Advertisement

Applied Microbiology and Biotechnology

, Volume 85, Issue 5, pp 1227–1239 | Cite as

Genetic engineering of macrolide biosynthesis: past advances, current state, and future prospects

  • Sung Ryeol Park
  • Ah Reum Han
  • Yeon-Hee Ban
  • Young Ji Yoo
  • Eun Ji Kim
  • Yeo Joon Yoon
Mini-Review

Abstract

Polyketides comprise one of the major families of natural products. They are found in a wide variety of bacteria, fungi, and plants and include a large number of medically important compounds. Polyketides are biosynthesized by polyketide synthases (PKSs). One of the major groups of polyketides are the macrolides, the activities of which are derived from the presence of a macrolactone ring to which one or more 6-deoxysugars are attached. The core macrocyclic ring is biosynthesized from acyl-CoA precursors by PKS. Genetic manipulation of PKS-encoding genes can result in predictable changes in the structure of the macrolactone component, many of which are not easily achieved through standard chemical derivatization or total synthesis. Furthermore, many of the changes, including post-PKS modifications such as glycosylation and oxidation, can be combined for further structural diversification. This review highlights the current state of novel macrolide production with a focus on the genetic engineering of PKS and post-PKS tailoring genes. Such engineering of the metabolic pathways for macrolide biosynthesis provides attractive alternatives for the production of diverse non-natural compounds. Other issues of importance, including the engineering of precursor pathways and heterologous expression of macrolide biosynthetic genes, are also considered.

Keywords

Genetic engineering Macrolide biosynthesis Post-PKS modification Heterologous expression 

Notes

Acknowledgement

The work performed in the authors' laboratory and summarized in this article was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST; R0A-2008-000-20030-0, 2009K000712), Seoul R&BD Program grant (KU080657M0209721), and the Marine and Extreme Genome Research Center Program of the Ministry of Land, Transportation, and Maritime Affairs, Republic of Korea.

