1932

Abstract

Polyketides are a large family of structurally complex natural products including compounds with important bioactivities. Polyketides are biosynthesized by polyketide synthases (PKSs), multienzyme complexes derived evolutionarily from fatty acid synthases (FASs). The focus of this review is to critically compare the properties of FASs with iterative aromatic PKSs, including type II PKSs and fungal type I nonreducing PKSs whose chemical logic is distinct from that of modular PKSs. This review focuses on structural and enzymological studies that reveal both similarities and striking differences between FASs and aromatic PKSs. The potential application of FAS and aromatic PKS structures for bioengineering future drugs and biofuels is highlighted.

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2018-06-20
2024-04-27
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Literature Cited

  1. 1.  Hopwood DA. 1997. Genetic contributions to understanding polyketide synthases. Chem. Rev. 97:2465–98
    [Google Scholar]
  2. 2.  Haight TH, Finland M 1952. The antibacterial action of erythromycin. Proc. Soc. Exp. Biol. Med. 81:175–83
    [Google Scholar]
  3. 3.  Malpartida F, Hopwood DA 1984. Molecular cloning of the whole biosynthetic pathway of a Streptomyces antibiotic and its expression in a heterologous host. Nature 309:462–64
    [Google Scholar]
  4. 4.  Motamedi H, Hutchinson CR 1987. Cloning and heterologous expression of a gene cluster for the biosynthesis of tetracenomycin C, the anthracycline antitumor antibiotic of Streptomyces glaucescens. PNAS 84:4445–49
    [Google Scholar]
  5. 5.  Otten SL, Stutzman-Engwall KJ, Hutchinson CR 1990. Cloning and expression of daunorubicin biosynthesis genes from Streptomyces peucetius and S. peucetius subsp. caesius. J. Bacteriol. 172:3427–34
    [Google Scholar]
  6. 6.  Jakobi K, Hertweck C 2004. A gene cluster encoding resistomycin biosynthesis in Streptomyces resistomycificus; exploring polyketide cyclization beyond linear and angucyclic patterns. J. Am. Chem. Soc. 126:2298–99
    [Google Scholar]
  7. 7.  Lombó F, Blanco G, Fernández E, Méndez C, Salas J 1996. Characterization of Streptomyces argillaceus genes encoding a polyketide synthase involved in the biosynthesis of the antitumor mithramycin. Gene 172:87–91
    [Google Scholar]
  8. 8.  Manzoni M, Rollini M 2002. Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl. Microbiol. Biotechnol. 58:555–64
    [Google Scholar]
  9. 9.  Schoppner A, Kindl H 1984. Purification and properties of a stilbene synthase from induced cell suspension cultures of peanut. J. Biol. Chem. 259:6806–11
    [Google Scholar]
  10. 10.  Schumann J, Hertweck C 2006. Advances in cloning, functional analysis and heterologous expression of fungal polyketide synthase genes. J. Biotechnol. 124:690–703
    [Google Scholar]
  11. 11.  Shen B. 2003. Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Curr. Opin. Chem. Biol. 7:285–95
    [Google Scholar]
  12. 12.  Caffrey P, Bevitt DJ, Staunton J, Leadlay PF 1992. Identification of DEBS 1, DEBS 2 and DEBS 3, the multienzyme polypeptides of the erythromycin-producing polyketide synthase from Saccharopolyspora erythraea. FEBS Lett 304:225–28
    [Google Scholar]
  13. 13.  Staunton J, Weissman KJ 2001. Polyketide biosynthesis: a millennium review. Nat. Prod. Rep. 18:380–416
    [Google Scholar]
  14. 14.  Keatinge-Clay AT. 2017. The uncommon enzymology of cis-acyltransferase assembly lines. Chem. Rev. 117:5334–66
    [Google Scholar]
  15. 15.  Robbins T, Liu YC, Cane DE, Khosla C 2016. Structure and mechanism of assembly line polyketide synthases. Curr. Opin. Struct. Biol. 41:10–18
