One oxidant, many pathways: A theoretical perspective of monooxygenation mechanisms by cytochrome P450 enzymes

Sason Shaik, Samuël P. De Visser, Devesh Kumar

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Density functional theoretical studies of monooxygenation reactivity of the high-valent oxoiron(IV) porphyrin cation-radical compound of cytochrome P450, the so-called Compound I, and of its precursor, the ferric(III)-hydroperoxide species, are described. The degeneracy of the spin states of Compound I, its electron deficiency, and dense orbital manifold lead to two-state and multi-state reactivity scenarios and may thereby create reactivity patterns as though belonging to two or more different oxidants. Most of the controversies in the experimental data are reconciled using Compound I as the sole competent oxidant. Theory finds ferric(III)-hydroperoxide to be a very sluggish oxidant, noncompetitive with Compound I. If and when Compound I is absent, P450 oxidation will logically proceed by another form, but this has to be more reactive than ferric(III)-hydroperoxide. Theoretical studies are conducted to pinpoint such an oxidant for P450.
    Original languageEnglish
    Pages (from-to)661-668
    Number of pages7
    JournalJournal of Biological Inorganic Chemistry
    Volume9
    Issue number6
    DOIs
    Publication statusPublished - Sep 2004

    Keywords

    • Compound I
    • Cytochrome P450
    • Density functional calculations
    • Enzyme catalysis
    • Two-state reactivity

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