Role of the somersault rearrangement in the oxidation step for flavin monooxygenases (FMO). A comparison between FMO and conventional xenobiotic oxidation with hydroperoxides.

Model quantum mechanical calculations presented for C-4a-flavin hydroperoxide (FlHOOH) at the B3LYP/6-311+G(d,p) level suggest a new mechanism for flavoprotein monooxygenase (FMO) oxidation involving a concerted homolytic O–O bond cleavage in concert with hydroxyl radical transfer from the flavin hydroperoxide rather than an SN2-like displacement by the substrate on the C-4a-hydroperoxide OOH group. Homolytic O–O bond cleavage in a somersault-like rearrangement of hydroperoxide C-4a-flavinhydroperoxide (1) (FLHO–OH → FLHO···HO) produces an internally hydrogen-bonded HO• radical intermediate with a classical activation barrier of 27.0 kcal/mol. Model hydroperoxide 1 is used to describe the transition state for the key oxidation step in the paradigm aromatic hydroxylase, p-hydroxybenzoate hydroxylase (PHBH). A comparison of the electron distribution in the transition structures for the PHBH hydroxylation of p-hydroxybenzoic acid (ΔE‡ = 23.0 kcal/mol) with that of oxidation of trimethylamine (ΔE‡ = 22.3 kcal...