title: Quantum mechanics/molecular mechanics studies on the sulfoxidation of dimethyl sulfide by compound I and compound 0 of cytochrome P450: which is the better oxidant?
abstract: The cytochromes P450 are ubiquitous enzymes that are involved in key metabolizing processes in the body through the monoxygenation of substrates; however, their active oxidant is elusive. There have been reports that implicate that two oxidants, namely, the iron(IV)-oxo porphyrin cation radical (compound I) and the iron(III)-hydroperoxo complex (compound 0), both act as oxidants of sulfoxidation reactions, which contrasts theoretical studies on alkene epoxidation by compounds I and 0 that implicated compound 0 as a sluggish oxidant. To resolve this controversy and to establish the potency of compound I and compound 0 in sulfoxidation reactions, we have studied dimethyl sulfide sulfoxidation by both oxidants using the quantum mechanics/molecular mechanics (QM/MM) technique on cytochrome P450 enzymes and have set up a model of two P450 isozymes: P450(cam) and P450(BM3). The calculations support earlier gas-phase density functional theory modeling and show that compound 0 is a sluggish oxidant that is unable to compete with compound I. Furthermore, compound I is shown to react with dimethyl sulfide via single-state reactivity on a dominant quartet spin state surface.
authors.affiliation: The Manchester Interdisciplinary Biocenter and the School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom.
authors.forename: Cristina S
authors.initials: CS
authors.lastname: Porro
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sutcliffe
authors.forename: Sam P
authors.initials: SP
authors.lastname: de Visser
mesh_terms: D019475:Camphor 5-Monooxygenase / Q000737:chemistry* / Q000378:metabolism*; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D008665:Metalloporphyrins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011789:Quantum Theory; D012451:Safrole / Q000031:analogs & derivatives* / Q000378:metabolism; D013440:Sulfides / Q000378:metabolism*
chemical_list: D008665:Metalloporphyrins; D016877:Oxidants; D013440:Sulfides; D007501:Iron; D019475:Camphor 5-Monooxygenase; C004784:dimethyl sulfide; D012451:Safrole; C005746:sulfoxide