Cross-linking of aromatic phenolate groups by cytochrome P450 enzymes: A model for the biosynthesis of vancomycin by OxyB

Hafiz Saqib Ali, Richard Henchman, Samuel De Visser

Research output: Contribution to journalArticlepeer-review

Abstract

The cytochromes P450 are a versatile class of enzymes involved in many chemical reactions in biosystems and as such they are involved in biodegradation as well as biosynthesis pathways in many organisms. These enzymes use molecular oxygen on a heme centre and often react as mono-oxygenases. Lesser known reactions catalyzed by the P450s include desaturation pathways and ring-closure reactions. In this work we study the aromatic cross-linking of glycopeptide units as, for instance, performed by the P450 isozyme OxyB as part of vancomycin biosynthesis. A series of density functional theory studies are reported on a large active site cluster model of 258 atoms containing the heme with its coordinated ligands, a representative substrate and its interacting protein residues. We show that the catalytic cycle intermediates Compound I and Compound II of P450 can rapidly and successively abstract a phenolic hydrogen atom from adjacent peptide groups to give a biradical intermediate with small reaction barriers. The latter can form the ether cross-link between the two aromatic residues, which is the rate-determining step in the reaction mechanism and involves a simultaneous proton transfer from the ipso-position to the ketone. A thermochemical analysis reveals that weak phenolic O‒H bonds are easily abstracted by Compound I and Compound II, enabling a selective aromatic cross-linking reaction.
Original languageEnglish
JournalOrg Biomol Chem
Publication statusPublished - 29 May 2020

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