Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs
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 mechani...
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sg-ntu-dr.10356-974202023-02-28T19:22:54Z Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs Xu, Kai Hirao, Hajime Thellamurege, Nandun Chuanprasit, Pratanphorn School of Physical and Mathematical Sciences DRNTU::Science::Chemistry::Physical chemistry::Molecular structure and bonding 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 2014-01-08T01:02:36Z 2019-12-06T19:42:33Z 2014-01-08T01:02:36Z 2019-12-06T19:42:33Z 2013 2013 Journal Article 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. 1422-0067 https://hdl.handle.net/10356/97420 http://hdl.handle.net/10220/18414 10.3390/ijms141224692 24351842 en International journal of molecular sciences © 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. application/pdf |
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DRNTU::Science::Chemistry::Physical chemistry::Molecular structure and bonding Xu, Kai Hirao, Hajime Thellamurege, Nandun Chuanprasit, Pratanphorn Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs |
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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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School of Physical and Mathematical Sciences |
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School of Physical and Mathematical Sciences Xu, Kai Hirao, Hajime Thellamurege, Nandun Chuanprasit, Pratanphorn |
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Article |
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Xu, Kai Hirao, Hajime Thellamurege, Nandun Chuanprasit, Pratanphorn |
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Xu, Kai |
title |
Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs |
title_short |
Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs |
title_full |
Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs |
title_fullStr |
Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs |
title_full_unstemmed |
Importance of H-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome P450 by amine-containing drugs |
title_sort |
importance of h-abstraction in the final step of nitrosoalkane formation in the mechanism-based inactivation of cytochrome p450 by amine-containing drugs |
publishDate |
2014 |
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https://hdl.handle.net/10356/97420 http://hdl.handle.net/10220/18414 |
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1759857159063994368 |