Int. J. Mol. Sci. 2013, 14(12), 24692-24705; doi:10.3390/ijms141224692
Article

Importance of H-Abstraction in the Final Step of Nitrosoalkane Formation in the Mechanism-Based Inactivation of Cytochrome P450 by Amine-Containing Drugs

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link 637371, Singapore
* Author to whom correspondence should be addressed.
Received: 13 October 2013; in revised form: 27 November 2013 / Accepted: 29 November 2013 / Published: 18 December 2013
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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.
Keywords: cytochrome P450; mechanism-based inactivation; reaction mechanism; metabolic-intermediate complex; density functional theory; energy decomposition analysis

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MDPI and ACS Style

Hirao, H.; Thellamurege, N.M.; Chuanprasit, P.; Xu, K. Importance of H-Abstraction in the Final Step of Nitrosoalkane Formation in the Mechanism-Based Inactivation of Cytochrome P450 by Amine-Containing Drugs. Int. J. Mol. Sci. 2013, 14, 24692-24705.

AMA Style

Hirao H, Thellamurege NM, Chuanprasit P, Xu K. Importance of H-Abstraction in the Final Step of Nitrosoalkane Formation in the Mechanism-Based Inactivation of Cytochrome P450 by Amine-Containing Drugs. International Journal of Molecular Sciences. 2013; 14(12):24692-24705.

Chicago/Turabian Style

Hirao, Hajime; Thellamurege, Nandun M.; Chuanprasit, Pratanphorn; Xu, Kai. 2013. "Importance of H-Abstraction in the Final Step of Nitrosoalkane Formation in the Mechanism-Based Inactivation of Cytochrome P450 by Amine-Containing Drugs." Int. J. Mol. Sci. 14, no. 12: 24692-24705.

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