1932

Abstract

Natural products are important sources of pharmaceuticals, in part owing to their diverse biological activities. Enzymes from natural product biosynthetic pathways have become attractive candidates as biocatalysts for modifying the structures and bioactivities of these complex compounds. Numerous enzymes have been harvested to generate innovative scaffolds, large-scale synthesis of chiral building blocks, and semisynthesis of medicinally relevant natural product derivatives. This review discusses recent examples from three areas: () polyketide catalytic domain engineering geared toward synthesis of new polyketides, () engineering of tailoring enzymes (other than oxidative enzymes) as biocatalysts, and () in vitro total synthesis of natural products using purified enzyme components. With the availability of exponentially increasing genomic information and new genome mining tools, many new and powerful biocatalysts tailored for pharmaceutical synthesis will likely emerge from secondary metabolism.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-chembioeng-060713-040008
2014-06-07
2024-06-24
Loading full text...

Full text loading...

/deliver/fulltext/chembioeng/5/1/annurev-chembioeng-060713-040008.html?itemId=/content/journals/10.1146/annurev-chembioeng-060713-040008&mimeType=html&fmt=ahah

Literature Cited

  1. Butler MS. 1.  2008. Natural products to drugs: natural product-derived compounds in clinical trials. Nat. Prod. Rep. 25:475–516 [Google Scholar]
  2. Hertweck C. 2.  2009. The biosynthetic logic of polyketide diversity. Angew. Chem. Int. Ed. 48:4688–716 [Google Scholar]
  3. Li JWH, Vederas JC. 3.  2009. Drug discovery and natural products: End of an era or an endless frontier?. Science 325:161–65 [Google Scholar]
  4. Newman DJ, Cragg GM. 4.  2012. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75:311–35 [Google Scholar]
  5. Schoemaker HE, Mink D, Wubbolts MG. 5.  2003. Dispelling the myths: biocatalysis in industrial synthesis. Science 299:1694–97 [Google Scholar]
  6. Huisman GW, Collier SJ. 6.  2013. On the development of new biocatalytic processes for practical pharmaceutical synthesis. Curr. Opin. Chem. Biol. 17:284–92 [Google Scholar]
  7. Bornscheuer UT, Huisman GW, Kazlauskas RJ, Lutz S, Moore JC, Robins K. 7.  2012. Engineering the third wave of biocatalysis. Nature 485:185–94 [Google Scholar]
  8. Savile CK, Janey JM, Mundorff EC, Moore JC, Tam S. 8.  et al. 2010. Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture. Science 329:305–9 [Google Scholar]
  9. Zabala AO, Cacho RA, Tang Y. 9.  2012. Protein engineering towards natural product synthesis and diversification. J. Ind. Microbiol. Biotechnol. 39:227–41 [Google Scholar]
  10. Dunn BJ, Khosla C. 10.  2013. Engineering the acyltransferase substrate specificity of assembly line polyketide synthases. J. R. Soc. Interface 10:20130297 [Google Scholar]
  11. Johannes TW, Zhao HM. 11.  2006. Directed evolution of enzymes and biosynthetic pathways. Curr. Opin. Microbiol. 9:261–67 [Google Scholar]
  12. Gao X, Wang P, Tang Y. 12.  2010. Engineered polyketide biosynthesis and biocatalysis in Escherichia coli. Appl. Microbiol. Biotechnol. 88:1233–42 [Google Scholar]
  13. Smith S, Tsai SC. 13.  2007. The type I fatty acid and polyketide synthases: a tale of two megasynthases. Nat. Prod. Rep. 24:1041–72 [Google Scholar]
  14. Cronan JE, Thomas J. 14.  2009. Bacterial fatty acid synthesis and its relationships with polyketide synthetic pathways. Method Enzymol. 459:395–433 [Google Scholar]