References

  1. Andersen JF, Tatsuta K, Gunji H, Ishiyama T, Hutchinson CR (1993) Substrate specificity of 6-deoxyerythronolide B hydroxylase, a bacterial cytochrome P450 of erythromycin A biosynthesis. Biochemistry 32:1905–1913Google Scholar
  2. Austin MB, Noel JP (2003) The chalcone synthase superfamily of type III polyketide synthases. Nat Prod Rep 20:79–110Google Scholar
  3. Basnet DB, Park JW, Yoon YJ (2008) Combinatorial biosynthesis of 5-O-desosaminyl erythronolide A as a potent precursor of ketolide antibiotics. J Biotechnol 135:92–96Google Scholar
  4. Bentley SD, Chater KF, Cerdeño-Tárraga AM, Challis GL, Thomson NR, James KD, Harris DE, Quail MA, Kieser H, Harper D, Bateman A, Brown S, Chandra G, Chen CW, Collins M, Cronin A, Fraser A, Goble A, Hidalgo J, Hornsby T, Howarth S, Huang CH, Kieser T, Larke L, Murphy L, Oliver K, O'Neil S, Rabbinowitsch E, Rajandream MA, Rutherford K, Rutter S, Seeger K, Saunders D, Sharp S, Squares R, Squares S, Taylor K, Warren T, Wietzorrek A, Woodward J, Barrell BG, Parkhill J, Hopwood DA (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147Google Scholar
  5. Bianchi A, Evans JL, Iverson AJ, Nordlund AC, Watts TD, WittersS LA (1990) Identification of an isozymic form of acetyl-CoA carboxylase. J Biol Chem 265:1502–1509Google Scholar
  6. Blunt JW, Copp BR, Munro MH, Northcote PT, Prinsep MR (2006) Marine natural products. Nat Prod Rep 23:26–78Google Scholar
  7. Borisova SA, Zhang C, Takahashi H, Zhang H, Wong AW, Thorson JS, Liu HW (2006) Substrate specificity of the macrolide glycosylating enzyme pair DesVII/DesVIII: opportunities, limitation, and mechamistic hypotheses. Angew Chem Int Ed Engl 45:2748–2753Google Scholar
  8. Borisova SA, Kim HJ, Pu X, Liu HW (2008) Glycosylation of acyclic and cyclic aglycone substrates by macrolide glycosyltransferase DesVII/DesVIII: analysis and implications. ChemBioChem 9:1554–1558Google Scholar
  9. Brautaset T, Sletta H, Nedal A, Borgos SE, Degnes KF, Bakke I, Volokhan O, Sekurova ON, Treshalin ID, Mirchink EP, Dikiy A, Ellingsen TE, Zotchev SB (2008) Improved antifungal polyene macrolides via engineering of the nystatin biosynthetic genes in Streptomyces noursei. Chem Biol 15:1198–1206Google Scholar
  10. Butler AR, Bate N, Kiehl DE, Kirst HA, Cundliffe E (2002) Genetic engineering of aminodeoxyhexose biosynthesis in Streptomyces fradiae. Nat Biotechnol 20:713–716Google Scholar
  11. Chan YA, Podevels AM, Kevany BM, Thomas MG (2009) Biosynthesis of polyketide synthase extender units. Nat Prod Rep 26:90–114Google Scholar
  12. 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 348:176–178Google Scholar
  13. Cupp-Vickery JR, Li H, Poulos TL (1994) Preliminary crystallographic analysis of an enzyme involved in erythromycin biosynthesis: cytochrome P450 eryF. Proteins 20:197–201Google Scholar
  14. Daniel R (2005) The metagenomics of soil. Nat Rev Microbiol 3:470–478Google Scholar
  15. Demain AL, Sanchez S (2009) Microbial drug discovery: 80 years of progress. J Antibiot 62:5–16Google Scholar
  16. Desai RP, Rodriguez E, Galazzo JL, Licari P (2004) Improved bioconversion of 15-fluoro-6-deoxyerythronolide B to 15-fluoro-erythromycin A by overexpression of the eryK gene in Saccharopolyspora erythraea. Biotechnol Prog 20:1660–1665Google Scholar
  17. Donadio S, Staver MJ, McAlpine JB, Swanson SJ, Katz L (1991) Modular organization of genes required for complex polyketide biosynthesis. Science 252:657–679Google Scholar
  18. Doumith M, Legrand R, Lang C, Salas JA, Raynal MC (1999) Interspecies complementation in Saccharopolyspora erythraea: elucidation of the function of oleP1, oleG1 and oleG2 from the oleandomycin biosynthetic gene cluster of Streptomyces antibioticus and generation of new erythromycin derivatives. Mol Microbiol 34:1039–1048Google Scholar
