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Avermectin: biochemical and molecular basis of its biosynthesis and regulation

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Abstract

Avermectin and its analogues, produced by Streptomyces avermitilis, are major commercial antiparasitic agents in the field of animal health, agriculture, and human infections. They are 16-membered pentacyclic lactone compounds derived from polyketide and linked to a disaccharide of the methylated deoxysugar l-oleandrose. Labeling studies, analyses of the biosynthetically blocked mutants, and the identification of the avermectin gene cluster allows characterization of most of the biosynthetic pathway. Recent completion of S. avermitilis genome sequencing is also expected to help in revealing the precise biosynthetic sequence and the complicated regulatory mechanism for avermectin biosynthesis, which has been long-awaited to be elucidated. The well characterized avermectin biosynthetic pathway and availability of S. avermitilis genome information in combination with the recent development of combinatorial biosynthesis should allow us to redesign more potent avermectin analogues and to engineer S. avermitilis as a more efficient host for the production of important commercial analogues.

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References

  • Aguirrezabalaga I, Olano C, Allende N, Rodriguez L, Brana AF, Mendez C, Salas JA (2000) Identification and expression of genes involved in biosynthesis of l-oleandrose and its intermediate l-olivose in the oleandomycin producer Streptomyces antibioticus. Antimicrob Agents Chemother 44:1266–1275

    Article  CAS  PubMed  Google Scholar 

  • Alber-Schönberg G, Arison BH, Chabala JC, Douglas AW, Eskola P, Fisher MH, Lusi A, Mrozik H, Smith JL, Toman RL (1981) Avermectins. Structure determination. J Am Chem Soc 103:4216–4221

    Google Scholar 

  • August PR, Tang L, Yoon YJ, Ning S, Muller R, Yu TW, Taylor M, Hoffmann D, Kim CG, Zhang X, Hutchinson CR, Floss HG (1998) Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699. Chem Biol 5:69–79

    CAS  PubMed  Google Scholar 

  • Aziz MA, Diallo S, Diop IM, Lariviere M, Porta M (1982) Efficacy and tolerance of ivermectin in human onchocerciasis. Lancet 2:171–173

    Article  CAS  PubMed  Google Scholar 

  • Bevitt DJ, Cortes J, Haydock SF, Leadlay PF (1992) 6-Deoxyerythronolide-B synthase 2 from Saccharopolyspora erythraea. Cloning of the structural gene, sequence analysis and inferred domain structure of the multifunctional enzyme. Eur J Biochem 204:39–49

    CAS  PubMed  Google Scholar 

  • Burg RW, Miller BM, Baker EE, Birnbaum J, Currie SA, Hartman R, Kong YL, Monaghan RL, Olson G, Putter I, Tunac JB, Wallick H, Stapley EO, Oiwa R, Omura S (1979) Avermectins, new family of potent anthelmintic agents: producing organism and fermentation. Antimicrob Agents Chemother 15:361–367

    CAS  PubMed  Google Scholar 

  • Cane DE, Liang TC, Kaplan L, Nallin MK, Schulman MD, Hensens OD, Douglas AW, Albers-Schownberg G (1983) Biosynthetic origin of the carbon skeleton and oxygen atoms of the avermectins. J Am Chem Soc 105:4110–4112

    CAS  Google Scholar 

  • Chabala JC, Mrozik H, Tolman RL, Eskola P, Lusi A, Peterson LH, Woods MF, Fisher MH, Campbell WC, Egerton JR, Ostlind DA (1980) Ivermectin, a new broad-spectrum antiparasitic agent. J Med Chem 23:1134–1136

    CAS  PubMed  Google Scholar 

  • Chater KF, Bibb MJ (1997) Regulation of bacterial antibiotic production. In: Kleinkauf H, Dohren H von (eds) Biotechnology, vol 7. VCH, Weinheim, pp 57–105

  • Chen TS, Inamine ES (1989) Studies on the biosynthesis of avermectins. Arch Biochem Biophys 270:521–525

