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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 language | English |
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Pages (from-to) | 968-976 |
Number of pages | 9 |
Journal | Nature Catalysis |
Volume | 1 |
Issue number | 12 |
Early online date | 26 Nov 2018 |
DOIs | |
Publication status | Published - Dec 2018 |
Structured keywords
- BrisSynBio
- Bristol BioDesign Institute
Keywords
- Synthetic biology
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Projects
- 1 Active
Profiles
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Professor Matthew P Crump
- Fundamental Bioscience
- School of Chemistry - Professor of NMR and Structural Biology
- Cancer
- Biological and Archaeological Chemistry
- Spectroscopy and Dynamics
Person: Academic , Member
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Professor Chris L Willis
- Fundamental Bioscience
- Synthesis
- School of Chemistry - Professor of Organic Chemistry
- Catalysis
- Biological and Archaeological Chemistry
Person: Academic , Member