  19. Erb TJ, Berg IA, Brecht V, Müller M, Fuchs G, Alber BE (2007) Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: the ethylmalonyl-CoA pathway. Proc Natl Acad Sci USA 104:10631–10636Google Scholar
  20. Eustáquio AS, McGlinchey RP, Liu Y, Hazzard C, Beer LL, Florova G, Alhamadsheh MM, Lechner A, Kale AJ, Kobayashi Y, Reynolds KA, Moore BS (2009) Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-l-methionine. Proc Natl Acad Sci USA 106:12295–12300Google Scholar
  21. Fischbach MA, Walsh CT (2006) Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics: logic, machinery, and mechanisms. Chem Rev 106:3468–3496Google Scholar
  22. Fish SA, Cundliffe E (1997) Stimulation of polyketide metabolism in Streptomyces fradiae by tylosin and its glycosylated precursors. Microbiology 143:3871–3876Google Scholar
  23. Gaisser S, Reather J, Wirtx G, Kellenberger L, Staunton J, Leadlay PF (2000) A defined system for hybrid macrolide biosynthesis in Saccharopolyspora erythraea. Mol Microbiol 36:391–401Google Scholar
  24. Gaisser S, Lill R, Wirtx G, Grolle F, Staunton J, Leadlay PF (2001) New erythromycin derivatives from Saccharopolyspora erythraea using sugar O-methyltransferases from the spinosyn biosynthetic gene cluster. Mol Microbiol 41:1223–1231Google Scholar
  25. Gaisser S, Lill R, Staunton J, Méndez C, Salas J, Leadlay PF (2002) Parallel pathways for oxidation of 14-membered polyketide macrolactones in Saccharopolyspora erythraea. Mol Microbiol 44:771–781Google Scholar
  26. Gantt RW, Goff RD, Williams GJ, Thorson JS (2008) Probing the aglycon promiscuity of an engineered glycosyltransferase. Angew Chem Int Ed Engl 478:8889–8892Google Scholar
  27. Han SJ, Sang Park SW, Kim BW, Sim SJ (2008) Selecitve production of epothilone B by heterologous expression of propionyl-CoA synthetase in Sorangium cellulosum. J Microbiol Biotechnol 18:135–137Google Scholar
  28. 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 125:5366–5374Google Scholar
  29. Hertweck C, Luzhetskyy A, Rebets Y, Bechthold A (2007) Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork. Nat Prod Rep 24:162–190Google Scholar
  30. Hong JSJ, Park SH, Choi CY, Sohng JK, Yoon YJ (2004) New olivosyl derivatives of methymycin/pikromycin from an engineered strain of Streptomyces venezuelae. FEMS Microbiol Lett 238:291–399Google Scholar
  31. Hong JS, Park SJ, Parajuli N, Park SR, Koh HS, Jung WS, Choi CY, Yoon YJ (2007) Functional analysis of desVIII homologues involved in glycosylation of macrolide antibiotics by interspecies complementation. Gene 386:123–130Google Scholar
  32. Hu Z, Desai RP, Volchegursky Y, Leaf T, Woo E, Licari P, Santi DV, Hutchinson CR, McDaniel R (2003) Approaches to stabilization of interdomain recombination in polyketide synthase gene expression plasmids. J Ind Microbiol Biotechnol 30:161–167Google Scholar
  33. Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Omura S (2003) Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol 21:526–531Google Scholar
  34. Julien B, Shah S (2002) Heterologous expression of epothilone biosynthetic genes in Myxococcus xanthus. Antimicrob Agents Chemother 46:2772–2778Google Scholar
  35. Jung WS, Lee SK, Hong JSJ, Park SR, Jeong SJ, Han AR, Sohng JK, Kim BG, Choi CY, Sherman DH, Yoon YJ (2006) Heterologous expression of tylosin polyketide synthase and production of a hybrid bioactive macrolide in Streptomyces venezuelae. Appl Microbiol Biotechnol 72:763–769Google Scholar