  15. Fujii I. 15.  2009. Heterologous expression systems for polyketide synthases. Nat. Prod. Rep. 26:155–69 [Google Scholar]
  16. Weissman KJ. 16.  2009. Introduction to polyketide biosynthesis. Method Enzymol. 459:3–16 [Google Scholar]
  17. Fischbach MA, Walsh CT. 17.  2006. Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics: logic, machinery, and mechanisms. Chem. Rev. 106:3468–96 [Google Scholar]
  18. Rawlings BJ. 18.  2001. Type I polyketide biosynthesis in bacteria (part B). Nat. Prod. Rep. 18:231–81 [Google Scholar]
  19. Ma SM, Li JWH, Choi JW, Zhou H, Lee KKM. 19.  et al. 2009. Complete reconstitution of a highly reducing iterative polyketide synthase. Science 326:589–92 [Google Scholar]
  20. Khosla C, Tang Y, Chen AY, Schnarr NA, Cane DE. 20.  2007. Structure and mechanism of the 6-deoxyerythronolide B synthase. Annu. Rev. Biochem. 76:195–221 [Google Scholar]
  21. Crawford JM, Townsend CA. 21.  2010. New insights into the formation of fungal aromatic polyketides. Nat. Rev. Microbiol. 8:879–89 [Google Scholar]
  22. Campbell CD, Vederas JC. 22.  2010. Biosynthesis of lovastatin and related metabolites formed by fungal iterative PKS enzymes. Biopolymers 93:755–63 [Google Scholar]
  23. Chooi YH, Tang Y. 23.  2012. Navigating the fungal polyketide chemical space: from genes to molecules. J. Org. Chem. 77:9933–53 [Google Scholar]
  24. Hertweck C, Luzhetskyy A, Rebets Y, Bechthold A. 24.  2007. Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork. Nat. Prod. Rep. 24:162–90 [Google Scholar]
  25. Yu DY, Xu FC, Zeng J, Zhan JX. 25.  2012. Type III polyketide synthases in natural product biosynthesis. IUBMB Life 64:285–95 [Google Scholar]
  26. Mo S, Kim DH, Lee JH, Park JW, Basnet DB. 26.  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. 133:976–85 [Google Scholar]
  27. Macherla VR, Mitchell SS, Manam RR, Reed KA, Chao T-H. 27.  et al. 2005. Structure-activity relationship studies of salinosporamide A (NPI-0052), a novel marine derived proteasome inhibitor. J. Med. Chem. 48:3684–87 [Google Scholar]
  28. An JH, Kim YS. 28.  1998. A gene cluster encoding malonyl-CoA decarboxylase (MatA), malonyl-CoA synthetase (MatB) and a putative dicarboxylate carrier protein (MatC) in Rhizobium trifolii. Eur. J. Biochem. 257:395–402 [Google Scholar]
  29. Pohl NL, Hans M, Lee HY, Kim YS, Cane DE, Khosla C. 29.  2001. Remarkably broad substrate tolerance of malonyl-CoA synthetase, an enzyme capable of intracellular synthesis of polyketide precursors. J. Am. Chem. Soc. 123:5822–23 [Google Scholar]
  30. Hughes AJ, Keatinge-Clay A. 30.  2011. Enzymatic extender unit generation for in vitro polyketide synthase reactions: structural and functional showcasing of Streptomyces coelicolor MatB. Chem. Biol. 18:165–76 [Google Scholar]
  31. Walker MC, Thuronyi BW, Charkoudian LK, Lowry B, Khosla C, Chang MC. 31.  2013. Expanding the fluorine chemistry of living systems using engineered polyketide synthase pathways. Science 341:1089–94 [Google Scholar]
  32. Koryakina I, Williams GJ. 32.  2011. Mutant malonyl-CoA synthetases with altered specificity for polyketide synthase extender unit generation. ChemBioChem 12:2289–93 [Google Scholar]
  33. Gokhale RS, Hunziker D, Cane DE, Khosla C. 33.  1999. Mechanism and specificity of the terminal thioesterase domain from the erythromycin polyketide synthase. Chem. Biol. 6:117–25 [Google Scholar]
