Skip to main content
SpringerLink
Log in

Iso-migrastatin titer improvement in the engineered Streptomyces lividans SB11002 strain by optimization of fermentation conditions

  • Research Paper
  • Published:
Biotechnology and Bioprocess Engineering Aims and scope Submit manuscript

Abstract

The heterologous production of iso-migrastatin (iso-MGS) was successfully demonstrated in an engineered S. lividans SB11002 strain, which was derived from S. lividans K4-114, following introduction of pBS11001, which harbored the entire mgs biosynthetic gene cluster. However, under similar fermentation conditions, the iso-MGS titer in the engineered strain was significantly lower than that in the native producer — Streptomyces platensis NRRL 18993. To circumvent the problem of low iso-MGS titers and to expand the utility of this heterologous system for iso-MGS biosynthesis and engineering, systematic optimization of the fermentation medium was carried out. The effects of major components in the cultivation medium, including carbon, organic and inorganic nitrogen sources, were investigated using a single factor optimization method. As a result, sucrose and yeast extract were determined to be the best carbon and organic nitrogen sources, resulting in optimized iso-MGS production. Conversely, all other inorganic nitrogen sources evaluated produced various levels of inhibition of iso-MGS production. The final optimized R2YE production medium produced iso-MGS with a titer of 86.5 mg/L, about 3.6-fold higher than that in the original R2YE medium, and 1.5 fold higher than that found within the native S. platensis NRRL 18993 producer.

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

Similar content being viewed by others

References

  1. Newman, D. J., G. M. Cragg, and K. M. Snader (2003) Natural products as sources of new drugs over the period 1981–2002. J. Nat. Prod. 66: 1022–1037.

    Article  CAS  Google Scholar 

  2. Bode, H. B. and R. Muller (2005) The impact of bacterial genomics on natural product research. Angew. Chem. Int. Ed. 44: 6828–6846.

    Article  CAS  Google Scholar 

  3. Wendt-Pienkowski, E., Y. Huang, J. Zhang, B. Li, H. Jiang, H. Kwon, C. R. Hutchinson, and B. Shen (2005) Cloning, sequencing, analysis, and heterologous expression of the fredericamycin biosynthetic gene cluster from Streptomyces griseus. J. Am. Chem. Soc. 127: 16442–16452.

    Article  CAS  Google Scholar 

  4. Sosio, M., F. Giusino, C. Cappellano, E. Bossi, A. M. Puglia, and S. Donadio (2000) Artificial chromosomes for antibiotic-producing actinomycetes. Nat. Biotechnol. 18: 343–345.

    Article  CAS  Google Scholar 

  5. Martinez, A., S. J. Kolvek, C. L. T. Yip, J. Hopke, K. A. Brown, I. A. MacNeil, and M. S. Osburne (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. Env. Microb. 70: 2452–2463.

    Article  CAS  Google Scholar 

  6. Zhang, H. R., Y. Wang, and B. A. Pfeifer (2008) Bacterial hosts for natural product production. Mol. Pharmacol. 5: 212–225.

    Article  CAS  Google Scholar 

  7. Ju, J., S. K. Lim, H. Jiang, and B. Shen (2005) Migrastatin and dorrigocins are shunt metabolites of iso-migrastain. J. Am. Chem. Soc. 127: 1622–1623.

    Article  CAS  Google Scholar 

  8. Shan, D., L. Chen, J. T. Njardarson, C. Gaul, X. Ma, S. J. Danishefsky, and X. Y. Huang (2005) Synthetic analogues of migrastatin that inhibit mammary tumor metastasis in mice. Proc. Natl. Acad. Sci. 102: 3772–3776.

    Article  CAS  Google Scholar 

  9. Metaferia, B. B., L. Chen, H. L. Baker, X. Y. Huang, and C. A. Bewley (2007) Synthetic macrolides that inhibit breast cancer cell migration in vitro. J. Am. Chem. Soc. 129: 2434–2435

    Article  CAS  Google Scholar 

  10. Reymond, S. and J. Cossy (2008) Migrastatin and analogues: New anti-metastatic agents. Comptes Rendus Chim. 11: 1447–1462.

    Article  CAS  Google Scholar 

  11. Ju, J., S. R. Rajski, S. K. Lim, J. W. Seo, N. R. Peters, F. Hoffmann, and B. Shen (2009) Lactimidomycin, iso-migrastatin and related glutarimide-containing 12-membered macrolides are extremely potent inhibitors of cell migration. J. Am. Chem. Soc. 131: 1370–1371.