  36. Jung WS, Han AR, Hong JSJ, Park SR, Choi CY, Park JW, Yoon YJ (2007) Bioconversion of 12-, 14-, and 16-membered ring aglycones to glycosylated macrolides in an engineered stain of Streptomyces venezuelae. Appl Microbiol Biotechnol 76:1373–1378Google Scholar
  37. Jung WS, Jeong SJ, Park SR, Choi CY, Park BC, Park JW, Yoon YJ (2008) Enhanced heterologous production of desosaminyl macrolides and their hydroxylated derivatives by overexpression of the pikD regulatory gene in Streptomyces venezuelae. Appl Environ Microbiol 74:1972–1979Google Scholar
  38. Kao CM, Katz L, Khosla C (1994) Engineered biosynthesis of a complete macrolactone in a heterologous host. Science 265:509–512Google Scholar
  39. Kao CM, Luo G, Katz L, Cane DE, Khosla C (1996) Engineered biosynthesis of structurally diverse tetraketides by a trimodular polyketide synthase. J Am Chem Soc 118:9184–9185Google Scholar
  40. Kao CL, Borisova SA, Kim HJ, Liu HW (2005) Linear aglycones are the substrates for glycosyltransferase DesVII in methymycin biosynthesis: analysis and implications. J Am Chem Soc 128:5606–5607Google Scholar
  41. 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-deoxy. J Am Chem Soc 124:5268–5269Google Scholar
  42. Khosla C (1997) Harnessing the biosynthetic potential of modular polyketide synthases. Chem Rev 97:319–329Google Scholar
  43. Kodumal SJ, Patel KG, Reid R, Menzella HG, Welch M, Santi DV (2004) Total synthesis of long DNA sequences: synthesis of a contiguous 32-kb polyketide synthase gene cluster. Proc Natl Acad Sci USA 101:15573–15578Google Scholar
  44. Lambalot RH, Cane DE, Aparicio JJ, Katz L (1995) Overproduction and characterization of the erythromycin C-12 hydroxylase, EryK. Biochemistry 34:1858–1866Google Scholar
  45. Lee SK, Basnet DB, Choi CY, Sohng JK, Ahn JS, Yoon YJ (2004) The role of erythromycin C-12 hydroxylase, EryK, as a substitute for PikC hydroxylase in pikromycin biosynthesis. Bioorg Chem 32:549–559Google Scholar
  46. Lee SK, Basnet DB, Hong JSJ, Jung WS, Choi CY, Lee HC, Sohng JK, Ryu KG, Kim DJ, Ahn JS, Kim BS, Oh HC, Sherman DH, Yoon YJ (2005) Structural diversification of macrolactones by substrate-flexible cytochrome P450 monooxygenases. Adv Synth Catal 347:1369–1378Google Scholar
  47. Lee SK, Park JW, Park SR, Ahn JS, Choi CY, Yoon YJ (2006a) Hydroxylation of indole by PikC cytochrome P450 from Streptomyces venezuelae and engineering its catalytic activity by site-directed mutagenesis. J Microbiol Biotechnol 16:974–978Google Scholar
  48. Lee SK, Park JW, Kim JW, Jung WS, Park SR, Choi CY, Kim ES, Kim BS, Ahn JS, Sherman DH, Yoon YJ (2006b) Neopikromycin and novapikromycin from the pikromycin biosynthetic pathway of Streptomyces venezuelae. J Nat Prod 69:847–849Google Scholar
  49. Liu H, Reynolds KA (2001) Precursor supply for polyketide biosynthesis: the role of crotonyl-CoA reductase. Metab Eng 3:40–48Google Scholar
  50. Long PF, Wilkinson CJ, Bisang CP, Cortés J, Dunster N, Oliynyk M, McCormick E, McArthur H, Mendez C, Salas JA, Staunton J, Leadlay PF (2002) Engineering specificity of starter unit selection by the erythromycin-producing polyketide synthase. Mol Microbiol 43:1215–1225Google Scholar
  51. Marsden AF, Wilkinson B, Cortés J, Dunster NJ, Staunton J, Leadlay PF (1998) Engineering broader specificity into an antibiotic-producing polyketide synthase. Science 279:199–202Google Scholar
  52. 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 96:1846–1851Google Scholar
  53. McDaniel R, Welch M, Hutchinson CR (2005) Genetic approaches to polyketide antibiotics. Chem Rev 105:543–558Google Scholar
  54. Melançon CE III, Liu HW (2007) Engineered biosynthesis of macrolide derivatives bearing the non-natural deoxysugars 4-epi-d-mycaminose and 3-N-monomethylamino-3-deoxy-d-fucose. J Am Chem Soc 129:4896–4897Google Scholar