  34. Koryakina I, McArthur J, Randall S, Draelos MM, Musiol EM. 34.  et al. 2012. Poly specific trans-acyltransferase machinery revealed via engineered Acyl-CoA synthetases. ACS Chem. Biol. 8:200–8 [Google Scholar]
  35. Wilson MC, Moore BS. 35.  2012. Beyond ethylmalonyl-CoA: the functional role of crotonyl-CoA carboxylase/reductase homologs in expanding polyketide diversity. Nat. Prod. Rep. 29:72–86 [Google Scholar]
  36. Erb TJ, Berg IA, Brecht V, Müller M, Fuchs G, Alber BE. 36.  2007. Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: the ethylmalonyl-CoA pathway. Proc. Natl. Acad. Sci. USA 104:10631–36 [Google Scholar]
  37. Erb TJ, Brecht V, Fuchs G, Müller M, Alber BE. 37.  2009. Carboxylation mechanism and stereochemistry of crotonyl-CoA carboxylase/reductase, a carboxylating enoyl-thioester reductase. Proc. Natl. Acad. Sci. USA 106:8871–76 [Google Scholar]
  38. Rachid S, Huo L, Herrmann J, Stadler M, Köpcke B. 38.  et al. 2011. Mining the cinnabaramide biosynthetic pathway to generate novel proteasome inhibitors. ChemBioChem 12:922–31 [Google Scholar]
  39. Quade N, Huo LJ, Rachid S, Heinz DW, Müller R. 39.  2012. Unusual carbon fixation gives rise to diverse polyketide extender units. Nat. Chem. Biol. 8:117–24 [Google Scholar]
  40. Koryakina I, McArthur JB, Draelos MM, Williams GJ. 40.  2013. Promiscuity of a modular polyketide synthase towards natural and non-natural extender units. Org. Biomol. Chem. 11:4449–58 [Google Scholar]
  41. Quadri LEN, Weinreb PH, Lei M, Nakano MM, Zuber P, Walsh CT. 41.  1998. Characterization of Sfp, a Bacillus subtilis phosphopantetheinyl transferase for peptidyl carrier protein domains in peptide synthetases. Biochemistry 37:1585–95 [Google Scholar]
  42. Yuzawa S, Eng CH, Katz L, Keasling JD. 42.  2013. Broad substrate specificity of the loading didomain of the lipomycin polyketide synthase. Biochemistry 52:3791–93 [Google Scholar]
  43. Moore BS, Hertweck C. 43.  2002. Biosynthesis and attachment of novel bacterial polyketide synthase starter units. Nat. Prod. Rep. 19:70–99 [Google Scholar]
  44. Xu Z, Schenk A, Hertweck C. 44.  2007. Molecular analysis of the benastatin biosynthetic pathway and genetic engineering of altered fatty acid-polyketide hybrids. J. Am. Chem. Soc. 129:6022–30 [Google Scholar]
  45. Xu Z, Metsä-Ketelä M, Hertweck C. 45.  2009. Ketosynthase III as a gateway to engineering the biosynthesis of antitumoral benastatin derivatives. J. Biotechnol. 140:107–13 [Google Scholar]
  46. Pan H, Tsai SC, Meadows ES, Miercke LJW, Keatinge-Clay AT. 46.  et al. 2002. Crystal structure of the priming β-ketosynthase from the R1128 polyketide biosynthetic pathway. Structure 10:1559–68 [Google Scholar]
  47. Bretschneider T, Zocher G, Unger M, Scherlach K, Stehle T, Hertweck C. 47.  2012. A ketosynthase homolog uses malonyl units to form esters in cervimycin biosynthesis. Nat. Chem. Biol. 8:154–61 [Google Scholar]
  48. White SW, Zheng J, Zhang YM, Rock CO. 48.  2005. The structural biology of type II fatty acid biosynthesis. Annu. Rev. Biochem. 74:791–831 [Google Scholar]
  49. Pickens LB, Kim W, Wang P, Zhou H, Watanabe K. 49.  et al. 2009. Biochemical analysis of the biosynthetic pathway of an anticancer tetracycline SF2575. J. Am. Chem. Soc. 131:17677–89 [Google Scholar]
  50. Zheng JT, Keatinge-Clay AT. 50.  2013. The status of type I polyketide synthase ketoreductases. Med. Chem. Commun. 4:34–40 [Google Scholar]
