Structural basis of head to head polyketide fusion by CorB

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  • Georg Zocher, University Tübingen
  • ,
  • Joachim Vilstrup
  • ,
  • Daniel Heine, Leibniz Institute for Natural Product Research and Infection Biology (HKI)
  • ,
  • Asis Hallab, Plant Breeding Research
  • ,
  • Emilie Goralski, University of Bonn
  • ,
  • Christian Hertweck, Friedrich Schiller University
  • ,
  • Mark Stahl, University Tübingen
  • ,
  • Till F. Schäberle, University of Bonn
  • ,
  • Thilo Stehle, Vanderbilt University

Corallopyronin A is a polyketide derived from the myxobacterium Corallococcus coralloides with potent antibiotic features. The gene cluster responsible for the biosynthesis of corallopyronin A has been described recently, and it was proposed that CorB acts as a ketosynthase to interconnect two polyketide chains in a rare head-to-head condensation reaction. We determined the structure of CorB, the interconnecting polyketide synthase, to high resolution and found that CorB displays a thiolase fold. Site-directed mutagenesis showed that the catalytic triad consisting of a cysteine, a histidine and an asparagine is crucial for catalysis, and that this triad shares similarities with the triad found in HMG-CoA synthases. We synthesized a substrate mimic to derivatize purified CorB and confirmed substrate attachment by ESI-MS. Structural analysis of the complex yielded an electron density-based model for the polyketide chain and showed that the unusually wide, T-shaped active site is able to accommodate two polyketides simultaneously. Our structural analysis provides a platform for understanding the unusual head-to-head polyketide-interconnecting reaction catalyzed by CorB.

Original languageEnglish
JournalChemical Science
Volume6
Issue11
Pages (from-to)6525-6536
Number of pages12
ISSN2041-6520
DOIs
Publication statusPublished - 2015

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