    [Google Scholar]
  16. 16.  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
    [Google Scholar]
  17. 17.  Khosla C, Gokhale RS, Jacobsen JR, Cane DE 1999. Tolerance and specificity of polyketide synthases. Annu. Rev. Biochem. 68:219–53
    [Google Scholar]
  18. 18.  Akey DL, Gehret JJ, Khare D, Smith JL 2012. Insights from the sea: structural biology of marine polyketide synthases. Nat. Prod. Rep. 29:1038–49
    [Google Scholar]
  19. 19.  Smith JL, Skiniotis G, Sherman DH 2015. Architecture of the polyketide synthase module: surprises from electron cryo-microscopy. Curr. Opin. Struct. Biol. 31:9–19
    [Google Scholar]
  20. 20.  Austin MB, Noel JP 2003. The chalcone synthase superfamily of type III polyketide synthases. Nat. Prod. Rep. 20:79–110
    [Google Scholar]
  21. 21.  White SW, Zheng J, Zhang YM, Rock CO 2005. The structural biology of type II fatty acid biosynthesis. Annu. Rev. Biochem. 74:791–831
    [Google Scholar]
  22. 22.  Clapham JC, Arch JR 2007. Thermogenic and metabolic antiobesity drugs: rationale and opportunities. Diabetes Obes. Metab. 9:259–75
    [Google Scholar]
  23. 23.  Kridel SJ, Lowther WT, Pemble CW IV 2007. Fatty acid synthase inhibitors: new directions for oncology. Expert Opin. Investig. Drugs 16:1817–29
    [Google Scholar]
  24. 24.  Wright HT, Reynolds KA 2007. Antibacterial targets in fatty acid biosynthesis. Curr. Opin. Microbiol. 10:447–53
    [Google Scholar]
  25. 25.  Purohit HJ, Cheema S, Lal S, Raut CP, Kalia VC 2007. In search of drug targets for Mycobacterium tuberculosis. Infect. Disord. Drug Targets 7:245–50
    [Google Scholar]
  26. 26.  Zargar A, Bailey CB, Haushalter RW, Eiben CB, Katz L, Keasling JD 2017. Leveraging microbial biosynthetic pathways for the generation of ‘drop-in’ biofuels. Curr. Opin. Biotechnol. 45:156–63
    [Google Scholar]
  27. 27.  Smith S, Tsai SC 2007. The type I fatty acid and polyketide synthases: a tale of two megasynthases. Nat. Prod. Rep. 24:1041–72
    [Google Scholar]
  28. 28.  Crosby J, Crump MP 2012. The structural role of the carrier protein – active controller or passive carrier. Nat. Prod. Rep. 29:1111–37
    [Google Scholar]
  29. 29.  Harris TM, Harris CM, Hindley KB 1974. Biogenetic-type syntheses of polyketide metabolites. Fortschr. Chem. Org. Naturst. 31:217–82
    [Google Scholar]
  30. 30.  Ames BD, Korman TP, Zhang W, Smith P, Vu T et al. 2008. Crystal structure and functional analysis of tetracenomycin ARO/CYC: implications for cyclization specificity of aromatic polyketides. PNAS 105:5349–54
    [Google Scholar]
  31. 31.  Ames BD, Lee MY, Moody C, Zhang W, Tang Y, Tsai SC 2011. Structural and biochemical characterization of ZhuI aromatase/cyclase from the R1128 polyketide pathway. Biochemistry 50:8392–406
    [Google Scholar]
  32. 32.  Caldara-Festin G, Jackson DR, Barajas JF, Valentic TR, Patel AB et al. 2015. Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases. PNAS 112:E6844–51
    [Google Scholar]
  33. 33.  Crawford JM, Korman TP, Labonte JW, Vagstad AL, Hill EA et al. 2009. Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization. Nature 461:1139–43
    [Google Scholar]
  34. 34.  Javidpour P, Bruegger J, Srithahan S, Korman TP, Crump MP et al. 2013. The determinants of activity and specificity in actinorhodin type II polyketide ketoreductase. Chem. Biol. 20:1225–34
    [Google Scholar]
  35. 35.  Javidpour P, Das A, Khosla C, Tsai SC 2011. Structural and biochemical studies of the hedamycin type II polyketide ketoreductase (HedKR): molecular basis of stereo- and regiospecificities. Biochemistry 50:7426–39
    [Google Scholar]
