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Yiorgo Skiniotis, University of Michigan

Host: Rick Cerione

Cryo-EM Visualization of a Modular Polyketide Synthase at Work

 

Polyketides are an important class of natural compounds that often constitute the core structures or complete chemical entities for many clinically approved therapeutic agents.  Their biosynthetic machinery, represented by type I polyketide synthases, has an architecture in which successive modules catalyze two-carbon linear extensions and keto group processing reactions on intermediates covalently tethered to carrier domains. We recently employed cryo-electron microscopy (cryo-EM) to visualize a full-length module from the biosynthetic pathway that creates the antibiotic pikromycin. The dimeric PKS module creates a single reaction chamber for the two acyl carrier protein (ACP) domains that carry building blocks and intermediates between acyltransferase (AT), ketosynthase (KS), and ketoreductase (KR) active sites. By trapping the PKS module in each of several biochemical states we obtained 3D maps that recapitulate its full enzymatic cycle. The structures reveal the ACP dynamics for sequential binding to catalytic domains within the reaction chamber, and for transferring the elongated and processed polyketide substrate to the next module in the PKS pathway.

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