  55. Melançon CE III, Takahashi H, Liu HW (2004) Characterization of tylM3/tylM2 and mydC/mycB pairs required for efficient glycosyltransfer in macrolide antibiotic biosynthesis. J Am Chem Soc 126:16726–16727Google Scholar
  56. Melançon CE III, Yu WL, Liu HW (2005) TDP-mycaminose biosynthetic pathway revised and conversion of desosamine pathway to mycaminose pathway with one gene. J Am Chem Soc 127:12240–12241Google Scholar
  57. Menzella HG, Reid R, Carney JR, Chandran SS, Reisinger SJ, Patel KG, Hopwood DA, Santi DV (2005) Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes. Nat Biotechnol 23:1171–1176Google Scholar
  58. Mo SJ, Ban YH, Park JW, Yoo YJ, Yoon YJ (2009) Enhanced FK506 production in Streptomyce clavuligerus CKD1119 by engineering the supply of methylmalonyl-CoA precursor. J Ind Microbiol Biotechnol. doi: 10.1007/s10295-009-0635-7 Google Scholar
  59. Moore BS, Hertweck C (2002) Biosynthesis and attachment of novel bacterial polyketide synthase starter units. Nat Prod Rep 19:70–99Google Scholar
  60. Murli S, Kennedy J, Dayem LC, Carney FR, Kealey JT (2003) Metabolic engineering of Escherichia coli for improved 6-deoxyerthronolide B production. J Ind Microbiol Biotechnol 30:500–509Google Scholar
  61. Mutka SC, Carney JR, Liu Y, Kennedy J (2006) Heterologous production of epothilone C and D in Escherichia coli. Biochemistry 45:1321–1330Google Scholar
  62. Oh TJ, Mo SJ, Yoon YJ, Sohng JK (2007) Discovery and molecular engineering of sugar-containing natural product biosynthetic pathways in actinomycetes. J Microbiol Biotechnol 17:1909–1921Google Scholar
  63. O’Hagan D (1991) The polyketide metabolites. Ellis Horwood, ChichesterGoogle Scholar
  64. Olano C, Lombo F, Mendez C, Salas JA (2008) Improving production of bioactive secondary metabolites in actinomycetes by metabolic engineering. Metab Eng 10:281–292Google Scholar
  65. Park JW, Jung WS, Park SR, Park BC, Yoon YJ (2007) Analysis of intracellular short organic acid-coenzyme A esters from actinomycetes using liquid chromatography–electrospray ionizationmass spectrometry. J Mass Spectrom 42:1136–1147Google Scholar
  66. Park JW, Hong JSJ, Parajuli N, Jung WS, Park SR, Lim S-K, Sohng JK, Yoon YJ (2008a) Genetic dissection of the biosynthetic route to gentamicin A2 by heterologous expression of its minimal gene set. Proc Natl Acad Sci USA 105:8399–8404Google Scholar
  67. Park SR, Park JW, Jung WS, Han AR, Ban Y-H, Kim EJ, Sohng JK, Sim SJ, Yoon YJ (2008b) Heterologous production of epothilone B and D in Streptomyces venezuelae. Appl Microbiol Biotechnol 81:109–117Google Scholar
  68. Pfeifer BA, Admiraal SJ, Gramajo H, Cane DE, Khosla C (2001) Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli. Sceince 291:1790–1792Google Scholar
  69. Power P, Dunne T, Murphy B, Nic Lochlainn L, Rai D, Borissow C, Rawlings B, Caffrey P (2008) Engineered synthesis of 7-oxo- and 15-deoxy-15-oxo-amphotericins: insights into structure-activity relationships in polyene antibiotics. Chem Biol 15:78–86Google Scholar
  70. 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 40:15464–15470Google Scholar
  71. Reeves AR, Brikun IA, Cernota WH, Leach BI, Gonzalez MC, Weber JM (2007) Engineering of the methylmalonyl-CoA metabolite node of Saccharopolyspora erythraea for increased erythromycin production. Metab Eng 9:293–303Google Scholar
  72. Reid R, Piagentini M, Rodriguez E, Ashley G, Viswanathan N, Carney J, Santi DV, Hutchinson CR, McDaniel R (2003) A model of structure and catalysis for ketoreductase domains in modular polyketide synthases. Biochemistry 42:72–79Google Scholar
