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J Am Chem Soc. 2018 Apr 18;140(15):4961-4964. doi: 10.1021/jacs.7b11793. Epub 2018 Apr 10.

An Oxetane-Based Polyketide Surrogate To Probe Substrate Binding in a Polyketide Synthase.

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Department of Chemistry , University of California Irvine , 1102 Natural Sciences II , Irvine , California 92697 , United States.
Departments of Molecular Biology and Biochemistry, Chemistry, and Pharmaceutical Sciences , University of California Irvine , 2218 Natural Sciences I , Irvine , California 92697 , United States.
Departments of Molecular Biology and Biochemistry, Biomedical Engineering, and Chemical Engineering & Materials Science , University of California Irvine , 2218 Natural Sciences I , Irvine , California 92697 , United States.
School of Chemistry , University of Bristol , Cantock's Close, Bristol BS8 1TS , United Kingdom.


Polyketides are a large class of bioactive natural products with a wide range of structures and functions. Polyketides are biosynthesized by large, multidomain enzyme complexes termed polyketide synthases (PKSs). One of the primary challenges when studying PKSs is the high reactivity of their poly-β-ketone substrates. This has hampered structural and mechanistic characterization of PKS-polyketide complexes, and, as a result, little is known about how PKSs position the unstable substrates for proper catalysis while displaying high levels of regio- and stereospecificity. As a first step toward a general plan to use oxetanes as carbonyl isosteres to broadly interrogate PKS chemistry, we describe the development and application of an oxetane-based PKS substrate mimic. This enabled the first structural determination of the acyl-enzyme intermediate of a ketosynthase (KS) in complex with an inert extender unit mimic. The crystal structure, in combination with molecular dynamics simulations, led to a proposed mechanism for the unique activity of DpsC, the priming ketosynthase for daunorubicin biosynthesis. The successful application of an oxetane-based polyketide mimic suggests that this novel class of probes could have wide-ranging applications to the greater biosynthetic community interested in the mechanistic enzymology of iterative PKSs.

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