Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/97420
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: Xu, Kai
Hirao, Hajime
Thellamurege, Nandun
Chuanprasit, Pratanphorn
Keywords: DRNTU::Science::Chemistry::Physical chemistry::Molecular structure and bonding
Issue Date: 2013
Source: Hirao, H., Thellamurege, N., Chuanprasit, P., & Xu, K. (2013). 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, 14(12), 24692-24705.
Series/Report no.: International journal of molecular sciences
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.
URI: https://hdl.handle.net/10356/97420
http://hdl.handle.net/10220/18414
ISSN: 1422-0067
DOI: 10.3390/ijms141224692
Rights: © 2013 The Authors, licensee MDPI. This paper was published in International Journal of Molecular Sciences and is made available as an electronic reprint (preprint) with permission of the authors, licensee MDPI. The paper can be found at the following official DOI: [http://dx.doi.org/10.3390/ijms141224692]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SPMS Journal Articles

SCOPUSTM   
Citations 20

21
Updated on Jan 28, 2023

Web of ScienceTM
Citations 20

19
Updated on Jan 29, 2023

Page view(s) 50

400
Updated on Jan 28, 2023

Download(s) 10

363
Updated on Jan 28, 2023

Google ScholarTM

Check

Altmetric


Plumx

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.