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

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.