Kinetic isotope effects implicate the iron-oxene as the sole oxidant in P450-catalyzed N-dealkylation |
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Authors: | Dowers Tamara S Rock Dan A Rock Denise A Jones Jeffrey P |
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Institution: | Department of Chemistry, P.O. Box 644630, Washington State University, Pullman, Washington 99164-4630, USA. |
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Abstract: | Multiple oxidants have been implicated as playing a role in cytochrome P450-mediated oxidations. Herein, we report results on N-dealkylation, one of the most facile reactions mediated by P450 enzymes. We have employed the N-oxides of a series of para-substituted 13C2H2-labeled N,N-dimethylanilines to function as both substrates and surrogate oxygen atom donors for P450cam and P4502E1. Kinetic isotope effect profiles obtained using the N-oxide system were found to closely match the profiles produced using the complete NAD(P)H/NAD(P)-P450 reductase/O2 system. The results are consistent with oxidation occurring solely through an iron-oxene species. |
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