Abstract
The cytochromes P450 are a versatile class of enzymes involved in many chemical reactions in biosystems and as such they take part 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 lead to hydrogen atom abstraction easily by Compound I and Compound II, enabling a selective aromatic cross-linking reaction.
Highlights
An unusual ring-closure reaction catalysed by the P450s is observed in bacteria, namely the aromatic cross-linking reaction between phenolic amino acid residues
Based on the crystal structure coordinates deposited under the 1LG9 protein databank file,[8] we created an active site model complex and studied the mechanism of aromatic cross-linking in OxyB enzymes
The axial cysteinate was abbreviated to methylmercaptate and the distal water molecule replaced by an oxo group to create a high-valent iron(IV)-oxo heme cation radical species commonly labelled as Compound I (CpdI)
Summary
An unusual ring-closure reaction catalysed by the P450s is observed in bacteria, namely the aromatic cross-linking reaction between phenolic amino acid residues. The calculations show that weak phenolic O–H bonds are abstracted by compound I and two consecutive hydrogen atom abstractions enables a cross-linking reactions while reducing dioxygen to two water molecules.
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