ArticleInternational journal of molecular sciences2013
Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs.
Article in International journal of molecular sciences, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed, 25 citations in OpenAlex.
- Mechanism of the Oxidative Ring-Closure Reaction during Gliotoxin Biosynthesis by Cytochrome P450 GliF.International journal of molecular sciences · 2024Article
- Theoretical study on the mechanism of N- and α-carbon oxidation of lapatinib catalyzed by cytochrome P450 monooxygenase.Journal of molecular modeling · 2019Article
- Suicide Inhibition of Cytochrome P450 Enzymes by Cyclopropylamines via a Ring-Opening Mechanism: Proton-Coupled Electron Transfer Makes a Difference.Frontiers in chemistry · 2017Article
- Bio-activation of 4-alkyl analogs of 1,4-dihydropyridine mediated by cytochrome P450 enzymes.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2015Article
- Applications of density functional theory to iron-containing molecules of bioinorganic interest.Frontiers in chemistry · 2014Review
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4 authors at 1 institution in 1 country.
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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.
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