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An Integrated Module Performs Selective 'On-Line' Epoxidation in the Biosynthesis of the Antibiotic Mupirocin.
Winter, Ashley J; de Courcy-Ireland, Felix; Phillips, Annabel P; Barker, Joseph M; Bakar, Nurfarhanim A; Akter, Nahida; Wang, Luoyi; Song, Zhongshu; Crosby, John; Williams, Christopher; Willis, Christine L; Crump, Matthew Philip.
Afiliación
  • Winter AJ; University of Bristol, School of Chemistry, Cantock's Close, BS8 1TS, Bristol, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
  • de Courcy-Ireland F; University of Bristol, School of Chemistry, Cantock's Close, BS8 1TS, Bristol, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
  • Phillips AP; University of Bristol, School of Chemistry, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
  • Barker JM; University of Bristol, School of Chemistry, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
  • Bakar NA; Taylor's University, School of Liberal Arts and Sciences, MALAYSIA.
  • Akter N; University of Barisal, Department of Chemistry, Barisal-8200, Barisal, BANGLADESH.
  • Wang L; Chinese Academy of Sciences, Institute of Microbiology, Beijing, CHINA.
  • Song Z; University of Bristol, School of Chemistry, BS8 1TS, Bristol, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
  • Crosby J; University of Bristol, School of Chemistry, BS8 1TS, Bristol, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
  • Williams C; University of Bristol, School of Chemistry, Cantock's Close, BS8 1TS, Bristol, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
  • Willis CL; University of Bristol, School of Chemistry, BS8 1TS, Bristol, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
  • Crump MP; University of Bristol, School of Chemistry, Cantock's Close, BS8 1TS, Bristol, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND.
Angew Chem Int Ed Engl ; : e202410502, 2024 Aug 06.
Article en En | MEDLINE | ID: mdl-39105412
ABSTRACT
The delineation of the complex biosynthesis of the potent antibiotic mupirocin, which consists of a mixture of pseudomonic acids (PAs) isolated from Pseudomonas fluorescens NCIMB 10586, presents significant challenges and the timing and mechanisms of several key transformations remain elusive.   Particularly intriguing are the steps that process the linear backbone from the initial polyketide assembly phase to generate the first cyclic intermediate PA-B. These include epoxidation as well as incorporation of the tetrahydropyran (THP) ring and fatty acid sidechain required for biological activity. Here, we show that the mini-module MmpE performs a rare online (ACP-substrate) epoxidation and is integrated ('in-cis') into the polyketide synthase via a docking domain. A linear polyketide fragment with 6 asymmetric centres was synthesised using a convergent approach and used to demonstrate substrate flux via an atypical KS0 and a previously unannotated ACP (MmpE_ACP). MmpE_ACP-bound synthetic substrates were critical in demonstrating successful epoxidation in vitro by the purified MmpE oxidoreductase domain. Alongside feeding studies, these results confirm the timing as well as chain length dependence of this selective epoxidation. These mechanistic studies pinpoint the location and nature of the polyketide substrate prior to the key formation of the THP ring and esterification that generate PA-B.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Angew Chem Int Ed Engl Año: 2024 Tipo del documento: Article Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Angew Chem Int Ed Engl Año: 2024 Tipo del documento: Article Pais de publicación: Alemania