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

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A Rieske oxygenase/epoxide hydrolase-catalysed reaction cascade creates oxygen heterocycles in mupirocin biosynthesis. / Wang, Luoyi; Parnell, Alice; Williams, Christopher; Bakar, Nurfarhanim A.; Challand, Martin R.; van der Kamp, Marc W.; Simpson, Thomas J.; Race, Paul R.; Crump, Matthew P.; Willis, Christine L.

In: Nature Catalysis, Vol. 1, No. 12, 12.2018, p. 968-976.

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@article{7a48b79a8f6e47d5b71a824fb3f4ef55,
title = "A Rieske oxygenase/epoxide hydrolase-catalysed reaction cascade creates oxygen heterocycles in mupirocin biosynthesis",
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.",
author = "Luoyi Wang and Alice Parnell and Christopher Williams and Bakar, {Nurfarhanim A.} and Challand, {Martin R.} and {van der Kamp}, {Marc W.} and Simpson, {Thomas J.} and Race, {Paul R.} and Crump, {Matthew P.} and Willis, {Christine L.}",
year = "2018",
month = "12",
doi = "10.1038/s41929-018-0183-5",
language = "English",
volume = "1",
pages = "968--976",
journal = "Nature Catalysis",
issn = "2520-1158",
publisher = "Springer Nature",
number = "12",

}

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TY - JOUR

T1 - A Rieske oxygenase/epoxide hydrolase-catalysed reaction cascade creates oxygen heterocycles in mupirocin biosynthesis

AU - Wang, Luoyi

AU - Parnell, Alice

AU - Williams, Christopher

AU - Bakar, Nurfarhanim A.

AU - Challand, Martin R.

AU - van der Kamp, Marc W.

AU - Simpson, Thomas J.

AU - Race, Paul R.

AU - Crump, Matthew P.

AU - Willis, Christine L.

PY - 2018/12

Y1 - 2018/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85057313859&partnerID=8YFLogxK

U2 - 10.1038/s41929-018-0183-5

DO - 10.1038/s41929-018-0183-5

M3 - Article

VL - 1

SP - 968

EP - 976

JO - Nature Catalysis

JF - Nature Catalysis

SN - 2520-1158

IS - 12

ER -