  73. Revill WP, Voda J, Reeves CR, Chung L, Schirmer A, Ashley G, Carney JR, Fardis M, Carreras CW, Zhou Y, Feng L, Tucker E (2002) Genetically engineered analogs of ascomycin for nerve regeneration. J Pharmacol Exp Ther 302:1278–1285Google Scholar
  74. Rix U, Fischer C, Remsing LL, Rohr J (2002) Modification of post-PKS tailoring steps through combinatorial biosynthesis. Nat Prod Rep 19:542–580Google Scholar
  75. Rodriguez AM, Olano C, Méndez C, Hutchinson CR, Salas JA (1995) A cytochrome P450-like gene possibly involved in oleandomycin biosynthesis by Streptomyces antibioticus. FEMS Microbiol Lett 127:117–120Google Scholar
  76. Rodriguez E, Hu Z, Ou S, Volchegursky Y, Hutchinson CR, McDaniel R (2003) Rapid engineering of polyketide overproduction by gene transfer to industrially optimized strains. J Ind Microbiol Biotechnol 30:480–488Google Scholar
  77. Rodriguez E, Ward S, Fu H, Revill WP, McDaniel R, Katz L (2004) Engineered biosynthesis of 16-membered macrolides that require methoxymalonyl-ACP precursors in Streptomyces fradiae. Appl Microbiol Biotechnol 66:85–91Google Scholar
  78. Rowe CJ, Böhm IU, Thomas IP, Wilkinson B, Rudd BA, Foster G, Blackaby AP, Sidebottom PJ, Roddis Y, Buss AD, Staunton J, Leadlay PF (2001) Engineering a polyketide with a longer chain by insertion of an extra module into the erythromycin-producing polyketide synthase. Chem Biol 8:475–485Google Scholar
  79. Schell U, Haydock SF, Kaja AL, Carletti I, Lill RE, Read E, Sheehan LS, Low L, Fernandez MJ, Grolle F, McArthur HAI, Sheridan RM, Leadlay PF, Wilkinson B, Gaisser S (2008) Engineered biosynthesis of hybrid macrolide polyketides containing d-angolosamine and d-mycaminose moieties. Org Biomol Chem 6:3315–3327Google Scholar
  80. Schwecke T, Aparicio JF, Molnár I, König A, Khaw LE, Haydock SF, Oliynyk M, Caffrey P, Cortés J, Lester JB, Böhm GA, Staunton J, Leadlay PF (1995) The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci USA 92:7839–7843Google Scholar
  81. Shafiee A, Hutchinson CR (1988) Purification and reconstitution of the electron transport components for 6-deoxyerythronolide B hydroxylase, a cytochrome P-450 enzyme of macrolide antibiotic (erythromycin) biosynthesis. J Bacteriol 170:1548–1553Google Scholar
  82. Shah S, Xue Q, Tang L, Carney JR, Betlach M, McDaniel R (2000) Cloning, characterization and heterologous expression of a polyketide synthase and P-450 oxidase involved in the biosynthesis of the antibiotic oleandomycin. J Antibiot (Tokyo) 53:502–508Google Scholar
  83. Shen B (2003) Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Curr Opin Chem Biol 7:285–295Google Scholar
  84. Sherman DH, Li S, Yermalitskaya LV, Kim Y, Smith JA, Waterman MR, Podust LM (2006) The structural basis for substrate anchoring, active site selectivity, and product formation by P450 PikC from Streptomyces venezuelae. J Biol Chem 281:26289–26297Google Scholar
  85. Stassi DL, Kakavas SJ, Reynolds KA, Gunawardana G, Swanson S, Zeidner D, Jackson M, Liu H, Buko A, Katz L (1998) Ethyl-substituted erythromycin derivatives produced by directed metabolic engineering. Proc Natl Acad Sci USA 95:7305–7309Google Scholar
  86. Tang L, McDaniel R (2001) Construction of desosamine containing polyketide libraries using a glycosyltransferase with broad substrate specificity. Chem Biol 8:547–555Google Scholar
  87. Tang L, Zhang YX, Hutchinson CR (1994) Amino acid catabolism and antibiotic synthesis: valine is a source of precursors for macrolide biosynthesis in Streptomyces ambofaciens and Streptomyces fradiae. J Bacteriol 176:6107–6119Google Scholar
  88. Tang L, Fu H, McDaniel R (2000a) Formation of functional heterologous complexes using subunits from the picromycin, erythromycin and oleandomycin polyketide synthases. Chem Biol 7:77–84Google Scholar
