title: Structure of a modular polyketide synthase.
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.
authors: 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2].
authors: Somnath
authors: S
authors: Dutta
authors: 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Chemical Biology Graduate Program, University of Michigan, Ann Arbor, Michigan 48109, USA [3].
authors: Jonathan R
authors: JR
authors: Whicher
authors: 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Douglas A
authors: DA
authors: Hansen
authors: Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Wendi A
authors: WA
authors: Hale
authors: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Joseph A
authors: JA
authors: Chemler
authors: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Grady R
authors: GR
authors: Congdon
authors: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Alison R H
authors: AR
authors: Narayan
authors: Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Kristina
authors: K
authors: Håkansson
authors: 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA [3] Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA [4] Department of Microbiology & Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: David H
authors: DH
authors: Sherman
authors: 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Janet L
authors: JL
authors: Smith
authors: 1] Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Georgios
authors: G
authors: Skiniotis
mesh_terms: D055162:Biocatalysis; D020134:Catalytic Domain; D020285:Cryoelectron Microscopy; D064429:Fatty Acid Synthases / Q000737:chemistry; D018942:Macrolides / Q000378:metabolism; D008958:Models, Molecular; D048630:Polyketide Synthases / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure*; D013302:Streptomyces / Q000201:enzymology*
chemical_list: D018942:Macrolides; D048630:Polyketide Synthases; D064429:Fatty Acid Synthases; C003145:picromycin