title: Reactivity Patterns of (Protonated) Compound II and Compound I of Cytochrome P450: Which is the Better Oxidant?
abstract: The cytochromes P450 are versatile enzymes in human physiology that perform substrate hydroxylation reactions extremely efficiently. In this work, we present results of a computational study on the reactivity patterns of Compound I, Compound II, and protonated Compound II with model substrates, and we address the question of which of these compounds is the most effective oxidant? All calculations, regardless of the substrate, implicated that Compound I is the superior oxidant of the three. However, Compound II and protonated Compound II were found to react with free energies of activation that are only a few kcal mol-1higher in energy than those obtained with Compound I. Therefore, Compound II and protonated Compound II should be able to react with aliphatic groups with moderate C-H bond strengths. We have analysed all results in detail and have given electronic, thermochemical, valence bond, and molecular orbital rationalizations on the reactivity differences and explained experimental product distributions. Overall, the findings implied that alternative oxidants could operate alongside Compound I in complex reaction mechanisms of enzymatic and synthetic iron porphyrinoid complexes.
authors.affiliation: State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou, 730000, P. R. China.
authors.forename: Xiao-Xi
authors.identifier: http://orcid.org/0000-0002-3593-7536
authors.initials: XX
authors.lastname: Li
authors.affiliation: Institut de Química Computacional i Catàlisi (IQCC) and Department de Química, Universitat de Girona, Campus de Montilivi, C/ Maria Aurèlia Capmany 6, 17003, Girona, Catalonia, Spain.|The Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
authors.forename: Verònica
authors.identifier: http://orcid.org/0000-0002-7467-9277
authors.initials: V
authors.lastname: Postils
authors.affiliation: State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou, 730000, P. R. China.
authors.forename: Wei
authors.identifier: http://orcid.org/0000-0003-4448-2390
authors.initials: W
authors.lastname: Sun
authors.affiliation: The Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
authors.forename: Abayomi S
authors.identifier: http://orcid.org/0000-0002-6989-0342
authors.initials: AS
authors.lastname: Faponle
authors.affiliation: Institut de Química Computacional i Catàlisi (IQCC) and Department de Química, Universitat de Girona, Campus de Montilivi, C/ Maria Aurèlia Capmany 6, 17003, Girona, Catalonia, Spain.
authors.forename: Miquel
authors.identifier: http://orcid.org/0000-0002-1917-7450
authors.initials: M
authors.lastname: Solà
authors.affiliation: State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou, 730000, P. R. China.
authors.forename: Yong
authors.identifier: http://orcid.org/0000-0002-7668-2234
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou, 730000, P. R. China.|Department of Chemistry and Nano Science, Ewha Womans University, Seoul, 03760, Korea.
authors.forename: Wonwoo
authors.identifier: http://orcid.org/0000-0001-8592-4867
authors.initials: W
authors.lastname: Nam
authors.affiliation: The Manchester Institute of Biotechnology and School of Chemical Engineering and Analytical Science, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.
authors.forename: Sam P
authors.identifier: http://orcid.org/0000-0002-2620-8788
authors.initials: SP
authors.lastname: de Visser
mesh_terms: D055162:Biocatalysis; D020134:Catalytic Domain; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007553:Isotope Labeling; D007700:Kinetics; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism*; D011522:Protons; D011789:Quantum Theory; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D016877:Oxidants; D011522:Protons; D003577:Cytochrome P-450 Enzyme System
keywords: cytochrome P450; density functional calculations; electronic structure; hydroxylation; oxidation