  36. 36.  Javidpour P, Korman TP, Shakya G, Tsai SC 2011. Structural and biochemical analyses of regio- and stereospecificities observed in a type II polyketide ketoreductase. Biochemistry 50:4638–49
    [Google Scholar]
  37. 37.  Korman TP, Hill JA, Vu TN, Tsai SC 2004. Structural analysis of actinorhodin polyketide ketoreductase: cofactor binding and substrate specificity. Biochemistry 43:14529–38
    [Google Scholar]
  38. 38.  Korman TP, Tan YH, Wong J, Luo R, Tsai SC 2008. Inhibition kinetics and emodin cocrystal structure of a type II polyketide ketoreductase. Biochemistry 47:1837–47
    [Google Scholar]
  39. 39.  Lee MY, Ames BD, Tsai SC 2012. Insight into the molecular basis of aromatic polyketide cyclization: crystal structure and in vitro characterization of WhiE-ORFVI. Biochemistry 51:3079–91
    [Google Scholar]
  40. 40.  Pan H, Tsai S, Meadows ES, Miercke LJ, Keatinge-Clay AT et al. 2002. Crystal structure of the priming β-ketosynthase from the R1128 polyketide biosynthetic pathway. Structure 10:1559–68
    [Google Scholar]
  41. 41.  Tsai SC, Ames BD 2009. Structural enzymology of polyketide synthases. Methods Enzymol 459:17–47
    [Google Scholar]
  42. 42.  Franke J, Hertweck C 2016. Biomimetic thioesters as probes for enzymatic assembly lines: synthesis, applications, and challenges. Cell Chem. Biol. 23:1179–92
    [Google Scholar]
  43. 43.  Shakya G, Rivera H Jr, Lee DJ, Jaremko MJ, La Clair JJ et al. 2014. Modeling linear and cyclic PKS intermediates through atom replacement. J. Am. Chem. Soc. 136:16792–99
    [Google Scholar]
  44. 44.  Bull JA, Croft RA, Davis OA, Doran R, Morgan KF 2016. Oxetanes: recent advances in synthesis, reactivity, and medicinal chemistry. Chem. Rev. 116:12150–233
    [Google Scholar]
  45. 45.  Nguyen C, Haushalter RW, Lee DJ, Markwick PR, Bruegger J et al. 2014. Trapping the dynamic acyl carrier protein in fatty acid biosynthesis. Nature 505:427–31
    [Google Scholar]
  46. 46.  Bao W, Sheldon PJ, Wendt-Pienkowski E, Hutchinson CR 1999. The Streptomyces peucetius dpsC gene determines the choice of starter unit in biosynthesis of the daunorubicin polyketide. J. Bacteriol. 181:4690–95
    [Google Scholar]
  47. 47.  Heath RJ, Rock CO 2002. The Claisen condensation in biology. Nat. Prod. Rep. 19:581–96
    [Google Scholar]
  48. 48.  Tang Y, Lee TS, Kobayashi S, Khosla C 2003. Ketosynthases in the initiation and elongation modules of aromatic polyketide synthases have orthogonal acyl carrier protein specificity. Biochemistry 42:6588–95
    [Google Scholar]
  49. 49.  Bisang C, Long PF, Cortes J, Westcott J, Crosby J et al. 1999. A chain initiation factor common to both modular and aromatic polyketide synthases. Nature 401:502–5
    [Google Scholar]
  50. 50.  McDaniel R, Ebert-Khosla S, Hopwood DA, Khosla C 1993. Engineered biosynthesis of novel polyketides. Science 262:1546–50
    [Google Scholar]
  51. 51.  O'Hagan D. 1993. Biosynthesis of fatty acid and polyketide metabolites. Nat. Prod. Rep. 10:593–624
    [Google Scholar]
  52. 52.  Kimber MS, Martin F, Lu Y, Houston S, Vedadi M et al. 2004. The structure of (3R)-hydroxyacyl-acyl carrier protein dehydratase (FabZ) from Pseudomonas aeruginosa. J. Biol. Chem 279:52593–602
    [Google Scholar]
  53. 53.  Heath RJ, Rock CO 1996. Roles of the FabA and FabZ β-hydroxyacyl-acyl carrier protein dehydratases in Escherichia coli fatty acid biosynthesis. J. Biol. Chem. 271:27795–801
    [Google Scholar]
  54. 54.  Rabbani A, Finn RM, Ausio J 2005. The anthracycline antibiotics: antitumor drugs that alter chromatin structure. BioEssays 27:50–56
    [Google Scholar]
