Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Alternative modular polyketide synthase expression controls macrolactone structure

Nature volume 403, pages 571–575 (2000)Cite this article

Abstract

Modular polyketide synthases are giant multifunctional enzymes that catalyse the condensation of small carboxylic acids such as acetate and propionate into structurally diverse polyketides that possess a spectrum of biological activities1,2. In a modular polyketide synthase, an enzymatic domain catalyses a specific reaction, and three to six enzymatic domains involved in a condensation-processing cycle are organized into a module3. A fundamental aspect of a modular polyketide synthase is that its module arrangement linearly specifies the structure of its polyketide product3. Here we report a natural example in which alternative expression of the pikromycin polyketide synthase results in the generation of two macrolactone structures. Expression of the full-length modular polyketide synthase PikAIV in Streptomyces venezuelae generates the 14-membered ring macrolactone narbonolide, whereas expression of the amino-terminal truncated form of PikAIV leads to ‘skipping’ of the final condensation cycle in polyketide biosynthesis to generate the 12-membered ring macrolactone 10-deoxymethynolide. Our findings provide insight into the structure and function of modular polyketide synthases, as well as a new set of tools to generate structural diversity in polyketide natural products.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure and biosynthesis of methymycin, pikromycin and related compounds in Streptomyces venezuelae ATCC 15439.
Figure 2: Alternative expression of pikAIV.
Figure 3: Plasmid complementation of S. venezuelae AX912 and polyketide production.
Figure 4: Structural models for PikAIV in 10-deoxymethynolide and narbonolide biosynthesis.

Similar content being viewed by others

References

  1. Hopwood, D. A. & Sherman, D. H. Molecular genetics of polyketides and its comparison to fatty acid biosynthesis. Annu. Rev. Genet. 24, 37–66 (1990).

    Article  CAS  Google Scholar 

  2. Cane, D. E., Walsh, C. T. & Khosla, C. Harnessing the biosynthetic code: combinations, permutations, and mutations. Science 282, 63–68 (1998).

    Article  CAS  Google Scholar 

  3. Donadio, S., Staver, M. J., McAlpine, J. B., Swanson, S. J. & Katz, L. Modular organization of genes required for complex polyketide biosynthesis. Science 252, 675–679 (1991).

    Article  ADS  CAS  Google Scholar 

  4. Cortes, J., Haydock, S. F., Roberts, G. A., Bevitt, D. J. & Leadlay, P. F. An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. Nature 348, 176–178 (1990).

    Article  ADS  CAS  Google Scholar 

  5. Lambalot, R. H. & Cane, D. E. Isolation and characterization of 10-deoxymethynolide produced by Streptomyces venezuelae. J. Antibiot. 45, 1981–1982 (1992).

    Article  CAS  Google Scholar 

  6. Hori, T., Maezawa, I., Nagahama, N. & Suzuki, M. Isolation and structure of narbonolide, narbomycin aglycone, from Streptomyces venezuelae and its biological transformation into picromycin via narbomycin. J. Chem. Soc. Chem. Commun. 304–305 (1971).

  7. Sherman, D. H. et al. in Proceedings of the 8th International Biotechnology Symposium Vol. 1 123–137 (Societe Francaise de Microbiologie, Paris, 1988).

    Google Scholar 

  8. Tang, L., Fu, H., Betlach, M. C. & McDaniel, R. Elucidating the mechanism of chain termination switching in the picromycin/methymycin polyketide synthase. Chem. Biol. 6, 553–558 (1999).

    Article  CAS  Google Scholar 

  9. Xue, Y., Zhao, L., H. W. & Sherman, D. H. A gene cluster for macrolide antibiotic biosynthesis in Streptomyces venezuelae: architecture of metabolic diversity. Proc. Natl Acad. Sci. USA 95, 12111–12116 (1998).

    Article  ADS  CAS  Google Scholar 

  10. Staunton, J. et al. Evidence for a double-helical structure for modular polyketide synthases. Nature Struct. Biol. 3, 188–192 (1996).

    Article  CAS  Google Scholar 

  11. Gokhale, R. S., Hunziker, D., Cane, D. E. & Khosla, C. Mechanism and specificity of the terminal thioesterase domain from the erythromycin polyketide synthase. Chem. Biol. 6, 117–125 (1999).

    Article  CAS  Google Scholar 

  12. Gokhale, R. S., Tsuji, S. Y., Cane, D. E. & Khosla, C. Dissecting and exploiting intermodular communication in polyketide synthases. Science 284, 482–485 (1999).

    Article  ADS  CAS  Google Scholar 

  13. Rangaswamy, V., Mitchell, R., Ullrich, M. & Bender, C. Analysis of genes involved in biosynthesis of coronafacic acid, the polyketide component of the phytotoxin coronatine. J. Bacteriol. 180, 3330–3338 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Butler, A. R., Bate, N. & Cundliffe, E. Impact of thioesterase activity on tylosin biosynthesis in Streptomyces fradiae. Chem. Biol. 6, 287–292 (1999).

    Article  CAS  Google Scholar 

  15. Schneider, A. & Marahiel, M. A. Genetic evidence for a role of thioesterase domains, integrated in or associated with peptide synthetases, in non-ribosomal peptide biosynthesis in Bacillus subtilis. Arch. Microbiol. 169, 404–410 (1998).

    Article  CAS  Google Scholar 

  16. Cortes, J. et al. Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage. Science 268, 1487–1489 (1995).

    Article  ADS  CAS  Google Scholar 

  17. Kao, C. M., Luo, G. L., Katz, L., Cane, D. E. & Khosla, C. Manipulation of macrolide ring size by directed mutagenesis of a modular polyketide synthase. J. Am. Chem. Soc. 117, 9105–9106 (1995).

    Article  Google Scholar 

  18. Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1989).

    Google Scholar 

  19. Lydiate, D. J., Malpartida, F. & Hopwood, D. A. The Streptomyces plasmid SCP2*: its functional analysis and development into useful cloning vectors. Gene 35, 223–235 (1985).

    Article  CAS  Google Scholar 

  20. Bisang, C. et al. A chain initiation factor common to both modular and aromatic polyketide synthases. Nature 401, 502–505 (1999).

    Article  ADS  CAS  Google Scholar 

  21. Xue, Y., Wilson, D., Zhao, L., Liu, H.-w. & Sherman, D. H. Hydroxylation of macrolactones YC-17 and narbomycin is mediated by the pikC-encoded cytochrome P450 in Streptomyces venezuelae. Chem. Biol. 5, 661–667 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H.-w. Liu, K. A. Reynolds and G. M. Dunny for comments on the manuscript, and X. He for expert technical assistance. This research was supported by the NIH and a grant from the Office of Naval Research (to D.H.S.).

Author information

Authors and Affiliations

  1. Department of Microbiology and Biological Process Technology Institute, University of Minnesota, Box 196, 1460 Mayo Memorial Building, Minneapolis, 55455, Minnesota, USA

    Yongquan Xue & David H. Sherman

Authors
  1. Yongquan Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David H. Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David H. Sherman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xue, Y., Sherman, D. Alternative modular polyketide synthase expression controls macrolactone structure. Nature 403, 571–575 (2000). https://doi.org/10.1038/35000624

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35000624

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing