Substrate controlled divergence in polyketide synthase catalysis

Journal of the American Chemical Society
Douglas A HansenDavid H Sherman

Abstract

Biochemical characterization of polyketide synthases (PKSs) has relied on synthetic substrates functionalized as electrophilic esters to acylate the enzyme and initiate the catalytic cycle. In these efforts, N-acetylcysteamine thioesters have typically been employed for in vitro studies of full PKS modules as well as excised domains. However, substrate engineering approaches to control the catalytic cycle of a full PKS module harboring multiple domains remain underexplored. This study examines a series of alternatively activated native hexaketide substrates on the catalytic outcome of PikAIV, the sixth and final module of the pikromycin (Pik) pathway. We demonstrate the ability to control product formation with greater than 10:1 selectivity for either full module catalysis, leading to a 14-membered macrolactone, or direct cyclization to a 12-membered ring. This outcome was achieved through modifying the type of hexaketide ester employed, demonstrating the utility of substrate engineering in PKS functional studies and biocatalysis.

References

Sep 5, 2003·Chemistry & Biology·R William BroadhurstKira J Weissman
Jun 9, 2005·Journal of the American Chemical Society·Courtney C AldrichDavid H Sherman
Jun 23, 2005·Journal of the American Chemical Society·Courtney C AldrichRobert A Fecik
Feb 6, 2010·Chembiochem : a European Journal of Chemical Biology·Manuela TosinPeter F Leadlay
Feb 10, 2012·Journal of Natural Products·David J Newman, Gordon M Cragg
Aug 30, 2012·Natural Product Reports·John Crosby, Matthew P Crump
Jul 20, 2013·Journal of the American Chemical Society·Douglas A HansenDavid H Sherman
Jun 27, 2014·Nature·Jonathan R WhicherGeorgios Skiniotis

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Citations

Oct 22, 2016·Cell Chemical Biology·Jakob Franke, Christian Hertweck
Oct 7, 2015·Proceedings of the National Academy of Sciences of the United States of America·Mashal M AlmutairiAlexander S Mankin
Sep 7, 2017·The Journal of Organic Chemistry·Yen-Lin ChouDuen-Ren Hou
Aug 25, 2017·Journal of the American Chemical Society·Aaron A KochDavid H Sherman
Aug 25, 2017·Journal of the American Chemical Society·Douglas A HansenDavid H Sherman

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Methods Mentioned

BETA
acylation

Software Mentioned

PikAIV

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