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Chem Sci. 2015 Nov 1;6(11):6525-6536. doi: 10.1039/c5sc02488a. Epub 2015 Aug 6.

Structural basis of head to head polyketide fusion by CorB.

Author information

1
Interfaculty Institute of Biochemistry , University Tübingen , Hoppe-Seyler-Str. 4 , 72076 Tübingen , Germany . Email: thilo.stehle@uni-tuebingen.de.
2
Department of Molecular Biology and Genetics , Aarhus University , Gustav Wieds Vej 10C , DK 8000 Aarhus C , Denmark.
3
Leibniz Institute for Natural Product Research and Infection Biology (HKI) , 07745 Jena , Germany.
4
Max Planck Institute for Plant Breeding Research , Carl-von-Linné-Weg 10 , 50829 Köln , Germany.
5
Institute for Pharmaceutical Biology , University of Bonn , Nussallee 6 , 53115 Bonn , Germany . Email: till.schaeberle@uni-bonn.de.
6
Chair for Natural Product Chemistry , Friedrich Schiller University , 07743 Jena , Germany.
7
Center for Plant Molecular Biology , University Tübingen , Auf der Morgenstelle 32 , 72076 Tübingen , Germany.
8
Department of Pediatrics , Vanderbilt University School of Medicine , Nashville , TN 37232 , USA.

Abstract

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.

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