Skip to main content
SpringerLink
Log in

Genome mining of the Streptomyces avermitilis genome and development of genome-minimized hosts for heterologous expression of biosynthetic gene clusters

  • Review
  • Published:
Journal of Industrial Microbiology & Biotechnology

Abstract

To date, several actinomycete genomes have been completed and annotated. Among them, Streptomyces microorganisms are of major pharmaceutical interest because they are a rich source of numerous secondary metabolites. S. avermitilis is an industrial microorganism used for the production of an anthelmintic agent, avermectin, which is a commercially important antiparasitic agent in human and veterinary medicine, and agricultural pesticides. Genome analysis of S. avermitilis provides significant information for not only industrial applications but also understanding the features of this genus. On genome mining of S. avermitilis, the microorganism has been found to harbor at least 38 secondary metabolic gene clusters and 46 insertion sequence (IS)-like sequences on the genome, which have not been searched so far. A significant use of the genome data of Streptomyces microorganisms is the construction of a versatile host for heterologous expression of exogenous biosynthetic gene clusters by genetic engineering. Since S. avermitilis is used as an industrial microorganism, the microorganism is already optimized for the efficient supply of primary metabolic precursors and biochemical energy to support multistep biosynthesis. The feasibility of large-deletion mutants of S. avermitilis has been confirmed by heterologous expression of more than 20 exogenous biosynthetic gene clusters.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Barbe V, Bouzon M, Mangenot S, Badet B, Poulain J, Segurens B, Vallenet D, Marlière P, Weissenbach J (2011) Complete genome sequence of Streptomyces cattleya NRRL 8057, a producer of antibiotics and fluorometabolites. J Bacteriol 193:5055–5056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bentley SD, Chater KF, Cerdeno-Tarraga 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 417:141–147

    Article  PubMed  Google Scholar 

  3. Bignell DRD, Seipke RF, Huguet-Tapia JC, Chambers AH, Parry RJ, Loria R (2010) Streptomyces scabies 87-22 contains a coronafacic acid-like biosynthetic cluster that contributes to plant–microbe interactions. Mol Plant Microbe Interact 23:161–175

    Article  CAS  PubMed  Google Scholar 

  4. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cane DE, He X, Kobayashi S, Omura S, Ikeda H (2006) Geosmin biosynthesis in Streptomyces avermitilis. J Antibiot 59:471–479

    Article  CAS  PubMed  Google Scholar 

  6. Cane DE, You Z, Omura S, Ikeda H (2007) Pentalenolactone biosynthesis. Molecular cloning and assignment of biochemical function to PtlF, a short-chain dehydrogenase from Streptomyces avermitilis, and identification of a new biosynthetic intermediate. Arch Biochem Biophys 459:233–240

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cánovas D, Vargas C, Calderon MI, Ventosa A, Nieto JJ (1998) Characterization of the genes for the biosynthesis of the compatible solute ectoine in the moderately halophilic bacterium Halomonas elongata DSM 3043. Syst Appl Microbiol 21:487–497

    Article  PubMed  Google Scholar 

  8. Carter GT, Nietsche JA, Hertz MR, Williams DR, Siegel MM, Morton GO, James JC, Borders DB (1988) LL-F28249 antibiotic complex: a new family of antiparasitic macrocyclic lactones: isolation, characterization and structures of LL-F28249 α, β, γ, λ. J Antibiot 41:519–529

    Article  CAS  PubMed  Google Scholar 

  9. Chou WKW, Fanizza I, Uchiyama T, Komatsu M, Ikeda H, Cane DE (2010) Genome mining in Streptomyces avermitilis: cloning and characterization of SAV_76, the synthase for a new sesquiterpene, avermitilol. J Am Chem Soc 132:8850–8851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chung ST (1987) Tn4556, a 6.8-kilobase-pair transposable element of Streptomyces fradiae. J Bacteriol 169:4436–4441

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Denoya CD, Skinner DD, Morgenstern MR (1994) A Streptomyces avermitilis gene encoding a 4-hydroxyphenylpyruvic acid dioxygenase-like protein that directs the production of homogentisic acid and an ochronotic pigment in Escherichia coli. J Bacteriol 176:5312–5319

