromycin biosynthesis: the acyltransferase KirCII loads ethylmalonyl-CoA extender onto a specific ACP of the trans-AT PKS. Chem. Biol. 18, 438-444. (doi:10.1016/j.chembiol.2011.02.007)
81. Piel J. 2010 Biosynthesis of polyketides by trans-AT polyketide synthases. Nat. Prod. Rep. 27, 996-1047. (doi:10.1039/b816430b)
82. Musiol EM, Weber T. 2012 Discrete acyltransferases involved in polyketide biosynthesis. Med. Chem. Comm. 3, 871-886. (doi:10.1039/c2md20048a)
83. Kumar P, Koppisch AT, Cane DE, Khosla C. 2003 Enhancing the modularity of the modular polyketide synthases: transacylation in modular polyketide synthases catalyzed by malonyl-CoA:ACP transacylase. J. Am. Chem. Soc. 125, 14 307-14 312. (doi:10.1021/ja037429l)
84. Lopanik NB, Shields JA, Buchholz TJ, Rath CM, Hothersall J, Haygood MG, Hakansson K, Thomas CM, Sherman DH. 2008 In vivo and in vitro transacylation by BryP, the putative bryostatin pathway acyltransferase derived from an uncultured marine symbiont. Chem. Biol. 15, 1175-1186. (doi:10.1016/j.chembiol.2008.09. 013)
85. Piel J, Hui D, Fusetani N, Matsunaga S. 2004 Targeting modular polyketide synthases with iteratively acting acyltransferases from metagenomes of uncultured bacterial consortia. Environ. Microbiol. 6, 921-927. (doi:10.1111/j.1462-2920.2004.00531.x)
86. Teta R, Gurgui M, Helfrich EJ, Kunne S, Schneider A, Van Echten-Deckert G, Mangoni A, Piel J. 2010 Genome mining reveals trans-AT polyketide synthase directed antibiotic biosynthesis in the bacterial phylum Bacteroidetes. Chembiochem 11, 2506-2512. (doi:10.1002/cbic.201000542)
87. Jenner M, Frank S, Kampa A, Kohlhaas C, Poplau P, Briggs GS, Piel J, Oldham NJ. 2013 Substrate Specificity in ketosynthase domains from trans-AT polyketide synthases. Angew. Chem. Int. Ed. Engl. 52, 1143-1147. (doi:10.1002/anie.201207690)
88. de Juan D, Pazos F, Valencia A. 2013 Emerging methods in protein co-evolution. Nat. Rev. Genet. 14, 249-261. (doi:10.1038/nrg3414)
89. Sandler I, Abu-Qarn M, Aharoni A. 2013 Protein co-evolution: how do we combine bioinformatics and experimental approaches? Mol. Biosyst. 9, 175-181. (doi:10.1039/c2mb25317h)
90. Codoner FM, Fares MA. 2008 Why should we care about molecular coevolution? Evol. Bioinform. Online 4, 29-38.
91. del Sol Mesa A, Pazos F, Valencia A. 2003 Automatic methods for predicting functionally important residues. J. Mol. Biol. 326, 1289-1302. (doi:10.1016/S0022-2836(02)01451-1)
92. Casari G, Sander C, Valencia A. 1995 A method to predict functional residues in proteins. Nat. Struct. Biol. 2, 171-178. (doi:10.1038/nsb0295-171)
93. Lichtarge O, Bourne HR, Cohen FE. 1996 An evolutionary trace method defines binding surfaces common to protein families. J. Mol. Biol. 257, 342-358. (doi:10.1006/jmbi.1996.0167)
94. Mirny LA, Gelfand MS. 2002 Using orthologous and paralogous proteins to identify specificity determining residues. J. Mol. Biol. 321, 7-20. (doi:10.1016/S0022-2836(02)00587-9).