  55. 55.  Rix U, Fischer C, Remsing LL, Rohr J 2002. Modification of post-PKS tailoring steps through combinatorial biosynthesis. Nat. Prod. Rep. 19:542–80
    [Google Scholar]
  56. 56.  Liscombe DK, Louie GV, Noel JP 2012. Architectures, mechanisms and molecular evolution of natural product methyltransferases. Nat. Prod. Rep. 29:1238–50
    [Google Scholar]
  57. 57.  Tang MC, Zou Y, Watanabe K, Walsh CT, Tang Y 2017. Oxidative cyclization in natural product biosynthesis. Chem. Rev. 117:5226–333
    [Google Scholar]
  58. 58.  Singh S, Phillips GN Jr., Thorson JS 2012. The structural biology of enzymes involved in natural product glycosylation. Nat. Prod. Rep. 29:1201–37
    [Google Scholar]
  59. 59.  Arthur CJ, Szafranska A, Evans SE, Findlow SC, Burston SG et al. 2005. Self-malonylation is an intrinsic property of a chemically synthesized type II polyketide synthase acyl carrier protein. Biochemistry 44:15414–21
    [Google Scholar]
  60. 60.  Arthur CJ, Williams C, Pottage K, Ploskon E, Findlow SC et al. 2009. Structure and malonyl CoA-ACP transacylase binding of Streptomyces coelicolor fatty acid synthase acyl carrier protein. ACS Chem. Biol. 4:625–36
    [Google Scholar]
  61. 61.  Beltran-Alvarez P, Cox RJ, Crosby J, Simpson TJ 2007. Dissecting the component reactions catalyzed by the actinorhodin minimal polyketide synthase. Biochemistry 46:14672–81
    [Google Scholar]
  62. 62.  Matharu AL, Cox RJ, Crosby J, Byrom KJ, Simpson TJ 1998. MCAT is not required for in vitro polyketide synthesis in a minimal actinorhodin polyketide synthase from Streptomyces coelicolor. Chem. Biol 5:699–711
    [Google Scholar]
  63. 63.  Szafranska AE, Hitchman TS, Cox RJ, Crosby J, Simpson TJ 2002. Kinetic and mechanistic analysis of the malonyl CoA:ACP transacylase from Streptomyces coelicolor indicates a single catalytically competent serine nucleophile at the active site. Biochemistry 41:1421–27
    [Google Scholar]
  64. 64.  Dreier J, Shah AN, Khosla C 1999. Kinetic analysis of the actinorhodin aromatic polyketide synthase. J. Biol. Chem. 274:25108–12
    [Google Scholar]
  65. 65.  Keatinge-Clay AT, Shelat AA, Savage DF, Tsai SC, Miercke LJ et al. 2003. Catalysis, specificity, and ACP docking site of Streptomyces coelicolor malonyl-CoA:ACP transacylase. Structure 11:147–54
    [Google Scholar]
  66. 66.  Koppisch AT, Khosla C 2003. Structure-based mutagenesis of the malonyl-CoA:acyl carrier protein transacylase from Streptomyces coelicolor. Biochemistry 42:11057–64
    [Google Scholar]
  67. 67.  Bao W, Sheldon PJ, Hutchinson CR 1999. Purification and properties of the Streptomyces peucetius DpsC β-ketoacyl:acyl carrier protein synthase III that specifies the propionate-starter unit for type II polyketide biosynthesis. Biochemistry 38:9752–57
    [Google Scholar]
  68. 68.  Rajgarhia VB, Priestley ND, Strohl WR 2001. The product of dpsC confers starter unit fidelity upon the daunorubicin polyketide synthase of Streptomyces sp. strain C5. Metab. Eng. 3:49–63
    [Google Scholar]
  69. 69.  Keatinge-Clay AT, Maltby DA, Medzihradszky KF, Khosla C, Stroud RM 2004. An antibiotic factory caught in action. Nat. Struct. Mol. Biol. 11:888–93
    [Google Scholar]
  70. 70.  Tang Y, Tsai SC, Khosla C 2003. Polyketide chain length control by chain length factor. J. Am. Chem. Soc. 125:12708–9
    [Google Scholar]
  71. 71.  Meurer G, Gerlitz M, Wendt-Pienkowski E, Vining LC, Rohr J, Hutchinson CR 1997. Iterative type II polyketide synthases, cyclases and ketoreductases exhibit context-dependent behavior in the biosynthesis of linear and angular decapolyketides. Chem. Biol. 4:433–43
    [Google Scholar]
