Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs
| Autor: | Nandun M. Thellamurege, Kai Xu, Hajime Hirao, Pratanphorn Chuanprasit |
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| Přispěvatelé: | School of Physical and Mathematical Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Reaction mechanism mechanism-based inactivation Science::Chemistry::Physical chemistry::Molecular structure and bonding [DRNTU] Stereochemistry cytochrome P450 Hydroxylamines energy decomposition analysis Article Catalysis Inorganic Chemistry lcsh:Chemistry chemistry.chemical_compound Cytochrome P-450 Enzyme System Alkanes Physical and Theoretical Chemistry Molecular Biology Heme reaction mechanism metabolic-intermediate complex density functional theory lcsh:QH301-705.5 Spectroscopy biology Organic Chemistry Cytochrome P450 General Medicine Metabolism Metabolic intermediate Calcium Channel Blockers Computer Science Applications chemistry lcsh:Biology (General) lcsh:QD1-999 biology.protein Thermodynamics Amine gas treating Hydrogen Methyl group |
| Zdroj: | International Journal of Molecular Sciences, Vol 14, Iss 12, Pp 24692-24705 (2013) International Journal of Molecular Sciences; Volume 14; Issue 12; Pages: 24692-24705 International Journal of Molecular Sciences |
| Popis: | 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. Published version |
| Databáze: | OpenAIRE |
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