  51. Patel RN. 51.  2008. Synthesis of chiral pharmaceutical intermediates by biocatalysis. Coord. Chem. Rev. 252:659–701 [Google Scholar]
  52. O'Hare HM, Baerga-Ortiz A, Popovic B, Spencer JB, Leadlay PF. 52.  2006. High-throughput mutagenesis to evaluate models of stereochemical control in ketoreductase domains from the erythromycin polyketide synthase. Chem. Biol. 13:287–96 [Google Scholar]
  53. Castonguay R, He W, Chen AY, Khosla C, Cane DE. 53.  2007. Stereospecificity of ketoreductase domains of the 6-deoxyerythronolide B synthase. J. Am. Chem. Soc. 129:13758–69 [Google Scholar]
  54. Keatinge-Clay AT. 54.  2007. A tylosin ketoreductase reveals how chirality is determined in polyketides. Chem. Biol. 14:898–908 [Google Scholar]
  55. Zheng J, Taylor CA, Piasecki SK, Keatinge-Clay AT. 55.  2010. Structural and functional analysis of A-type ketoreductases from the amphotericin modular polyketide synthase. Structure 18:913–22 [Google Scholar]
  56. Bali S, O'Hare HM, Weissman KJ. 56.  2006. Broad substrate specificity of ketoreductases derived from modular polyketide synthases. ChemBioChem 7:478–84 [Google Scholar]
  57. Piasecki SK, Taylor CA, Detelich JF, Liu J, Zheng J. 57.  et al. 2011. Employing modular polyketide synthase ketoreductases as biocatalysts in the preparative chemoenzymatic syntheses of diketide chiral building blocks. Chem. Biol. 18:1331–40 [Google Scholar]
  58. Harper AD, Bailey CB, Edwards AD, Detelich JF, Keatinge-Clay AT. 58.  2012. Preparative, in vitro biocatalysis of triketide lactone chiral building blocks. ChemBioChem 13:2200–3 [Google Scholar]
  59. Kellenberger L, Galloway IS, Sauter G, Böhm G, Hanefeld U. 59.  et al. 2008. A polylinker approach to reductive loop swaps in modular polyketide synthases. ChemBioChem 9:2740–49 [Google Scholar]
  60. Ding W, Lei C, He QL, Zhang QL, Bi YR, Liu W. 60.  2010. Insights into bacterial 6-methylsalicylic acid synthase and its engineering to orsellinic acid synthase for spirotetronate generation. Chem. Biol. 17:495–503 [Google Scholar]
  61. Olano C, Méndez C, Salas JA. 61.  2010. Post-PKS tailoring steps in natural product-producing actinomycetes from the perspective of combinatorial biosynthesis. Nat. Prod. Rep. 27:571–616 [Google Scholar]
  62. Jacobsen JR, Hutchinson CR, Cane DE, Khosla C. 62.  1997. Precursor-directed biosynthesis of erythromycin analogs by an engineered polyketide synthase. Science 277:367–69 [Google Scholar]
  63. Walsh CT, Wencewicz TA. 63.  2013. Flavoenzymes: versatile catalysts in biosynthetic pathways. Nat. Prod. Rep. 30:175–200 [Google Scholar]
  64. Podust LM, Sherman DH. 64.  2012. Diversity of P450 enzymes in the biosynthesis of natural products. Nat. Prod. Rep. 29:1251–66 [Google Scholar]
  65. Kharel MK, Pahari P, Shepherd MD, Tibrewal N, Nybo SE. 65.  et al. 2012. Angucyclines: biosynthesis, mode-of-action, new natural products, and synthesis. Nat. Prod. Rep. 29:264–325 [Google Scholar]
  66. Xie X, Watanabe K, Wojcicki WA, Wang CC, Tang Y. 66.  2006. Biosynthesis of lovastatin analogs with a broadly specific acyltransferase. Chem. Biol. 13:1161–69 [Google Scholar]
  67. Xie XK, Tang Y. 67.  2007. Efficient synthesis of simvastatin by use of whole-cell biocatalysis. Appl. Environ. Microbiol. 73:2054–60 [Google Scholar]
  68. Gao X, Xie X, Pashkov I, Sawaya MR, Laidman J. 68.  et al. 2009. Directed evolution and structural characterization of a simvastatin synthase. Chem. Biol. 16:1064–74 [Google Scholar]
