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- Title
Importance of H-Abstraction in the Final Step of Nitrosoalkane Formation in the Mechanism-Based Inactivation of Cytochrome P450 by Amine-Containing Drugs.
- Authors
Hajime Hirao; Thellamurege, Nandun M.; Pratanphorn Chuanprasit; Kai Xu
- Abstract
The metabolism of amine-containing drugs by cytochrome P450 enzymes (P450s) is prone to form a nitrosoalkane metabolic intermediate (MI), which subsequently coordinates to the heme iron of a P450, to produce a metabolic-intermediate complex (MIC). This type of P450 inhibition, referred to as mechanism-based inactivation (MBI), presents a serious concern in drug discovery processes. We applied density functional theory (DFT) to the reaction between N-methylhydroxylamine (NMH) and the compound I reactive species of P450, in an effort to elucidate the mechanism of the putative final step of the MI formation in the alkylamine metabolism. Our DFT calculations show that H-abstraction from the hydroxyl group of NMH is the most favorable pathway via which the nitrosoalkane intermediate is produced spontaneously. H-abstraction from the N-H bond was slightly less favorable. In contrast, N-oxidation and H-abstraction from the C-H bond of the methyl group had much higher energy barriers. Hence, if the conversion of NMH to nitrosoalkane is catalyzed by a P450, the reaction should proceed preferentially via H-abstraction, either from the O-H bond or from the N-H bond. Our theoretical analysis of the interaction between the MI and pentacoordinate heme moieties provided further insights into the coordination bond in the MIC.
- Subjects
HYDROCARBONS; PROTEINS; AMINES; CYTOCHROME P-450; CYTOCHROMES
- Publication
International Journal of Molecular Sciences, 2013, Vol 14, Issue 12, p24692
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms141224692