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Polyketide synthase chimeras reveal key role of ketosynthase domain in chain branching

Nature Chemical Biology volume 11, pages 949–951 (2015)Cite this article

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Abstract

Biosynthesis of rhizoxin in Burkholderia rhizoxinica affords an unusual polyketide synthase module with ketosynthase and branching domains that install the δ-lactone, conferring antimitotic activity. To investigate their functions in chain branching, we designed chimeric modules with structurally similar domains from a glutarimide-forming module and a dehydratase. Biochemical, kinetic and mutational analyses reveal a structural role of the accessory domains and multifarious catalytic actions of the ketosynthase.

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Figure 1: Polyketide chain branches introduced by polyketide synthase modules.
Figure 2: In vitro lactone and glutarimide formation by chimeric modules.

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Acknowledgements

We thank A. Perner for MS analyses and M. Poetsch for MALDI measurements. We are grateful for financial support by the International Leibniz Research School (to S.S.) and the Studienstiftung des Deutschen Volkes (to D.H.).

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Authors and Affiliations

  1. Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology (HKI), Jena, Germany

    Srividhya Sundaram, Daniel Heine & Christian Hertweck

  2. Chair of Natural Product Chemistry, Friedrich Schiller University, Jena, Germany

    Christian Hertweck

Authors
  1. Srividhya Sundaram
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  2. Daniel Heine
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  3. Christian Hertweck
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Contributions

S.S. and C.H. designed experiments; S.S. performed genetic and biochemical experiments and analyzed data; D.H. synthesized substrates and reference compounds; and S.S. and C.H. wrote the manuscript.

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Correspondence to Christian Hertweck.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Notes 1 and 2 and Supplementary Figures 1–10. (PDF 3399 kb)

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Sundaram, S., Heine, D. & Hertweck, C. Polyketide synthase chimeras reveal key role of ketosynthase domain in chain branching. Nat Chem Biol 11, 949–951 (2015). https://doi.org/10.1038/nchembio.1932

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