  72. 72.  Rajgarhia VB, Strohl WR 1997. Minimal Streptomyces sp. strain C5 daunorubicin polyketide biosynthesis genes required for aklanonic acid biosynthesis. J. Bacteriol. 179:2690–96
    [Google Scholar]
  73. 73.  Hadfield AT, Limpkin C, Teartasin W, Simpson TJ, Crosby J, Crump MP 2004. The crystal structure of the actIII actinorhodin polyketide reductase: proposed mechanism for ACP and polyketide binding. Structure 12:1865–75
    [Google Scholar]
  74. 74.  Persson B, Kallberg Y, Oppermann U, Jornvall H 2003. Coenzyme-based functional assignments of short-chain dehydrogenases/reductases (SDRs). Chem. Biol. Interact. 143–44:271–78
    [Google Scholar]
  75. 75.  Caffrey P. 2003. Conserved amino acid residues correlating with ketoreductase stereospecificity in modular polyketide synthases. ChemBioChem 4:654–57
    [Google Scholar]
  76. 76.  Reid R, Piagentini M, Rodriguez E, Ashley G, Viswanathan N et al. 2003. A model of structure and catalysis for ketoreductase domains in modular polyketide synthases. Biochemistry 42:72–79
    [Google Scholar]
  77. 77.  Price AC, Zhang YM, Rock CO, White SW 2004. Cofactor-induced conformational rearrangements establish a catalytically competent active site and a proton relay conduit in FabG. Structure 12:417–28
    [Google Scholar]
  78. 78.  Kantola J, Blanco G, Hautala A, Kunnari T, Hakala J et al. 1997. Folding of the polyketide chain is not dictated by minimal polyketide synthase in the biosynthesis of mithramycin and anthracycline. Chem. Biol. 4:751–55
    [Google Scholar]
  79. 79.  Zawada RJ, Khosla C 1999. Heterologous expression, purification, reconstitution and kinetic analysis of an extended type II polyketide synthase. Chem. Biol. 6:607–15
    [Google Scholar]
  80. 80.  Fu H, Ebertkhosla S, Hopwood DA, Khosla C 1994. Engineered biosynthesis of novel polyketides: dissection of the catalytic specificity of the act ketoreductase. J. Am. Chem. Soc. 116:4166–70
    [Google Scholar]
  81. 81.  Dutler H, Kull A, Mislin R 1971. Fatty acid synthetase from pig liver. 2. Characterization of the enzyme complex with oxidoreductase activity for alicyclic ketones as a fatty acid synthetase. Eur. J. Biochem. 22:213–17
    [Google Scholar]
  82. 82.  Joshi AK, Smith S 1993. Construction, expression, and characterization of a mutated animal fatty acid synthase deficient in the dehydrase function. J. Biol. Chem. 268:22508–13
    [Google Scholar]
  83. 83.  Fritzsche K, Ishida K, Hertweck C 2008. Orchestration of discoid polyketide cyclization in the resistomycin pathway. J. Am. Chem. Soc. 130:8307–16
    [Google Scholar]
  84. 84.  Fitzgerald JT, Charkoudian LK, Watts KR, Khosla C 2013. Analysis and refactoring of the A-74528 biosynthetic pathway. J. Am. Chem. Soc. 135:3752–55
    [Google Scholar]
  85. 85.  Iyer LM, Koonin EV, Aravind L 2001. Adaptations of the helix-grip fold for ligand binding and catalysis in the START domain superfamily. Proteins 43:134–44
    [Google Scholar]
  86. 86.  Gajhede M, Osmark P, Poulsen FM, Ipsen H, Larsen JN et al. 1996. X-ray and NMR structure of Bet v 1, the origin of birch pollen allergy. Nat. Struct. Biol. 3:1040–45
    [Google Scholar]
  87. 87.  Leesong M, Henderson BS, Gillig JR, Schwab JM, Smith JL 1996. Structure of a dehydratase-isomerase from the bacterial pathway for biosynthesis of unsaturated fatty acids: two catalytic activities in one active site. Structure 4:253–64
    [Google Scholar]
  88. 88.  Dreier J, Li Q, Khosla C 2001. Malonyl-CoA:ACP transacylase from Streptomyces coelicolor has two alternative catalytically active nucleophiles. Biochemistry 40:12407–11
    [Google Scholar]