95. Pupko T, Bell RE, Mayrose I, Glaser F, Ben-Tal N. 2002 Rate4Site: an algorithmic tool for the identification of functional regions in proteins by surface mapping of evolutionary determinants within their homologues. Bioinformatics 18(Suppl. 1), S71-S77. (doi:10.1093/bioinformatics/18.suppl-1. S71)
96. Mayer KM, McCorkle SR, Shanklin J. 2005 Linking enzyme sequence to function using conserved property difference locator to identify and annotate positions likely to control specific functionality. BMC Bioinformatics 6, 284. (doi:10.1186/1471-2105-6-284)
97. Kalinina OV, Rassel RB, Rakhmaninova AB, Gel'fand MS. 2007 Computational method for prediction of protein functional sites using specificity determinants. Mol. Biol. (Mosk) 41, 151-162. (doi:10.1134/S0026893307010189)
98. Bonella S, Rocchia W, Amat P, Nifosí R, Tozzini V. 2009 SDPhound, a mutual information-based method to investigate specificity-determining positions. Algorithms 2, 764-789. (doi:10.3390/a2020764)
99. Mazin PV, Gelfand MS, Mironov AA, Rakhmaninova AB, Rubinov AR, Russell RB, Kalinina OV. 2010 An automated stochastic approach to the identification of the protein specificity determinants and functional subfamilies. Algorithms Mol. Biol. 5, 29. (doi:10.1186/1748-7188-5-29)
100. Rausell A, Juan D, Pazos F, Valencia A. 2010 Protein interactions and ligand binding: from protein subfamilies to functional specificity. Proc. Natl Acad. Sci. USA 107, 1995-2000. (doi:10.1073/pnas.0908044107)
101. Ye K, Feenstra KA, Heringa J, Ijzerman AP, Marchiori E. 2008 Multi-RELIEF: a method to recognize specificity determining residues from multiple sequence alignments using a machine-learning approach for feature weighting. Bioinformatics 24, 18-25. (doi:10.1093/bioinformatics/btm537)
102. Muth T, Garcia-Martin JA, Rausell A, Juan D, Valencia A, Pazos F. 2012 JDet: interactive calculation and visualization of function-related conservation patterns in multiple sequence alignments and structures. Bioinformatics 28, 584-586. (doi:10.1093/bioinformatics/btr688)
103. Mayer KM, Shanklin J. 2007 Identification of amino acid residues involved in substrate specificity of plant acyl-ACP thioesterases using a bioinformatics-guided approach. BMC Plant Biol. 7, 1. (doi:10.1186/1471-2229-7- 1)
104. Lockless SW, Ranganathan R. 1999 Evolutionarily conserved pathways of energetic connectivity in protein families. Science 286, 295-299. (doi:10.1126/science.286.5438.295)
105. Halabi N, Rivoire O, Leibler S, Ranganathan R. 2009 Protein sectors: evolutionary units of three-dimensional structure. Cell 138, 774-786. (doi:10.1016/j.cell.2009.07.038)
106. Smock RG, Rivoire O, Russ WP, Swain JF, Leibler S, Ranganathan R, Gierasch LM. 2010 An interdomain sector mediating allostery in Hsp70 molecular chaperones. Mol. Syst. Biol. 6, 414. (doi:10.1038/msb.2010.65)
107. Reynolds KA, McLaughlin RN, Ranganathan R. 2011 Hot spots for allosteric regulation on protein surfaces. Cell 147, 1564-1575. (doi:10.1016/j.cell.2011. 10.049)
108. Socolich M, Lockless SW, Russ WP, Lee H, Gardner KH, Ranganathan R. 2005 Evolutionary information for specifying a protein fold. Nature 437, 512-518. (doi:10.1038/nature03991)
109. Russ WP, Lowery DM, Mishra P, Yaffe MB, Ranganathan R. 2005 Natural-like function in artificial WW domains. Nature 437, 579-583. (doi:10.1038/ nature03990)
110. Anand S, Mohanty D. 2012 Modeling holo-ACP:DH and holo-ACP:KR complexes of modular polyketide synthases: a docking and molecular dynamics study. BMC Struct. Biol. 12, 10. (doi:10.1186/1472-6807-12-10)
