Structure of a modular polyketide synthase

Somnath Dutta, Jonathan R. Whicher, Douglas A. Hansen, Wendi A. Hale, Joseph A. Chemler, Grady R. Congdon, Alison R. H. Narayan, Kristina Håkansson, David H. Sherman, Janet L. Smith and Georgios Skiniotis ()
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Somnath Dutta: Life Sciences Institute, University of Michigan
Jonathan R. Whicher: Life Sciences Institute, University of Michigan
Douglas A. Hansen: Life Sciences Institute, University of Michigan
Wendi A. Hale: University of Michigan
Joseph A. Chemler: Life Sciences Institute, University of Michigan
Grady R. Congdon: Life Sciences Institute, University of Michigan
Alison R. H. Narayan: Life Sciences Institute, University of Michigan
Kristina Håkansson: University of Michigan
David H. Sherman: Life Sciences Institute, University of Michigan
Janet L. Smith: Life Sciences Institute, University of Michigan
Georgios Skiniotis: Life Sciences Institute, University of Michigan

Nature, 2014, vol. 510, issue 7506, 512-517

Abstract: Abstract Polyketide natural products constitute a broad class of compounds with diverse structural features and biological activities. Their biosynthetic machinery, represented by type I polyketide synthases (PKSs), has an architecture in which successive modules catalyse two-carbon linear extensions and keto-group processing reactions on intermediates covalently tethered to carrier domains. Here we used electron cryo-microscopy to determine sub-nanometre-resolution three-dimensional reconstructions of a full-length PKS module from the bacterium Streptomyces venezuelae that revealed an unexpectedly different architecture compared to the homologous dimeric mammalian fatty acid synthase. A single reaction chamber provides access to all catalytic sites for the intramodule carrier domain. In contrast, the carrier from the preceding module uses a separate entrance outside the reaction chamber to deliver the upstream polyketide intermediate for subsequent extension and modification. This study reveals for the first time, to our knowledge, the structural basis for both intramodule and intermodule substrate transfer in polyketide synthases, and establishes a new model for molecular dissection of these multifunctional enzyme systems.

Date: 2014
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DOI: 10.1038/nature13423

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