title: Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs.
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.
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link 637371, Singapore. hirao@ntu.edu.sg.
authors.forename: Hajime
authors.initials: H
authors.lastname: Hirao
authors.forename: Nandun M
authors.initials: NM
authors.lastname: Thellamurege
authors.forename: Pratanphorn
authors.initials: P
authors.lastname: Chuanprasit
authors.forename: Kai
authors.initials: K
authors.lastname: Xu
mesh_terms: D000473:Alkanes / Q000737:chemistry / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006859:Hydrogen / Q000737:chemistry; D006898:Hydroxylamines / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D013816:Thermodynamics
chemical_list: D000473:Alkanes; D002121:Calcium Channel Blockers; D006898:Hydroxylamines; D006859:Hydrogen; D003577:Cytochrome P-450 Enzyme System; C018338:N-methylhydroxylamine