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The Role of Cytochrome P450 AbyV in the Final Stages of Abyssomicin C Biosynthesis.
Devine, Andrew J; Parnell, Alice E; Back, Catherine R; Lees, Nicholas R; Johns, Samuel T; Zulkepli, Ainul Z; Barringer, Rob; Zorn, Katja; Stach, James E M; Crump, Matthew P; Hayes, Martin A; van der Kamp, Marc W; Race, Paul R; Willis, Christine L.
Afiliação
  • Devine AJ; School of Chemistry, University of Bristol, BS81TS, Bristol, UK.
  • Parnell AE; School of Biochemistry, University of Bristol, BS81TD, Bristol, UK.
  • Back CR; School of Biochemistry, University of Bristol, BS81TD, Bristol, UK.
  • Lees NR; School of Chemistry, University of Bristol, BS81TS, Bristol, UK.
  • Johns ST; School of Biochemistry, University of Bristol, BS81TD, Bristol, UK.
  • Zulkepli AZ; School of Biochemistry, University of Bristol, BS81TD, Bristol, UK.
  • Barringer R; School of Biochemistry, University of Bristol, BS81TD, Bristol, UK.
  • Zorn K; BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
  • Stach JEM; School of Natural and Environmental Sciences, Newcastle University, NE17RU, Newcastle-upon-Tyne, UK.
  • Crump MP; School of Chemistry, University of Bristol, BS81TS, Bristol, UK.
  • Hayes MA; BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 43183, Mölndal, Sweden.
  • van der Kamp MW; School of Biochemistry, University of Bristol, BS81TD, Bristol, UK.
  • Race PR; School of Biochemistry, University of Bristol, BS81TD, Bristol, UK.
  • Willis CL; School of Chemistry, University of Bristol, BS81TS, Bristol, UK.
Angew Chem Int Ed Engl ; 62(3): e202213053, 2023 01 16.
Article em En | MEDLINE | ID: mdl-36314667
Abyssomicin C and its atropisomer are potent inhibitors of bacterial folate metabolism. They possess complex polycyclic structures, and their biosynthesis has been shown to involve several unusual enzymatic transformations. Using a combination of synthesis and in vitro assays we reveal that AbyV, a cytochrome P450 enzyme from the aby gene cluster, catalyses a key late-stage epoxidation required for the installation of the characteristic ether-bridged core of abyssomicin C. The X-ray crystal structure of AbyV has been determined, which in combination with molecular dynamics simulations provides a structural framework for our functional data. This work demonstrates the power of combining selective carbon-13 labelling with NMR spectroscopy as a sensitive tool to interrogate enzyme-catalysed reactions in vitro with no need for purification.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos Bicíclicos Heterocíclicos com Pontes / Sistema Enzimático do Citocromo P-450 Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2023 Tipo de documento: Article País de publicação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos Bicíclicos Heterocíclicos com Pontes / Sistema Enzimático do Citocromo P-450 Idioma: En Revista: Angew Chem Int Ed Engl Ano de publicação: 2023 Tipo de documento: Article País de publicação: Alemanha