  89. 89.  Qiu X, Choudhry AE, Janson CA, Grooms M, Daines RA et al. 2005. Crystal structure and substrate specificity of the β-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus. Protein Sci 14:2087–94
    [Google Scholar]
  90. 90.  Garwin JL, Klages AL, Cronan JE Jr 1980. Structural, enzymatic, and genetic studies of β-ketoacyl-acyl carrier protein synthases I and II of Escherichia coli. J. Biol. Chem 255:11949–56
    [Google Scholar]
  91. 91.  Zhang YM, Hurlbert J, White SW, Rock CO 2006. Roles of the active site water, histidine 303, and phenylalanine 396 in the catalytic mechanism of the elongation condensing enzyme of Streptococcus pneumoniae. J. Biol. Chem 281:17390–99
    [Google Scholar]
  92. 92.  Price AC, Zhang YM, Rock CO, White SW 2001. Structure of β-ketoacyl-[acyl carrier protein] reductase from Escherichia coli: negative cooperativity and its structural basis. Biochemistry 40:12772–81
    [Google Scholar]
  93. 93.  Bergler H, Wallner P, Ebeling A, Leitinger B, Fuchsbichler S et al. 1994. Protein EnvM is the NADH-dependent enoyl-ACP reductase (FabI) of Escherichia coli. J. Biol. Chem 269:5493–96
    [Google Scholar]
  94. 94.  Heath RJ, Rock CO 1995. Enoyl-acyl carrier protein reductase (fabI) plays a determinant role in completing cycles of fatty acid elongation in Escherichia coli. J. Biol. Chem 270:26538–42
    [Google Scholar]
  95. 95.  Green PR, Merrill AH Jr., Bell RM 1981. Membrane phospholipid synthesis in Escherichia coli. Purification, reconstitution, and characterization of sn-glycerol-3-phosphate acyltransferase. J. Biol. Chem. 256:11151–59
    [Google Scholar]
  96. 96.  Tang Y, Lee TS, Khosla C 2004. Engineered biosynthesis of regioselectively modified aromatic polyketides using bimodular polyketide synthases. PLOS Biol 2:E31
    [Google Scholar]
  97. 97.  Townsend CA. 2014. Aflatoxin and deconstruction of type I, iterative polyketide synthase function. Nat. Prod. Rep. 31:1260–65
    [Google Scholar]
  98. 98.  Zhang W, Li Y, Tang Y 2008. Engineered biosynthesis of bacterial aromatic polyketides in Escherichia coli. PNAS 105:20683–88
    [Google Scholar]
  99. 99.  Crawford JM, Dancy BCR, Hill EA, Udwary DW, Townsend CA 2006. Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase. PNAS 103:16728–33
    [Google Scholar]
  100. 100.  Crawford JM, Vagstad AL, Ehrlich KC, Townsend CA 2008. Starter unit specificity directs genome mining of polyketide synthase pathways in fungi. Bioorg. Chem. 36:16–22
    [Google Scholar]
  101. 101.  Crawford JM, Vagstad AL, Whitworth KP, Ehrlich KC, Townsend CA 2008. Synthetic strategy of nonreducing iterative polyketide synthases and the origin of the classical “starter-unit effect. .” ChemBioChem 9:1019–23
    [Google Scholar]
  102. 102.  Winter JM, Cascio D, Dietrich D, Sato M, Watanabe K et al. 2015. Biochemical and structural basis for controlling chemical modularity in fungal polyketide biosynthesis. J. Am. Chem. Soc. 137:9885–93
    [Google Scholar]
  103. 103.  Li Y, Image II, Xu W, Image I, Tang Y 2010. Classification, prediction, and verification of the regioselectivity of fungal polyketide synthase product template domains. J. Biol. Chem. 285:22764–73
    [Google Scholar]
  104. 104.  Pidugu LS, Maity K, Ramaswamy K, Surolia N, Suguna K 2009. Analysis of proteins with the ‘hot dog’ fold: prediction of function and identification of catalytic residues of hypothetical proteins. BMC Struct. Biol. 9:37
    [Google Scholar]
  105. 105.  Barajas JF, Shakya G, Moreno G, Rivera H Jr., Jackson DR et al. 2017. Polyketide mimetics yield structural and mechanistic insights into product template domain function in nonreducing polyketide synthases. PNAS 114:E4142–48
    [Google Scholar]
