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

Bryan D. Ellis, Jacob C. Milligan, Alexander R. White, Vy Duong, Pilar X. Altman, Lina Y. Mohammed, Matthew P. Crump, John Crosby, Ray Luo, Christopher D. Vanderwal*, Shiou Chuan Tsai

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

20 Citations (Scopus)
319 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)4961-4964
Number of pages4
JournalJournal of the American Chemical Society
Issue number15
Early online date5 Apr 2018
Publication statusPublished - 18 Apr 2018


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