111. Anand S, Mohanty D. 2012 Inter-domain movements in polyketide synthases: a molecular dynamics study. Mol. Biosyst. 8, 1157-1171. (doi:10.1039/c2mb05425f)
112. Durrant JD, McCammon JA. 2011 Molecular dynamics simulations and drug discovery. BMC Biol. 9, 71. (doi:10.1186/1741-7007-9-71)
113. Cornell WD et al. 1995 A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J. Am. Chem. Soc. 117, 5179-5197. (doi:10.1021/ja00124a002)
114. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA. 2004 Development and testing of a general amber force field. J. Comput. Chem. 25, 1157-1174. (doi:10.1002/jcc.20035)
115. Lilien RH, Stevens BW, Anderson AC, Donald BR. 2005 A novel ensemble-based scoring and search algorithm for protein redesign and its application to modify the substrate specificity of the gramicidin synthetase a phenylalanine adenylation enzyme. J. Comput. Biol. 12, 740-761. (doi:10.1089/cmb.2005.12.740)
116. Stevens BW, Joska TM, Anderson AC. 2005 Progress toward re-engineering non-ribosomal peptide synthetase proteins: a potential new source of pharmacological agents. Drug Dev. Res. 66, 9-18. (doi:10.1002/ddr.20041)
117. Georgiev I, Lilien RH, Donald BR. 2006 Improved pruning algorithms and divide-and-conquer strategies for dead-end elimination, with application to protein design. Bioinformatics 22, e174-e183. (doi:10.1093/bioinformatics/ btl220)
118. Georgiev I, Donald BR. 2007 Dead-end elimination with backbone flexibility. Bioinformatics 23, i185-i194. (doi:10.1093/bioinformatics/btm197)
119. Georgiev I, Lilien RH, Donald BR. 2008 The minimized dead-end elimination criterion and its application to protein redesign in a hybrid scoring and search algorithm for computing partition functions over molecular ensembles. J. Comput. Chem. 29, 1527-1542. (doi:10.1002/jcc.20909)
120. Chen CY, Georgiev I, Anderson AC, Donald BR. 2009 Computational structure-based redesign of enzyme activity. Proc. Natl Acad. Sci. USA 106, 3764-3769. (doi:10.1073/pnas.0900266106)
121. Worthington AS, Rivera H, Torpey JW, Alexander MD, Burkart MD. 2006 Mechanism-based protein cross-linking probes to investigate carrier protein-mediated biosynthesis. ACS Chem. Biol. 1, 687-691. (doi:10.1021/ cb6003965)
122. Kapur S, Worthington A, Tang Y, Cane DE, Burkart MD, Khosla C. 2008 Mechanism based protein crosslinking of domains from the 6-deoxyerythronolide B synthase. Bioorg. Med. Chem. Lett. 18, 3034-3038. (doi:10.1016/j.bmcl.2008.01. 073)
123. Jackel C, Kast P, Hilvert D. 2008 Protein design by directed evolution. Annu. Rev. Biophys. 37, 153-173. (doi:10.1146/annurev.biophys.37.032807.125832)
124. Tracewell CA, Arnold FH. 2009 Directed enzyme evolution: climbing fitness peaks one amino acid at a time. Curr. Opin. Chem. Biol. 13, 3-9. (doi:10.1016/j.cbpa.2009.01.017)
125. Dalby PA. 2011 Strategy and success for the directed evolution of enzymes. Curr. Opin. Struct. Biol. 21, 473-480. (doi:10.1016/j.sbi.2011.05.003)
126. Damborsky J, Brezovsky J. 2009 Computational tools for designing and engineering biocatalysts. Curr. Opin. Chem. Biol. 13, 26-34. (doi:10.1016/j.cbpa.2009.02.021)
127. Gao X, Xie X, Pashkov I, Sawaya MR, Laidman J, Zhang W, Cacho R, Yeates TO, Tang Y. 2009 Directed evolution and structural characterization of a simvastatin synthase. Chem. Biol. 16, 1064-1074. (doi:10.1016/j.chembiol.2009. 09.017)