P450-catalyzed hydrogen atom abstraction

FIGURE 4.51 Mechanism for cytochrome P450-catalyzed N-dealkylation via an initial single electron pathway, SET, or via the hydrogen atom abstraction pathway, HAT. 

TJ Carlson, JP Jones, L Peterson, N Castagnoli Jr, KR Iyer, WF Trager. Stereoselectivity and isotope effects associated with cytochrome P450-catalyzed oxidation of (S)-nicotine the possibility of initial hydrogen atom abstraction in the formation of the delta l ,5 -nicotinium ion. Drug Metab Disp 23 749—756,1995. 

Miwa, G.T. Walsh, J.S. Kedderis, G.L. and Hollenberg, P.F. The use of intramolecular isotope effects to distinguish between deprotonation and hydrogen atom abstraction mechanisms in cytochrome-P450- and peroxidase-catalyzed N-demethylation reactions. J Biol Chem 258(23) 14445-14449, 1983. 

The hybridization of the carbon in an alkene makes it even more difficult to break the carbon-hydrogen bond of a vinylic carbon than of a saturated carbon. As a consequence, cytochrome P450, rather than abstracting a hydrogen atom, catalyzes the addition of an oxygen atom to the double bond leading to the formation of an epoxide as shown in Figure 4.72. 

One biological reaction that involves radicals is the one responsible for the conversion of toxic hydrocarbons to less toxic alcohols. Carried out in the liver, the hydroxyl-ation of the hydrocarbon is catalyzed by an iron-porphyrin-containing enzyme called cytochrome P450 (Section 12.8). An alkyl radical intermediate is created when Fe O abstracts a hydrogen atom from an alkane. In the next step, Fe OH dissociates homolytically into Fe and HO, and the HO immediately combines with the radical intermediate to form the alcohol. 

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