  106. 106.  Korman TP, Crawford JM, Labonte JW, Newman AG, Wong J et al. 2010. Structure and function of an iterative polyketide synthase thioesterase domain catalyzing Claisen cyclization in aflatoxin biosynthesis. PNAS 107:6246–51
    [Google Scholar]
  107. 107.  Tsai SC, Miercke LJ, Krucinski J, Gokhale R, Chen JC et al. 2001. Crystal structure of the macrocycle-forming thioesterase domain of the erythromycin polyketide synthase: versatility from a unique substrate channel. PNAS 98:14808–13
    [Google Scholar]
  108. 108.  Tsai SC, Lu H, Cane DE, Khosla C, Stroud RM 2002. Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases. Biochemistry 41:12598–606
    [Google Scholar]
  109. 109.  Giraldes JW, Akey DL, Kittendorf JD, Sherman DH, Smith JL, Fecik RA 2006. Structural and mechanistic insights into polyketide macrolactonization from polyketide-based affinity labels. Nat. Chem. Biol. 2:531–36
    [Google Scholar]
  110. 110.  Akey DL, Kittendorf JD, Giraldes JW, Fecik RA, Sherman DH, Smith JL 2006. Structural basis for macrolactonization by the pikromycin thioesterase. Nat. Chem. Biol. 2:537–42
    [Google Scholar]
  111. 111.  Bruner SD, Weber T, Kohli RM, Schwarzer D, Marahiel MA et al. 2002. Structural basis for the cyclization of the lipopeptide antibiotic surfactin by the thioesterase domain SrfTE. Structure 10:301–10
    [Google Scholar]
  112. 112.  Samel SA, Wagner B, Marahiel MA, Essen LO 2006. The thioesterase domain of the fengycin biosynthesis cluster: a structural base for the macrocyclization of a non-ribosomal lipopeptide. J. Mol. Biol. 359:876–89
    [Google Scholar]
  113. 113.  Frueh DP, Arthanari H, Koglin A, Vosburg DA, Bennett AE et al. 2008. Dynamic thiolation-thioesterase structure of a non-ribosomal peptide synthetase. Nature 454:903–6
    [Google Scholar]
  114. 114.  Maier T, Leibundgut M, Ban N 2008. The crystal structure of a mammalian fatty acid synthase. Science 321:1315–22
    [Google Scholar]
  115. 115.  Herbst DA, Jakob RP, Zahringer F, Maier T 2016. Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases. Nature 531:533–37
    [Google Scholar]
  116. 116.  Whicher JR, Dutta S, Hansen DA, Hale WA, Chemler JA et al. 2014. Structural rearrangements of a polyketide synthase module during its catalytic cycle. Nature 510:560–64
    [Google Scholar]
  117. 117.  Ishikawa F, Haushalter RW, Lee DJ, Finzel K, Burkart MD 2013. Sulfonyl 3-alkynyl pantetheinamides as mechanism-based cross-linkers of acyl carrier protein dehydratase. J. Am. Chem. Soc. 135:8846–49
    [Google Scholar]
  118. 118.  Leibundgut M, Maier T, Jenni S, Ban N 2008. The multienzyme architecture of eukaryotic fatty acid synthases. Curr. Opin. Struct. Biol. 18:714–25
    [Google Scholar]
  119. 119.  Cronan JE. 2014. The chain-flipping mechanism of ACP (acyl carrier protein)-dependent enzymes appears universal. Biochem. J. 460:157–63
    [Google Scholar]
  120. 120.  Dillon SC, Bateman A 2004. The Hotdog fold: wrapping up a superfamily of thioesterases and dehydratases. BMC Bioinform 5:109–23
    [Google Scholar]
  121. 121.  Maier T, Leibundgut M, Ban N 2008. The crystal structure of a mammalian fatty acid synthase. Science 321:1315–22
    [Google Scholar]
  122. 122.  Zhou H, Qiao K, Gao Z, Meehan MJ, Li JW et al. 2010. Enzymatic synthesis of resorcylic acid lactones by cooperation of fungal iterative polyketide synthases involved in hypothemycin biosynthesis. J. Am. Chem. Soc. 132:4530–31
    [Google Scholar]
  123. 123.  Crawford JM, Dancy BC, Hill EA, Udwary DW, Townsend CA 2006. Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase. PNAS 103:16728–33
    [Google Scholar]