    Article  CAS  Google Scholar 

  12. Nakae, K., Y. Nishimura, S. Ohba, and Y. Akamatsu (2006) Migrastatin acts as a muscarinic acetylcholine receptor antagonist. J. Antibiot. 59: 685–692.

    Article  CAS  Google Scholar 

  13. Takemoto, Y., E. Tashiro, and M. Imoto (2006) Suppression of multidrug resistance by migrastatin. J. Antibiot. 59: 435–438.

    Article  CAS  Google Scholar 

  14. Lim, S. K., J. Ju, E. Zazopoulos, H. Jiang, J. W. Seo, Y. Chen, Z. Feng, S. R. Rajski, C. M. Farnet, and B. Shen (2009) iso-Migrastatin, migrastatin, and dorrigocin production in Streptomyces platensis NRRL 18993 is governed by single biosynthetic machinery featuring an acyltransferase-less Type I polyketide synthase. J. Biol. Chem. 284: 29746–29756.

    Article  CAS  Google Scholar 

  15. Feng, Z., L. Wang, S. R. Rajski, Z. Xu, M. F. Coeffet-LeGal, and B. Shen (2009) Engineered production of iso-migrastatin in heterologous hosts. Bioorg. Med. Chem. 17: 2147–2153.

    Article  CAS  Google Scholar 

  16. Ju, J., S. K. Lim, H. Jiang, J. W. Seo, and B. Shen (2005) Isomigrastatin congeners from Streptomyces platensis and generation of a glutarimide polyketide library featuring the dorrigocin, lactimidomycin, migrastatin, and NK 30424 scaffolds. J. Am. Chem. Soc. 127: 11930–11931.

    Article  CAS  Google Scholar 

  17. Kieser, T., M. J. Bibb, M. J. Buttner, K. F. Chater, and D. A. Hopwood (2000) Practical Streptomyces genetics: A Laboratory Manual. 2nd Ed. The John Innes Foundation, Norwich, U.K.

    Google Scholar 

  18. Ju, J., S. K. Lim, H. Jiang, J. W. Seo, Y. Her, and B. Shen (2006) Thermolysis of Iso-migrastatin and its congeners via [3,3]-sigmatropic rearrangment: A new route to the synthesis of migrastatin and its analogues. Org. Lett. 8: 5865–5868.

    Article  CAS  Google Scholar 

  19. Buese, M., A. Kopmann, H. Diekmann, and M. Thoma (1999) Oxygen, pH value, and carbon sources induced changes of the mode of oscillation in synchronous continuous culture of Saccharomyces cerevisiae. Biotechnol. Bioeng. 63: 410–417.

    Article  Google Scholar 

  20. Nakamura, M. and B. L. Pitsch (1961) Effect of size of inocula on growth of Shigella sonnei in a chemically defined medium. Can. J. Microbiol. 7: 848–849.

    Article  CAS  Google Scholar 

  21. Olano, C., F. Lombó, C. Méndez, and A. S. José (2008) Improving production of bioactive secondary metabolites in actinomycetes by metabolic engineering. Metab. Eng. 10: 281–292.

    Article  CAS  Google Scholar 

  22. Galm, U. and B. Shen (2006) Expression of biosynthetic gene cluster in heterologous hosts for natural product production and combinatorial biosynthesis. Expert Opin. Drug Discov. 1: 409–437.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Biochemistry, Zhejiang Sci-Tech University, Hangzhou, 310-018, China

    Xueyun Wu, Zhengbin Lv & Yaozhou Zhang

  2. Department of Chemical and Biological Engineering, Institute of Bioengineering, Zhejiang University, Hangzhou, 310-027, China

    Xueyun Wu, Dong Yang, Xiangcheng Zhu & Zhinan Xu

  3. Division of Pharmaceutical Science, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, 53705, USA

    Zhiyang Feng & Ben Shen

Authors
  1. Xueyun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiangcheng Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhiyang Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhengbin Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yaozhou Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ben Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhinan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhinan Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, X., Yang, D., Zhu, X. et al. Iso-migrastatin titer improvement in the engineered Streptomyces lividans SB11002 strain by optimization of fermentation conditions. Biotechnol Bioproc E 15, 664–669 (2010). https://doi.org/10.1007/s12257-009-3129-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12257-009-3129-6

Keywords

Search

Navigation