    CAS  PubMed  Google Scholar 

  • Cropp TA, Wilson DJ, Reynolds KA (2000) Identification of a cyclohexylcarbonyl CoA biosynthetic gene cluster and application in the production of doramectin. Nat Biotechnol 18:980–983

    Article  CAS  PubMed  Google Scholar 

  • Denoya CD, Fedechko RW, Hafner EW, McArthur HA, Morgenstern MR, Skinner DD, Stutzman-Engwall K, Wax RG, Wernau WC (1995) A second branched-chain alpha-keto acid dehydrogenase gene cluster (bkdFGH) from Streptomyces avermitilis: its relationship to avermectin biosynthesis and the construction of a bkdF mutant suitable for the production of novel antiparasitic avermectins. J Bacteriol 177:3504–3511

    CAS  PubMed  Google Scholar 

  • Donadio S, Staver MJ, McAlpine JB, Swanson SJ, Katz L (1991) Modular organization of genes required for complex polyketide biosynthesis. Science 252:675–679

    CAS  PubMed  Google Scholar 

  • Draeger G, Park SH, Floss HG (1990) Mechanism of the 2-deoxygenation step in the biosynthesis of the deoxyhexose moieties of the antibiotics granaticin and oleandomycin. J Am Chem Soc 121:2611–2612

    Article  Google Scholar 

  • Dutton CJ, Gibson SP, Goudie AC, Holdom KS, Pacey MS, Ruddock JC, Bu’Lock JD, Richards MK (1991) Novel avermectins produced by mutational biosynthesis. J Antibiot (Tokyo) 44:357–365

  • Egerton JR, Ostling DA, Blair LS, Eary Ch, Suhayda D, Cifelli S, Riek RF, Campbell WC (1979) Avermectins, new family of potent anthelmintic agents: efficacy of the B1a component. Antimicrob Agents Chemother 15:372–378

    CAS  PubMed  Google Scholar 

  • Fernandez-Moreno MA, Martin-Triana AJ, Martinez E, Niemi J, Kieser HM, Hopwood DA, Malpartida F (1992) abaA, a new pleiotropic regulatory locus for antibiotic production in Streptomyces coelicolor. J Bacteriol 174:2958–2967

    CAS  PubMed  Google Scholar 

  • Hafner EW, Holley BW, Holdom KS, Lee SE, Wax RG, Beck D, McArthur HA, Wernau WC (1991) Branched-chain fatty acid requirement for avermectin production by a mutant of Streptomyces avermitilis lacking branched-chain 2-oxo acid dehydrogenase activity. J Antibiot (Tokyo) 44:349–356

  • Hwang YS, Kim ES, Biro S, Choi CY (2003) Cloning and analysis of a DNA fragment stimulating avermectin production in various Streptomyces avermitilis strains. Appl Environ Microbiol 69:1263–1269

    Article  CAS  PubMed  Google Scholar 

  • Ikeda H, Ōmura S (1995) Control of avermectin biosynthesis in Streptomyces avermitilis for the selective production of a useful component. J Antibiot (Tokyo) 48:549–562

  • Ikeda H, Ōmura S (1997) Avermectin biosynthesis. Chem Rev 97:2591–2610

    Article  CAS  PubMed  Google Scholar 

  • Ikeda H, Kotaki H, Ōmura S (1987) Genetic studies of avermectin biosynthesis in Streptomyces avermitilis. J Bacteriol 169:5615–5621

    CAS  PubMed  Google Scholar 

  • Ikeda H, Takada Y, Pang CH, Tanaka H, Ōmura S (1993) Transposon mutagenesis by Tn4560 and applications with avermectin-producing Streptomyces avermitilis. J Bacteriol 175:2077–2082

    CAS  PubMed  Google Scholar 

  • Ikeda H, Pang CH, Endo H, Ohta T, Tanaka H, Ōmura S (1995a) Construction of a single component producer from the wild type avermectin producer Streptomyces avermitilis. J Antibiot (Tokyo) 48:532–534

