Structure of a modular polyketide synthase

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. Polyketide synthases are multidomain enzymes that produce polyketides, which form the basis of many therapeutic agents; here, electron cryo-microscopy is used to establish the structure of a bacterial full-length module, and to elucidate the structural basis of both intramodule and intermodule substrate transfer. Modular polyketide synthase structure Polyketide synthases (PKSs) are multi-domain enzyme complexes producing polyketides, a large class of secondary metabolites — in other words, natural products. Two papers from Georgios Skiniotis and colleagues use cryo-electron microscopy to probe the structure of an intact module of a full-length multienzyme PKS module involved in pikromycin biosynthesis in the bacterium Streptomyces venezuelae in different functional states. The structures reveal how the ketosynthase, acyltransferase, ketoreductase and acyl carrier protein (ACP) domains interact during the catalytic cycle. In each state the ACP is differentially positioned to facilitate intermediate transfer for the next catalytic step and for transfer to the next module.