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

Luoyi Wang, Alice Parnell, Christopher Williams, Nurfarhanim A. Bakar, Martin R. Challand, Marc W. van der Kamp, Thomas J. Simpson, Paul R. Race, Matthew P. Crump*, Christine L. Willis

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

3 Citations (Scopus)
173 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)968-976
Number of pages9
JournalNature Catalysis
Volume1
Issue number12
Early online date26 Nov 2018
DOIs
Publication statusPublished - Dec 2018

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

Keywords

  • Synthetic biology

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