  • Ikeda H, Takada Y, Pang CH, Matsuzaki K, Tanaka H, Ōmura S (1995b) Direct production of 5-oxo derivatives of avermectins by a recombinant strain of Streptomyces avermitilis. J Antibiot (Tokyo) 48:95–97

  • Ikeda H, Wang LR, Ohta T, Inokoshi J, Ōmura S (1998) Cloning of the gene encoding avermectin B 5-O-methyltransferase in avermectin-producing Streptomyces avermitilis. Gene 206:175–180

    Article  CAS  PubMed  Google Scholar 

  • Ikeda H, Nonomiya T, Usami M, Ohta T, Ōmura S (1999) Organization of the biosynthetic gene cluster for the polyketide anthelmintic macrolide avermectin in Streptomyces avermitilis. Proc Natl Acad Sci USA 96:9509–9514

    Article  CAS  PubMed  Google Scholar 

  • Ikeda H, Nonomiya T, Ōmura S (2001) Organization of biosynthetic gene cluster for avermectin in Streptomyces avermitilis: analysis of enzymatic domains in four polyketide synthases. J Ind Microbiol Biotechnol 27:170–176

    Article  CAS  PubMed  Google Scholar 

  • Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Ōmura S (2003) Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol 21:526–531

    Article  PubMed  Google Scholar 

  • Ishizuka H, Horinouchi S, Kieser HM, Hopwood DA, Beppu T (1992) A putative two-component regulatory system involved in secondary metabolism in Streptomyces spp. J Bacteriol 174:7585–7594

    CAS  PubMed  Google Scholar 

  • Lee JY, Hwang YS, Kim SS, Kim ES, Choi CY (2000) Effect of a global regulatory gene, afsR2, from Streptomyces lividans on avermectin production in Streptomyces avermitilis. J Biosci Bioeng 89:602–605

    Article  Google Scholar 

  • MacNeil T, Gewain KM, MacNeil DJ (1993) Deletion analysis of the avermectin biosynthetic genes of Streptomyces avermitilis by gene cluster displacement. J Bacteriol 175:2552–2563

    CAS  PubMed  Google Scholar 

  • McArthur HAI (1998) The novel avermectin, doramectin—a successful application of mutasynthesis. In: Hutchinson CR, McAlpine J (eds) Development in industrial microbiology (MBP 97). Society for Industrial Microbiology, Fairfax, Va., pp 43–48

  • Miller TW, Chaiet L, Cole DJ, Cole LJ, Flor JE, Goegelman RT, Gullo VP, Joshua H, Kempf AJ, Krellwitz WR, Monaghan RL, Ormond RE, Wilson KE, Albers-Schonberg G, Putter I (1979) Avermectins, new family of potent anthelmintic agents: isolation and chromatographic properties. Antimicrob Agents Chemother 15:368–371

    CAS  PubMed  Google Scholar 

  • Ōmura S, Ikeda H, Tanaka H (1991) Selective production of specific components of avermectins in Streptomyces avermitilis. J Antibiot (Tokyo) 44:560–563

  • Ōmura S, Ikeda H, Ishikawa J, Hanamoto A, Takahashi C, Shinose M, Takahashi Y, Horikawa H, Nakazawa H, Osonoe T, Kikuchi H, Shiba T, Sakaki Y, Hattori M (2001) Genome sequence of an industrial microorganism Streptomyces avermitilis: deducing the ability of producing secondary metabolites. Proc Natl Acad Sci USA 98:12215–12220

    CAS  PubMed  Google Scholar 

  • Pang CH, Matsuzaki K, Ikeda H, Tanaka H, Ōmura S (1995) Production of 6,8a-seco-6,8a-deoxy derivatives of avermectins by a mutant strain of Streptomyces avermitilis. J Antibiot (Tokyo) 48:59–66

  • Rodriguez L, Rodriguez D, Olano C, Brana AF, Mendez C, Salas JA (2001) Functional analysis of OleY l-oleandrosyl 3-O-methyltransferase of the oleandomycin biosynthetic pathway in Streptomyces antibioticus. J Bacteriol 183:5358–5363