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Feng Z, Wang L, Rajski SR, Xu Z, Coeffet-LeGal MF, Shen B (2009) Engineered production of iso-migrastatin in heterologous Streptomyces hosts. Bioorg Med Chem 17:2147–2153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hsiao NH, Nakayama S, Merlo ME, Vries M, Bunet R, Kitani S, Nihira T, Takano T (2009) Analysis of two additional signaling molecules in Streptomyces coelicolor and the development of a butyrolactone-specific reporter system. Chem Biol 16:951–960

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 21:526–531

    Article  PubMed  Google Scholar 

  18. Inbar L, Lapidot A (1988) The structure and biosynthesis of new tetrahydropyrimidine derivatives in actinomycin D producer Streptomyces parvulus. J Biol Chem 263:16014–16022

    CAS  PubMed  Google Scholar 

  19. Inokoshi J, Matsuhama M, Miyake M, Ikeda H, Tomoda H (2012) Molecular cloning of the gene cluster for lariatin biosynthesis of Rhodococcus jostii K01-B0171. Appl Microb Biotechnol 95:451–460

    Article  CAS  Google Scholar 

  20. Jiang J, Tetzlaff CN, Takamatsu S, Iwatsuki M, Komatsu M, Ikeda H, Cane DE (2009) Genome mining in Streptomyces avermitilis: a biochemical Baeyer-Villiger reaction and discovery of a new branch of the pentalenolactone family tree. Biochemistry 48:6431–6440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kitani S, Miyamoto KT, Takamatsu S, Herawati E, Iguchi H, Nishitomi K, Uchida M, Nagamitsu T, Omura S, Ikeda H, Nihira T (2011) Avenolide, a Streptomyces hormone controlling antibiotic production in Streptomyces avermitilis. Proc Natl Acad Sci U S A 108:16410–16415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Komatsu M, Tsuda M, Omura S, Oikawa H, Ikeda H (2008) Identification and functional analysis of genes controlling biosynthesis of 2-methylisoborneol. Proc Natl Acad Sci U S A 105:7422–7427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Komatsu M, Uchiyama T, Omura S, Cane DE, Ikeda H (2010) Genome-minimized Streptomyces host for the heterologous expression of secondary metabolism. Proc Natl Acad Sci U S A 107:2646–2651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Komatsu M, Komatsu K, Koiwai H, Yamada Y, Kozone I, Izumikawa M, Hashimoto J, Takagi M, Omura S, Shin-ya K, Cane DE, Ikeda H (2013) Engineered Streptomyces avermitilis host for heterologous expression of biosynthetic gene cluster for secondary metabolites. ACS Syn Biol 2:384–396

    Article  CAS  Google Scholar 

  25. Kuhlmann AU, Bremer E (2002) Osmotically regulated synthesis of the compatible solute ectoine in Bacillus pasteurii and related Bacillus spp. Appl Env Microbiol 68:772–783

    Article  CAS  Google Scholar 

  26. Lamb DC, Ikeda Nelson DR, Ishikawa J, Skaug T, Jackson C, Omura S, Waterman MR, Kelly SL (2003) Cytochrome P450 complement of the avermectin-producer Streptomyces avermitilis and comparison to that of Streptomyces coelicolor A3(2). Biochem Biophys Res Commun 307:610–619

    Article  CAS  PubMed  Google Scholar 

  27. Lautru S, Deeth RJ, Bailey LM, Challis GL (2005) Discovery of a new peptide natural product by Streptomyces coelicolor genome mining. Nat Chem Biol 1:265–269

    Article  CAS  PubMed  Google Scholar 

  28. Lin X, Cane DE (2009) Biosynthesis of sesquiterpene antibiotic albaflavenone in Streptomyces coelicolor. Mechanism and stereochemistry of the enzymatic formation of epi-isozizaene. J Am Chem Soc 131:6332–6333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Louis P, Galinski EA (1997) Characterization of genes for the biosynthesis of the compatible solute ectoine from Marinococcus halophilus and osmoregulated expression in Escherichia coli. Microbiology 143:1141–1149