  69. Newbert RW, Barton B, Greaves P, Harper J, Turner G. 69.  1997. Analysis of a commercially improved Penicillium chrysogenum strain series: involvement of recombinogenic regions in amplification and deletion of the penicillin biosynthesis gene cluster. J. Ind. Microbiol. Biotechnol. 19:18–27 [Google Scholar]
  70. Fierro F, Barredo JL, Díez B, Gutierrez S, Fernández FJ, Martín JF. 70.  1995. The penicillin gene cluster is amplified in tandem repeats linked by conserved hexanucleotide sequences. Proc. Natl. Acad. Sci. USA 92:6200–4 [Google Scholar]
  71. Nijland JG, Ebbendorf B, Woszczynska M, Boer R, Bovenberg RAL, Driessen AJM. 71.  2010. Nonlinear biosynthetic gene cluster dose effect on penicillin production by Penicillium chrysogenum. Appl. Environ. Microbiol. 76:7109–15 [Google Scholar]
  72. Weber SS, Polli F, Boer R, Bovenberg RAL, Driessen AJM. 72.  2012. Increased penicillin production in Penicillium chrysogenum production strains via balanced overexpression of isopenicillin N acyltransferase. Appl. Environ. Microbiol. 78:7107–13 [Google Scholar]
  73. Loncaric C, Merriweather E, Walker KD. 73.  2006. Profiling a taxol pathway 10β-acetyltransferase: assessment of the specificity and the production of baccatin III by in vivo acetylation in E. coli. Chem. Biol. 13:309–17 [Google Scholar]
  74. Ondari ME, Walker KD. 74.  2008. The taxol pathway 10-O-acetyltransferase shows regioselective promiscuity with the oxetane hydroxyl of 4-deacetyltaxanes. J. Am. Chem. Soc. 130:17187–94 [Google Scholar]
  75. García B, González-Sabín J, Menéndez N, Braña AF, Nuñez LE. 75.  et al. 2011. The chromomycin CmmA acetyltransferase: a membrane-bound enzyme as a tool for increasing structural diversity of the antitumour mithramycin. Microbiol. Biotechnol. 4:226–38 [Google Scholar]
  76. Menéndez N, Nur-e-Alam M, Braña AF, Rohr J, Salas JA, Méndez C. 76.  2004. Tailoring modification of deoxysugars during biosynthesis of the antitumour drug chromomycin A3 by Streptomyces griseus ssp. griseus. Mol. Microbiol. 53:903–15 [Google Scholar]
  77. Méndez C, Salas JA. 77.  2001. Altering the glycosylation pattern of bioactive compounds. Trends Biotechnol. 19:449–56 [Google Scholar]
  78. Weymouth-Wilson AC. 78.  1997. The role of carbohydrates in biologically active natural products. Nat. Prod. Rep. 14:99–110 [Google Scholar]
  79. Ahmed A, Peters NR, Fitzgerald MK, Watson JA, Hoffmann FM, Thorson JS. 79.  2006. Colchicine glycorandomization influences cytotoxicity and mechanism of action. J. Am. Chem. Soc. 128:14224–25 [Google Scholar]
  80. Thibodeaux CJ, Melançon CE, Liu H-W. 80.  2008. Natural-product sugar biosynthesis and enzymatic glycodiversification. Angew. Chem. Int. Ed. 47:9814–59 [Google Scholar]
  81. Williams GJ, Zhang C, Thorson JS. 81.  2007. Expanding the promiscuity of a natural-product glycosyltransferase by directed evolution. Nat. Chem. Biol. 3:657–62 [Google Scholar]
  82. Williams GJ, Thorson JS. 82.  2008. A high-throughput fluorescence-based glycosyltransferase screen and its application in directed evolution. Nat. Protoc. 3:357–62 [Google Scholar]
  83. Williams GJ, Goff RD, Zhang CS, Thorson JS. 83.  2008. Optimizing glycosyltransferase specificity via “hot spot” saturation mutagenesis presents a catalyst for novobiocin glycorandomization. Chem. Biol. 15:393–401 [Google Scholar]
  84. Park S-H, Park H-Y, Cho B-K, Yang Y-H, Sohng JK. 84.  et al. 2009. Reconstitution of antibiotics glycosylation by domain exchanged chimeric glycosyltransferase. J. Mol. Catal. B 60:29–35 [Google Scholar]
