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A Rieske oxygenase/epoxide hydrolase-catalysed reaction cascade creates oxygen heterocycles in mupirocin biosynthesis

Lookup NU author(s): Professor Paul RaceORCiD

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Abstract

© 2018, The Author(s), under exclusive licence to Springer Nature Limited.Oxygen heterocycles—in particular, tetrahydropyrans (THPs) and tetrahydrofurans—are common structural features of many biologically active polyketide natural products. Mupirocin is a clinically important antibiotic isolated from Pseudomonas fluorescens and is assembled on a THP ring, which is essential for bioactivity. However, the biosynthesis of this moiety has remained elusive. Here, we show an oxidative enzyme-catalysed cascade that generates the THP ring of mupirocin. Rieske non-haem oxygenase (MupW)-catalysed selective oxidation of the C8–C16 single bond in a complex acyclic precursor is combined with an epoxide hydrolase (MupZ) to catalyse the subsequent regioselective ring formation to give the hydroxylated THP. In the absence of MupZ, a five-membered tetrahydrofuran ring is isolated, and model studies are consistent with cyclization occurring via an epoxide intermediate. High-resolution X-ray crystallographic studies, molecular modelling and mutagenesis experiments of MupZ provide insights into THP ring formation proceeding via an anti-Baldwin 6-endo-tet cyclization.

Publication metadata

Author(s): Wang L, Parnell A, Williams C, Bakar NA, Challand MR, van der Kamp MW, Simpson TJ, Race PR, Crump MP, Willis CL

Publication type: Article

Publication status: Published

Journal: Nature Catalysis

Year: 2018

Volume: 1

Issue: 12

Pages: 968-976

Print publication date: 01/12/2018

Online publication date: 26/11/2018

Acceptance date: 11/10/2018

ISSN (electronic): 2520-1158

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41929-018-0183-5

DOI: 10.1038/s41929-018-0183-5

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