    Article  CAS  PubMed  Google Scholar 

  30. Malin G, Lapidot A (1996) Induction of synthesis of tetrahydropyrimidine derivatives in Streptomyces strains and their effect on Escherichia coli in response to osmotic and heat stress. J Bactriol 178:385–395

    CAS  Google Scholar 

  31. Martinez A, Kolvek SJ, Yip CLT, Hopke J, Brown KA, MacNeil IA, Osburne MS (2004) Genetically modified bacterial strains and novel bacterial artificial chromosome shuttle vectors for constructing environmental libraries and detecting heterologous natural products in multiple expression hosts. Appl Environ Microbiol 70:2452–2463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Medema MH, Trefzer A, Kovalchuk A, Berg M, Müller U, Heijne W, Wu L, Alam MT, Ronning CM, Nierman WC, Bovenberg RAL, Breitling R, Takano E (2010) The sequence of a 1.8-Mb bacterial linear plasmid reveals a rich evolutionary reservoir of secondary metabolic pathways. Genome Biol Evol 2:212–224

    Article  PubMed  PubMed Central  Google Scholar 

  33. Nett M, Ikeda H, Moore BS (2009) Genomic basis for natural product biosynthetic diversity in the actinomycetes. Nat Prod Rep 26:1326–1384

    Article  Google Scholar 

  34. Ohnishi Y, Ishikawa J, Hara H, Suzuki H, Ikenoya M, Ikeda H, Yamashita A, Hattori M, Horinouchi S (2008) Genome sequence of the streptomycin-producing microorganism Streptomyces griseus IFO 13350. J Bacteriol 190:4050–4060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Omura 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 U S A 98:12215–12220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pfeifer B, Hu Z, Licari P, Khosla C (2002) Process and metabolic strategies for improved production of Escherichia coli-derived 6-deoxyerythronolide B. Appl Environ Microbiol 68:3287–3292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pullan ST, Chandra G, Bibb MJ, Merrick M (2011) Genome-wide analysis of the role of GlnR in Streptomyces venezuelae provides new insights into global nitrogen regulation in actinomycetes. BMC Genomics 12:175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Quaderer R, Omura S, Ikeda H, Cane DE (2006) Pentalenolactone biosynthesis. Molecular cloning and assignment of biochemical function to PtlI, a cytochrome P450 of Streptomyces avermitilis. J Am Chem Soc 128:13036–13037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Seo MJ, Zhu D, Endo S, Ikeda H, Cane DE (2011) Genome mining in Streptomyces. Elucidation of the role of Baeyer-Villiger monooxygenases and non-heme iron-dependent dehydrogenase/oxygenases in the final steps of the biosynthesis of pentalenolactone and neopentalenolactone. Biochemistry 50:1739–1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Solenberg PJ, Burgett SG (1989) Method for selection of transposable DNA and characterization of a new insertion sequence, IS493, from Streptomyces lividans. J Bacteriol 171:4807–4813

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Takamatsu S, Xu LH, Fushinobu S, Shoun H, Komastu M, Cane DE, Ikeda H (2011) Pentalenic acid is a shunt metabolite in the biosynthesis of the pentalenolactone family of metabolites: hydroxylation of 1-deoxypentalenic acid mediated by CYP105D7 (SAV_7469) of Streptomyces avermitilis. J. Antibiot 64:65–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Takamatsu S, Lin X, Nara A, Komatsu M, Cane DE, Ikeda H (2011) Characterization of a silent sesquiterpenoid biosynthetic pathway in Streptomyces avermitilis controlling epi-isozizaene albaflavenone biosynthesis and isolation of a new oxidized epi-isozizaene metabolite. Microb Biotechnol 4:184–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Takiguchi Y, Mishima H, Okuda M, Terao M, Aoki A, Fukuda R (1980) Milbemycins, a new family of macrolide antibiotics: fermentation, isolation and physico-chemical properties. J Antibiot 33:1120–1127