  89. Tang L, Shah S, Chung L, Carney J, Katz L, Khosla C, Julien B (2000b) Cloning and heterologous expression of the epothilone gene cluster. Science 287:640–642Google Scholar
  90. Volchegursky Y, Hu Z, Katz L, McDaniel R (2000) Biosynthesis of the anti-parasitic agent megalomicin: transformation of erythromycin to megalomicin in Saccharopolyspora erythraea. Mol Microbiol 40:1045–1046Google Scholar
  91. Ward SL, Hu Z, Schirmer A, Reid R, Revill WP, Reeves CD, Petrakovsky OV, Dong SD, Katz L (2004) Chalcomycin biosynthesis gene cluster from Streptomyces bikiniensis: novel features of an unusual ketolide produced through expression of the chm polyketide synthase in Streptomyces fradiae. Antimicrob Agents Chemother 48:4703–4712Google Scholar
  92. Weymouth-Wilson AC (1997) The role of carbohydrates in biologically active natural products. Nat Prod Rep 14:88–110Google Scholar
  93. Williams GJ, Zhang C, Thorson JS (2007) Expanding the promiscuity of a natural-product glycosyltransferase by directed evolution. Nat Chem Biol 3:657–662Google Scholar
  94. Wohlert S, Lomovskaya N, Kulowski K, Fonstein L, Occi JL, Gewain KM, MacNeil DJ, Hutchinson CR (2001) Insights about the biosynthesis of the avermectin deoxysugar l-oleandrose through heterologous expression of Streptomyces avermitilis deoxysugar genes in Streptomyces lividans. Chem Biol 8:681–700Google Scholar
  95. Xiang H, Tschirret-Guth RA, Ortiz De Montellano PR (2000) An A245T mutation conveys on cytochrome P450eryF the ability to oxidize alternative substrates. J Biol Chem 275:35999–36006Google Scholar
  96. Xue Y, Sherman DH (2001) Biosynthesis and combinatorial biosynthesis of pikromycin-related macrolides in Streptomyces venezuelae. Metab Eng 3:15–26Google Scholar
  97. Yoon YJ, Beck BJ, Kim BS, Kang HY, Reynolds KA, Sherman DH (2002) Generation of multiple bioactive macrolides by hybrid modular polyketide synthases in Streptomyces venezuelae. Chem Biol 9:203–214Google Scholar
  98. Yuan Y, Chung HS, Leimkuhler C, Walsh CT, Kahne D, Walker S (2005) In vitro reconstitution of EryCIII activity for the preparation of unnatural macrolides. J Am Chem Soc 127:14128–14129Google Scholar
  99. Zhanel GG, Dueck M, Hoban DJ, Vercaigne LM, Embil JM, Gin AS, Karlowsky JA (2001) Review of macrolides and ketolides: focus on respiratory tract infections. Drugs 61:443–498Google Scholar
  100. Zhang Q, Sherman DH (2001) Isolation and structure determination of novamethymycin, a new bioactive metabolite of the methymycin biosynthetic pathway in Streptomyces venezuelae. J Nat Prod 64:1447–1450Google Scholar
  101. Zhang C, Albermann C, Fu X, Thorson JS (2006) The in vitro characterization of the iterative avermectin glycosyltransferase AveBI reveals reaction reversibility and sugar nucleotide flexibility. J Am Chem Soc 128:16420–16421Google Scholar
  102. Zhang C, Fu Q, Albermann C, Li L, Thorson JS (2007) The in vitro characterization of the erythronolide mycarosyltransferase EryBV and its utility in macrolide diversification. Chembiochem 8:385–390Google Scholar
  103. Zirkle R, Liqon JM, Molnár I (2004) Heterologous production of the antifungal polyketide antibiotic soraphen A of Sorangium cellulosum So ce26 in Streptomyces lividans. Microbiology 150:2761–2774Google Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Sung Ryeol Park
    • 1
  • Ah Reum Han
    • 2
  • Yeon-Hee Ban
    • 1
  • Young Ji Yoo
    • 1
  • Eun Ji Kim
    • 1
  • Yeo Joon Yoon
    • 1
  1. 1.Department of Chemistry and Nano ScienceEwha Womans UniversitySeoulRepublic of Korea
  2. 2.Interdisciplinary Program of BioengineeringSeoul National UniversitySeoulRepublic of Korea

Personalised recommendations