Skip to main content
Log in

Nutrient regulation of epothilone biosynthesis in heterologous and native production strains

  • Original Paper
  • Published:
Applied Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Fermentation media with different initial concentrations of ammonium and phosphate salts were used to study the inhibitory effects of those ions on growth and production of epothilone in Sorangium cellulosum and Myxococcus xanthus. The native epothilone producer, S. cellulosum was more sensitive to ammonium and phosphate than the heterologous producer, M. xanthus. An ammonium concentration of 12 mM reduced epothilone titers by 90% in S. cellulosum but by only 40% in M. xanthus. When 5 mM phosphate was added to the medium, production in both strains was 60% lower. Higher phosphate concentrations had little additional effect on M. xanthus titers, but epothilone production with 17 mM extra-cellular phosphate in S. cellulosum was 95% lower than in the control condition. The effect of iron supplementation to the fermentation medium was also investigated. Both strains showed best production with 20 μM iron added to the medium.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.

Similar content being viewed by others

References

  • Boeck LD, Favret ME, Wetzel RW (1992) Biosynthesis of thiopeptide antibiotic A10255 in stirred reactors using a chemically defined medium supplemented with continuous nutrient feeds. J Antibiot (Tokyo) 45:1278–1285

    Google Scholar 

  • Carreras C, Frykman S, Ou S, Cadapan L, Zavala S, Woo E, Leaf T, Carney J, Burlingame M, Patel S, Ashley G, Licari P (2002) Saccharopolyspora erthraea-catalyzed bioconversion of 6-deoxyerythronolide B analogs for production of novel erythromycins. J Biotechnol 92:217–228

    Article  CAS  PubMed  Google Scholar 

  • Desai RP, Leaf T, Woo E, Licari P (2002) Enhanced production of heterologous macrolide aglycones by fed-batch cultivation of Streptomyces coelicolor. J Ind Microbiol Biotechnol 28:297–301

    Article  CAS  PubMed  Google Scholar 

  • Dworkin M (1962) Nutritional requirements for vegetative growth of Myxococcus xanthus. J Bacteriol 84:250–257

    CAS  Google Scholar 

  • Gerth K, Bedorf N, Höfle G, Irschik H, Reichenbach H (1996) Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (myxobacteria)—production, physio-chemical, and biological properties. J Antibiot (Tokyo) 49:560–563

    Google Scholar 

  • Gerth K, Steinmetz H, Höfle G, Reichenbach H (2001) Studies on the biosynthesis of epothilones: the PKS and epothilone C/D monooxygenase. J Antibiot (Tokyo) 54:144–148

    Google Scholar 

  • Hajjah H, Niederberger P, Duboc P (2001) Lovastatin biosynthesis by Aspergillus terreus in a chemically defined medium. Appl Microbiol Biotechnol 67:2596–2602

    Google Scholar 

  • Hecht V, Bischoff L, Gerth K (1990) Hollow fiber supported gas membrane for in situ removal of ammonium during an antibiotic fermentation. Biotechnol Bioeng 35:1042–1050

    CAS  Google Scholar 

  • Jacobsen JR, Hutchinson CR, Cane DE, Khosla C (1997) Precursor-directed biosynthesis of erythromycin analogs by an engineered polyketide synthase. Science 277:367–369

    Article  CAS  PubMed  Google Scholar 

  • Jain D, Nielsen JBK, Buckland BC (1992) Kinetics of efrotomycin synthesis in a synthetic fermentation medium. Bioprocess Eng 7:257–263

    CAS  Google Scholar 

  • Jaoua S, Neff S, Schupp T (1992) Transfer of mobilized plasmids to Sorangium cellulosum and evidence for their integration into the chromosome. Plasmid 28:157–165

    Google Scholar 

  • Julien B, Shah S (2002) Heterologous expression of Epothilone biosynthetic genes in Myxococcus xanthus. Antimicrob Agents Chemother 46:2772–2778

    Article  CAS  PubMed  Google Scholar 

  • Junker B, Mann Z, Gailliot K, Wilson BJ (1998) Use of soybean oil and ammonium sulfate additions to optimize secondary metabolite production. Biotechnol Bioeng 60:580–588

    Article  CAS  PubMed  Google Scholar 

  • Kao CM, Katz L, Khosla C (1994) Engineered biosynthesis of a complete macrolactone in a heterologous host. Science 265:509–512

    CAS  PubMed  Google Scholar 

  • Kealey JT, Liu L, Santi DV, Betlach MC, Barr PJ (1998) Production of a polyketide natural product in nonpolyketide-producing prokaryotic and eukaryotic hosts. Proc Natl Acad Sci USA 95:505–509

    CAS  PubMed  Google Scholar 

  • Lau J, Frykman S, Regentin R, Ou S, Tsuruta H, Licari P (2002) Optimizing the heterologous production of epothilone D in Myxococcus xanthus. Biotechnol Bioeng 78:280–288

    Article  CAS  PubMed  Google Scholar 

  • Martin J (1989) Molecular mechanisms for the control by phosphate of the biosynthesis of antibiotics and other secondary metabolites. In: Shapiro S (ed) Regulation of secondary metabolism in Actinomycetes. CRC Press, Boca Raton, Fla., pp 213–238

  • Omura S, Tanaka Y, Kitao C, Tanaka H, Iwai Y (1980) Stimulation of Leucomycin production by magnesium phosphate and its relevance to nitrogen catabolite regulation. Antimicrob Agents Chemother 18:691–695

    CAS  PubMed  Google Scholar 

  • Pfeifer BA, Admiraal SJ, Gramajo H, Cane DE, Khosla C (2001) Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli. Science 291:1790–1792

    CAS  PubMed  Google Scholar 

  • Reichenbach H (1999) Myxobacteria. In: Flickinger MC, Drew SW (eds) The encyclopedia of bioprocess technology: fermentation, biocatalysis, and bioseparation. Wiley, New York, pp 1822–1832

    Google Scholar 

  • Schimana J, Walker M, Zeeck A, Fielder HP (2001) Simocyclinones: diversity of metabolites is dependent on fermentation conditions. J Ind Microbiol Biotechnol 27:144–148

    CAS  PubMed  Google Scholar 

  • Shapiro S (1989) Nitrogen assimilation in Actinomycetes and the influence of nitrogen nutrition on Actinomycete secondary metabolism. In: Shapiro S (ed) Regulation of secondary metabolism in Actinomycetes. CRC Press, Boca Raton, Fla., pp 135–212

  • Tolchinsky S, Fuchs N, Varon M, Rosenberg E (1992) Use of Tn5lac to study expression of genes required for production of the antibiotic TA. Antimicrob Agents Chemother 36:2322–2327

    CAS  PubMed  Google Scholar 

  • Yalpani N, Altier DJ, Barbour E, Cigan AL, Scelonge CJ (2001) Production of 6-methylsalicylic acid by expression of a fungal polyketide synthase activates disease resistance in tobacco. Plant Cell 13:1401–1409

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to R. Regentin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Regentin, R., Frykman, S., Lau, J. et al. Nutrient regulation of epothilone biosynthesis in heterologous and native production strains. Appl Microbiol Biotechnol 61, 451–455 (2003). https://doi.org/10.1007/s00253-003-1263-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00253-003-1263-1

Keywords

Navigation