The Role of Cytochrome P450 AbyV in the Final Stages of Abyssomicin C Biosynthesis.

Autor: 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.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2023 Jan 16; Vol. 62 (3), pp. e202213053. Date of Electronic Publication: 2022 Dec 08.
DOI: 10.1002/anie.202213053
Abstrakt: 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.
(© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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