    Article  CAS  PubMed  Google Scholar 

  • Scheu AK, Martinez E, Soliveri J, Malpartida F (1997) abaB, a putative regulator for secondary metabolism in Streptomyces. FEMS Microbiol Lett 147:29–36

    Article  CAS  PubMed  Google Scholar 

  • Schulman MD, Ruby C (1987) Methylation of demethylavermectins. Antimicrob Agents Chemother 31:964–965

    CAS  PubMed  Google Scholar 

  • Schwecke T, Aparicio JF, Molnar I, Konig A, Khaw LE, Haydock SF, Oliynyk M, Caffrey P, Cortes J, Lester JB (1995) The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc Natl Acad Sci USA 92:7839–7843

    CAS  PubMed  Google Scholar 

  • Shikiya K, Kinjo N, Uehara T, Uechi H, Ohshiro J, Arakaki T, Kinjo F, Saito A, Iju M, Kobari K (1992) Efficacy of ivermectin against Strongyloides stercoralis in humans. Intern Med 31:310–312

    CAS  PubMed  Google Scholar 

  • Skinner DD, Morgenstern MR, Fedechko RW, Denoya CD (1995) Cloning and sequencing of a cluster of genes encoding branched-chain alpha-keto acid dehydrogenase from Streptomyces avermitilis and the production of a functional E1 [alpha beta] component in Escherichia coli. J Bacteriol 177:183–190

    CAS  PubMed  Google Scholar 

  • Streicher SL, Rubby CL, Paress PS, Danis JB, MacNeil DJ, Gewain K, MacNeil T, Foor F, Morin N, Cimis G, Rubin R, Goldberg R, Nallin M, Schulman MD, Gibbons P (1989) In: Hershberger CL, Queener SW, Hegeman G (eds) Genetics and molecular biology of industrial microorganisms. American Society for Microbiology, Washington, D.C., p. 44

  • Stutzman-Engwall K, Conlon S, Fedechko R, Kaczmarek F, McArthur H, Krebber A, Chen Y, Minshull J, Raillard SA, Gustafsson C (2003) Engineering the aveC gene to enhance the ratio of doramectin to its CHC-B2 analogue produced in Streptomyces avermitilis. Biotechnol Bioeng 82:359–369

    Article  CAS  PubMed  Google Scholar 

  • Toutain PL, Upson DW, Terhune TN, McKenzie ME (1997) Comparative pharmacokinetics of doramectin and ivermectin in cattle. Vet Parasitol 72:3–8

    Article  CAS  PubMed  Google Scholar 

  • Vogtli M, Chang PC, Cohen SN (1994) afsR2: a previously undetected gene encoding a 63-amino-acid protein that stimulates antibiotic production in Streptomyces lividans. Mol Microbiol 14:643–653

    PubMed  Google Scholar 

  • Wohlert SE, Lomovskaya N, Kulowski K, Fonstein L, Occi JL, Gewain KM, MacNeil DJ, Hutchinson CR (1993) Insights about the biosynthesis of the avermectin deoxysugar l-oleandrose through heterologous expression of Streptomyces avermitilis deoxysugar genes In Streptomyces lividans. Chem Biol 8:681–700

    Article  Google Scholar 

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Acknowledgements

Work in our laboratories was supported by grant R01-2002-000-00050-0 from the Basic Research Program of the Korea Science & Engineering Foundation (KOSEF; to Y.Y.J.), the ERC for the Advanced Bioseparation Technology, KOSEF (to E.S.K.), and the Brain Korea 21 program supported by the Korean Ministry of Education (to C.Y.C.).

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Correspondence to C.-Y. Choi.

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Yoon, Y.J., Kim, ES., Hwang, YS. et al. Avermectin: biochemical and molecular basis of its biosynthesis and regulation. Appl Microbiol Biotechnol 63, 626–634 (2004). https://doi.org/10.1007/s00253-003-1491-4

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  • DOI: https://doi.org/10.1007/s00253-003-1491-4

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