title: Direct Observation of an Oxepin from a Bacterial Cytochrome P450-Catalyzed Oxidation.
abstract: The cytochromes P450 are hemoproteins that catalyze a range of oxidative C-H functionalization reactions, including aliphatic and aromatic hydroxylation. These transformations are important in a range of biological contexts, including biosynthesis and xenobiotic biodegradation. Much work has been carried out on the mechanism of aliphatic hydroxylation, implicating hydrogen atom abstraction, but aromatic hydroxylation is postulated to proceed differently. One mechanism invokes as the key intermediate an arene oxide (and/or its oxepin tautomer). Conclusive isolation of this intermediate has remained elusive and, currently, direct formation of phenols from a Meisenheimer intermediate is believed to be favored. We report here the identification of a P450 [P450cam (CYP101A1) and P450cin (CYP176A1)]-generated arene oxide as a product of in vitro oxidation of tert-butylbenzene. Computations (CBS-QB3) predict that the arene oxide and oxepin have similar stabilities to other arene oxides/oxepins implicated (but not detected) in P450-mediated transformations, suggesting that arene oxides can be unstable terminal products of P450-catalyzed aromatic oxidation that can explain the origin of some observed metabolites.
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane Qld, 4072, Australia.
authors.forename: Jeanette E
authors.identifier: http://orcid.org/0000-0002-8759-3931
authors.initials: JE
authors.lastname: Stok
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane Qld, 4072, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Chow
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane Qld, 4072, Australia.
authors.forename: Elizabeth H
authors.identifier: http://orcid.org/0000-0003-1911-0501
authors.initials: EH
authors.lastname: Krenske
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane Qld, 4072, Australia.
authors.forename: Clementina
authors.initials: C
authors.lastname: Farfan Soto
authors.affiliation: Department of Chemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X7, Canada.
authors.forename: Csongor
authors.initials: C
authors.lastname: Matyas
authors.affiliation: Department of Chemistry, Memorial University of Newfoundland, St. John's, NL, A1B 3X7, Canada.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Poirier
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane Qld, 4072, Australia. c.williams3@uq.edu.au.
authors.forename: Craig M
authors.identifier: http://orcid.org/0000-0002-3834-7398
authors.initials: CM
authors.lastname: Williams
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane Qld, 4072, Australia. j.devoss@uq.edu.au.
authors.forename: James J
authors.identifier: http://orcid.org/0000-0002-2659-5140
authors.initials: JJ
authors.lastname: De Voss
mesh_terms: D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D006900:Hydroxylation; D010082:Oxepins / Q000737:chemistry*; D010084:Oxidation-Reduction; D010087:Oxides / Q000737:chemistry*
chemical_list: D010082:Oxepins; D010087:Oxides; D003577:Cytochrome P-450 Enzyme System
keywords: arene oxide; benzene oxide; cytochrome p450; oxepin; tert-butyl benzene