  85. Krauth C, Fedoryshyn M, Schleberger C, Luzhetskyy A, Bechthold A. 85.  2009. Engineering a function into a glycosyltransferase. Chem. Biol. 16:28–35 [Google Scholar]
  86. Cartwright AM, Lim E-K, Kleanthous C, Bowles DJ. 86.  2008.. A kinetic analysis of regiospecific glucosylation by two glycosyltransferases of Arabidopsis thaliana: domain swapping to introduce new activities. J. Biol. Chem. 283:15724–31 [Google Scholar]
  87. Mulichak AM, Losey HC, Lu W, Wawrzak Z, Walsh CT, Garavito RM. 87.  2003. Structure of the TDP-epi-vancosaminyltransferase GtfA from the chloroeremomycin biosynthetic pathway. Proc. Natl. Acad. Sci. USA 100:9238–43 [Google Scholar]
  88. Hu Y, Chen L, Ha S, Gross B, Falcone B. 88.  et al. 2003. Crystal structure of the MurG:UDP-GlcNAc complex reveals common structural principles of a superfamily of glycosyltransferases. Proc. Natl. Acad. Sci. USA 100:845–49 [Google Scholar]
  89. Truman AW, Dias MVB, Wu S, Blundell TL, Huang FL, Spencer JB. 89.  2009. Chimeric glycosyltransferases for the generation of hybrid glycopeptides. Chem. Biol. 16:676–85 [Google Scholar]
  90. Zhang CS, Griffith BR, Fu Q, Albermann C, Fu X. 90.  et al. 2006. Exploiting the reversibility of natural product glycosyltransferase-catalyzed reactions. Science 313:1291–94 [Google Scholar]
  91. Gantt RW, Peltier-Pain P, Cournoyer WJ, Thorson JS. 91.  2011. Using simple donors to drive the equilibria of glycosyltransferase-catalyzed reactions. Nat. Chem. Biol. 7:685–91 [Google Scholar]
  92. Williams GJ, Yang J, Zhang C, Thorson JS. 92.  2010. Recombinant E. coli prototype strains for in vivo glycorandomization. ACS Chem. Biol. 6:95–100 [Google Scholar]
  93. Gantt RW, Goff RD, Williams GJ, Thorson JS. 93.  2008. Probing the aglycon promiscuity of an engineered glycosyltransferase. Angew. Chem. Int. Ed. 47:8889–92 [Google Scholar]
  94. Peltier-Pain P, Marchillo K, Zhou MQ, Andes DR, Thorson JS. 94.  2012. Natural product disaccharide engineering through tandem glycosyltransferase catalysis reversibility and neoglycosylation. Org. Lett. 14:5086–89 [Google Scholar]
  95. Gantt RW, Peltier-Pain P, Singh S, Zhou MQ, Thorson JS. 95.  2013. Broadening the scope of glycosyltransferase-catalyzed sugar nucleotide synthesis. Proc. Natl. Acad. Sci. USA 110:7648–53 [Google Scholar]
  96. Chen R, Zhang H, Zhang G, Li S, Zhang G. 96.  et al. 2013. Characterizing amosamine biosynthesis in amicetin reveals AmiG as a reversible retaining glycosyltransferase. J. Am. Chem. Soc. 135:12152–55 [Google Scholar]
  97. Vaillancourt FH, Yeh E, Vosburg DA, Garneau-Tsodikova S, Walsh CT. 97.  2006. Nature's inventory of halogenation catalysts: oxidative strategies predominate. Chem. Rev. 106:3364–78 [Google Scholar]
  98. Hernandes MZ, Cavalcanti SMT, Moreira DRM, de Azevedo WF, Leite ACL. 98.  2010. Halogen atoms in the modern medicinal chemistry: hints for the drug design. Curr. Drug Targets 11:303–14 [Google Scholar]
  99. Yeh E, Cole LJ, Barr EW, Bollinger JM, Ballou DP, Walsh CT. 99.  2006. Flavin redox chemistry precedes substrate chlorination during the reaction of the flavin-dependent halogenase RebH. Biochemistry 45:7904–12 [Google Scholar]
  100. Glenn WS, Nims E, O'Connor SE. 100.  2011. Reengineering a tryptophan halogenase to preferentially chlorinate a direct alkaloid precursor. J. Am. Chem. Soc. 133:19346–49 [Google Scholar]
  101. Payne JT, Andorfer MC, Lewis JC. 101.  2013. Regioselective arene halogenation using the FAD-dependent halogenase RebH. Angew. Chem. Int. Ed. 52:5271–74 [Google Scholar]