  124. 124.  Crawford JM, Vagstad AL, Ehrlich KC, Townsend CA 2008. Starter unit specificity directs genome mining of polyketide synthase pathways in fungi. Bioorg. Chem. 36:16–22
    [Google Scholar]
  125. 125.  Huitt-Roehl CR, Hill EA, Adams MM, Vagstad AL, Li JW, Townsend CA 2015. Starter unit flexibility for engineered product synthesis by the nonreducing polyketide synthase PksA. ACS Chem. Biol. 10:1443–49
    [Google Scholar]
  126. 126.  Naviaux RK, Curtis B, Li K, Naviaux JC, Bright AT et al. 2017. Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial. Ann. Clin. Transl. Neurol. 4:491–505
    [Google Scholar]
  127. 127.  Jackson DR, Shakya G, Patel AB, Mohhammed LY, Vasilakis K et al. 2018. Structural and functional studies of daunorubicin priming ketosynthase DpsC. ACS Chem. Biol. 13:141–51
    [Google Scholar]
  128. 128.  Choi KH, Kremer L, Besra GS, Rock CO 2000. Identification and substrate specificity of β-ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. J. Biol. Chem 275:28201–7
    [Google Scholar]
  129. 129.  Choi KH, Heath RJ, Rock CO 2000. β-Ketoacyl-acyl carrier protein synthase III (FabH) is a determining factor in branched-chain fatty acid biosynthesis. J. Bacteriol. 182:365–70
    [Google Scholar]
  130. 130.  Price AC, Rock CO, White SW 2003. The 1.3-Angstrom-resolution crystal structure of β-ketoacyl-acyl carrier protein synthase II from Streptococcus pneumoniae. J. Bacteriol 185:4136–43
    [Google Scholar]
  131. 131.  Olsen JG, Kadziola A, von Wettstein-Knowles P, Siggaard-Andersen M, Lindquist Y, Larsen S 1999. The X-ray crystal structure of β-ketoacyl [acyl carrier protein] synthase I. FEBS Lett 460:46–52
    [Google Scholar]
  132. 132.  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. 14:931–43
    [Google Scholar]
  133. 133.  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. PNAS 103:11124–29
    [Google Scholar]
  134. 134.  Das A, Khosla C 2009. Biosynthesis of aromatic polyketides in bacteria. Acc. Chem. Res. 42:631–39
    [Google Scholar]
  135. 135.  Kalaitzis JA, Moore BS 2004. Heterologous biosynthesis of truncated hexaketides derived from the actinorhodin polyketide synthase. J. Nat. Prod. 67:1419–22
    [Google Scholar]
  136. 136.  Weissman KJ, Leadlay PF 2005. Combinatorial biosynthesis of reduced polyketides. Nat. Rev. Microbiol. 3:925–36
    [Google Scholar]
  137. 137.  Anderson VE, Hammes GG 1984. Stereochemistry of the reactions catalyzed by chicken liver fatty acid synthase. Biochemistry 23:2088–94
    [Google Scholar]
  138. 138.  Nakajima K, Yamashita A, Akama H, Nakatsu T, Kato H et al. 1998. Crystal structures of two tropinone reductases: different reaction stereospecificities in the same protein fold. PNAS 95:4876–81
    [Google Scholar]
  139. 139.  Kallberg Y, Oppermann U, Jornvall H, Persson B 2002. Short-chain dehydrogenase/reductase (SDR) relationships: a large family with eight clusters common to human, animal, and plant genomes. Protein Sci 11:636–41
    [Google Scholar]
  140. 140.  Zhang HL, He XG, Adefarati A, Gallucci J, Cole SP et al. 1990. Mutactin, a novel polyketide from Streptomyces coelicolor: structure and biosynthetic relationship to actinorhodin. J. Organ. Chem. 55:1682–84
    [Google Scholar]
  141. 141.  Liu L, Zhang Z, Shao CL, Wang JL, Bai H, Wang CY 2015. Bioinformatical analysis of the sequences, structures and functions of fungal polyketide synthase product template domains. Sci. Rep. 5:10463
    [Google Scholar]
  142. 142.  Xu Y, Zhou T, Zhou Z, Su S, Roberts SA et al. 2013. Rational reprogramming of fungal polyketide first-ring cyclization. PNAS 110:5398–403
    [Google Scholar]
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