Structural and evolutionary relationships of "AT-less" type I polyketide synthase ketosynthases.

Abstract

Acyltransferase (AT)-less type I polyketide synthases (PKSs) break the type I PKS paradigm. They lack the integrated AT domains within their modules and instead use a discrete AT that acts in trans, whereas a type I PKS module minimally contains AT, acyl carrier protein (ACP), and ketosynthase (KS) domains. Structures of canonical type I PKS KS-AT didomains reveal structured linkers that connect the two domains. AT-less type I PKS KSs have remnants of these linkers, which have been hypothesized to be AT docking domains. Natural products produced by AT-less type I PKSs are very complex because of an increased representation of unique modifying domains. AT-less type I PKS KSs possess substrate specificity and fall into phylogenetic clades that correlate with their substrates, whereas canonical type I PKS KSs are monophyletic. We have solved crystal structures of seven AT-less type I PKS KS domains that represent various sequence clusters, revealing insight into the large structural and subtle amino acid residue differences that lead to unique active site topologies and substrate specificities. One set of structures represents a larger group of KS domains from both canonical and AT-less type I PKSs that accept amino acid-containing substrates. One structure has a partial AT-domain, revealing the structural consequences of a type I PKS KS evolving into an AT-less type I PKS KS. These structures highlight the structural diversity within the AT-less type I PKS KS family, and most important, provide a unique opportunity to study the molecular evolution of substrate specificity within the type I PKSs.

DOI: 10.1073/pnas.1515460112

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Cite this paper

@article{Lohman2015StructuralAE, title={Structural and evolutionary relationships of "AT-less" type I polyketide synthase ketosynthases.}, author={Jeremy R. Lohman and Ming Ma and Jerzy Osipiuk and Boguslaw P. Nocek and Youngchang Kim and Changsoo Chang and Marianne E. Cuff and Jamey C. Mack and Lance Bigelow and Hui Li and Michael J. Endres and Gyorgy Babnigg and Andrzej J. Joachimiak and George N. Phillips and Ben Shen}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2015}, volume={112 41}, pages={12693-8} }