  102. Zeng J, Zhan J. 102.  2010. A novel fungal flavin-dependent halogenase for natural product biosynthesis. ChemBioChem 11:2119–23 [Google Scholar]
  103. Zhu T, Cheng X, Liu Y, Deng Z, You D. 103.  2013. Deciphering and engineering of the final step halogenase for improved chlortetracycline biosynthesis in industrial Streptomyces aureofaciens. Metab. Eng. 19:69–78 [Google Scholar]
  104. Dong CJ, Huang FL, Deng H, Schaffrath C, Spencer JB. 104.  et al. 2004. Crystal structure and mechanism of a bacterial fluorinating enzyme. Nature 427:561–65 [Google Scholar]
  105. Neumann CS, Fujimori DG, Walsh CT. 105.  2008. Halogenation strategies in natural product biosynthesis. Chem. Biol. 15:99–109 [Google Scholar]
  106. Eustaquio AS, Pojer F, Noe JP, Moore BS. 106.  2008. Discovery and characterization of a marine bacterial SAM-dependent chlorinase. Nat. Chem. Biol. 4:69–74 [Google Scholar]
  107. Eustaquio AS, Moore BS. 107.  2008. Mutasynthesis of fluorosalinosporamide, a potent and reversible inhibitor of the proteasome. Angew. Chem. Int. Ed. 47:3936–38 [Google Scholar]
  108. Piel J. 108.  2010. Natural products via enzymatic reactions. Preface. Top. Curr. Chem. 297:ix–x [Google Scholar]
  109. Sattely ES, Fischbach MA, Walsh CT. 109.  2008. Total biosynthesis: in vitro reconstitution of polyketide and nonribosomal peptide pathways. Nat. Prod. Rep. 25:757–93 [Google Scholar]
  110. Xiang L, Kalaitzis JA, Moore BS. 110.  2004. EncM, a versatile enterocin biosynthetic enzyme involved in Favorskii oxidative rearrangement, aldol condensation, and heterocycle-forming reactions. Proc. Natl. Acad. Sci. USA 101:15609–14 [Google Scholar]
  111. Cheng Q, Xiang L, Izumikawa M, Meluzzi D, Moore BS. 111.  2007. Enzymatic total synthesis of enterocin polyketides. Nat. Chem. Biol. 3:557–58 [Google Scholar]
  112. Kalaitzis JA, Cheng Q, Thomas PM, Kelleher NL, Moore BS. 112.  2009. In vitro biosynthesis of unnatural enterocin and wailupemycin polyketides. J. Nat. Prod. 72:469–72 [Google Scholar]
  113. Pahari P, Kharel MK, Shepherd MD, van Lanen SG, Rohr J. 113.  2012. Enzymatic total synthesis of defucogilvocarcin M and its implications for gilvocarcin biosynthesis. Angew. Chem. Int. Ed. 51:1216–20 [Google Scholar]
  114. Hansen DA, Rath CM, Eisman EB, Narayan AR, Kittendorf JD. 114.  et al. 2013. Biocatalytic synthesis of pikromycin, methymycin, neomethymycin, novamethymycin, and ketomethymycin. J. Am. Chem. Soc. 135:11232–38 [Google Scholar]
  115. Mortison JD, Kittendorf JD, Sherman DH. 115.  2009. Synthesis and biochemical analysis of complex chain-elongation intermediates for interrogation of molecular specificity in the erythromycin and pikromycin polyketide synthases. J. Am. Chem. Soc. 131:15784–93 [Google Scholar]
  116. Zhang W, Ntai I, Bolla ML, Malcolmson SJ, Kahne D. 116.  et al. 2011. Nine enzymes are required for assembly of the pacidamycin group of peptidyl nucleoside antibiotics. J. Am. Chem. Soc. 133:5240–43 [Google Scholar]
  117. Cacho RA, Chooi YH, Zhou H, Tang Y. 117.  2013. Complexity generation in fungal polyketide biosynthesis: a spirocycle-forming P450 in the concise pathway to the antifungal drug griseofulvin. ACS Chem. Biol. 8:2322–30 [Google Scholar]
/content/journals/10.1146/annurev-chembioeng-060713-040008
Loading
/content/journals/10.1146/annurev-chembioeng-060713-040008
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error