    Article  CAS  PubMed  Google Scholar 

  44. Tetzlaff CN, You Z, Cane DE, Takamatsu S, Omura S, Ikeda H (2006) A gene cluster for biosynthesis of the sesquiterpenoid antibiotic pentalenolactone in Streptomyces avermitilis. Biochemistry 45:6179–6186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Uchida M, Takamatsu S, Arima S, Miyamoto KT, Kitani S, Nihira T, Ikeda H, Nagamitsu T (2011) Total synthesis and absolute configuration of avenolide, extracelluar factor in Streptomyces avermitilis. J Antibiot 64:781–787

    Article  CAS  PubMed  Google Scholar 

  46. Ueki M, Suzuki R, Takamatsu S, Takagi H, Uramoto M, Ikeda H, Osada H (2009) Nocardamin production by Streptomyces avermitilis. Actinomycetologica 23:34–39

    Article  CAS  Google Scholar 

  47. Wang XJ, Yan YJ, Zhang B, An J, Wang JJ, Tian J, Jiang L, Chen YH, Huang SX, Yin M, Zhang J, Gao AL, Liu CX, Zhu ZX, Xiang WS (2010) Genome sequence of the milbemycin-producing bacterium Streptomyces bingchenggensis. J Bacteriol 192:4526–4527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Xu L, Fushinobu S, Ikeda H, Wakagi T, Shoun H (2009) Crystal structures of cytochrome P450 105P1 from Streptomyces avermitilis: conformational flexibility and histidine-liganded state. J Bacteriol 191:1211–1219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Xu L, Fushinobu S, Takamatsu S, Wakagi T, Ikeda H, Shoun H (2010) Regio- and stereospecificity of filipin hydroxylation sites revealed by crystal structures of cytochrome P450 105P1 and 105D6 from Streptomyces avermitilis. J Biol Chem 285:16844–16853

    Article  CAS  PubMed  Google Scholar 

  50. You Z, Omura S, Ikeda H, Cane DE (2006) Pentalenolactone biosynthesis. Moleclar cloning and assignment of biochemical function to PtlH, a non-heme iron dioxygenase of Streptomyces avermitilis. J Am Chem Soc 128:6566–6567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. You Z, Omura S, Ikeda H, Cane DE, Jogl G (2007) Crystal structure of the non-heme iron dioxygenase PtlH in pentalenolactone biosynthesis. J Biol Chem 282:36552–36560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhu D, Seo MJ, Ikeda H, Cane DE (2011) Genome mining in Streptomyces. Discovery of an unprecedented P450-catalyzed oxidative rearrangement that is the final step in the biosynthesis of pentalenolactone. J Am Chem Soc 133:2128–2131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank M. Komatsu, K. Komatsu, H. Koiwai, S. Takamatsu, I. Kozone, M. Izumikawa, and J. Hashimoto for the collaborative experiments. We also thank Y. Shiga for valuable advice about IS elements. We gratefully acknowledge support from a research Grant-in-Aid for Scientific Research on Priority Areas (to H.I.), a research Grant-in-Aid for Scientific Research on Innovative Areas (to H.I.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a research grant from the Institute for Fermentation, Osaka, Japan (to H.I.), and a research Grant-in-Aid for Scientific Research from the New Energy and Industrial Technology Development Organization (NEDO; to K.S. and H.I.).

Author information

Authors and Affiliations

  1. Kitasato Institute for Life Sciences, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa, 252-0373, Japan

    Haruo Ikeda

  2. Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Satoshi Omura

  3. National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan

    Kazuo Shin-ya

Authors
  1. Haruo Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuo Shin-ya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satoshi Omura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Haruo Ikeda.

Additional information

Dedicated to Prof. Sir David A. Hopwood on the occasion of his 80th birthday and in recognition of his exceptional contributions to Streptomyces genetics and molecular biology, and the honor of his friendship.

Special issue: Genome Mining for Natural Products Discovery.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 94 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ikeda, H., Shin-ya, K. & Omura, S. Genome mining of the Streptomyces avermitilis genome and development of genome-minimized hosts for heterologous expression of biosynthetic gene clusters. J Ind Microbiol Biotechnol 41, 233–250 (2014). https://doi.org/10.1007/s10295-013-1327-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10295-013-1327-x

Keywords

Search

Navigation