Oxygen-18 Labeling Defines a Ferric Peroxide (Compound 0) Mechanism in the Oxidative Deformylation of Aldehydes by Cytochrome P450 2B4
Yasuhiro Tateishi, Kevin D. McCarty, Martha V. Martin, F. Peter Guengerich
Abstract
Most cytochrome P450 (P450) oxidations are considered to occur with the active oxidant being a perferryl oxygen (FeO 3+, Compound I). However, a ferric peroxide (FeO 2 ̅, Compound 0) mechanism has been proposed, as well, particularly for aldehyde substrates. We investigated three of these systems, the oxidative deformylation of the model substrates citronellal, 2-phenylpropionaldehyde, and 2-methyl-2-phenylpropionaldehyde by rabbit P450 2B4, using 18 O labeling. The formic acid product contained one 18 O derived from 18 O 2, which is indicative of a dominant Compound 0 mechanism. The formic acid also contained only one 18 O derived from H 2 18 O, which ruled out a Compound I mechanism. The possibility of a Baeyer–Villiger reaction was examined by using synthesized possible intermediates, but our data do not support its presence. Overall, these findings unambiguously demonstrate the role of the Compound 0 pathway in these aldehyde oxidative deformylation reactions.