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

DOI: 10.1038/s41929-018-0183-5 DOI Help

Authors: Luoyi Wang (University of Bristol) , Alice Parnell (University of Bristol) , Christopher Williams (University of Bristol) , Nurfarhanim A. Bakar (University of Bristol) , Martin R. Challand (University of Bristol) , Marc W. Van Der Kamp (University of Bristol) , Thomas J. Simpson (University of Bristol) , Paul R. Race (University of Bristol) , Matthew P. Crump (University of Bristol) , Christine L. Willis (University of Bristol)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Catalysis , VOL 1 , PAGES 968 - 976

State: Published (Approved)
Published: December 2018
Diamond Proposal Number(s): 12342

Abstract: 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.

Journal Keywords: Antibiotics; Biosynthesis; Hydrolases; Natural products; Oxidoreductases

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography