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...
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2013-12-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | http://www.mdpi.com/1422-0067/14/12/24692 |
id |
doaj-1d66c293af8a47ca94c9e24ba1d94b7e |
---|---|
record_format |
Article |
spelling |
doaj-1d66c293af8a47ca94c9e24ba1d94b7e2020-11-24T21:46:03ZengMDPI AGInternational Journal of Molecular Sciences1422-00672013-12-011412246922470510.3390/ijms141224692ijms141224692Importance of H-Abstraction in the Final Step of Nitrosoalkane Formation in the Mechanism-Based Inactivation of Cytochrome P450 by Amine-Containing DrugsHajime Hirao0Nandun M. Thellamurege1Pratanphorn Chuanprasit2Kai Xu3Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link 637371, SingaporeDivision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link 637371, SingaporeDivision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link 637371, SingaporeDivision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link 637371, SingaporeThe 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.http://www.mdpi.com/1422-0067/14/12/24692cytochrome P450mechanism-based inactivationreaction mechanismmetabolic-intermediate complexdensity functional theoryenergy decomposition analysis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hajime Hirao Nandun M. Thellamurege Pratanphorn Chuanprasit Kai Xu |
spellingShingle |
Hajime Hirao Nandun M. Thellamurege Pratanphorn Chuanprasit Kai Xu 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 cytochrome P450 mechanism-based inactivation reaction mechanism metabolic-intermediate complex density functional theory energy decomposition analysis |
author_facet |
Hajime Hirao Nandun M. Thellamurege Pratanphorn Chuanprasit Kai Xu |
author_sort |
Hajime Hirao |
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 |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2013-12-01 |
description |
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. |
topic |
cytochrome P450 mechanism-based inactivation reaction mechanism metabolic-intermediate complex density functional theory energy decomposition analysis |
url |
http://www.mdpi.com/1422-0067/14/12/24692 |
work_keys_str_mv |
AT hajimehirao importanceofhabstractioninthefinalstepofnitrosoalkaneformationinthemechanismbasedinactivationofcytochromep450byaminecontainingdrugs AT nandunmthellamurege importanceofhabstractioninthefinalstepofnitrosoalkaneformationinthemechanismbasedinactivationofcytochromep450byaminecontainingdrugs AT pratanphornchuanprasit importanceofhabstractioninthefinalstepofnitrosoalkaneformationinthemechanismbasedinactivationofcytochromep450byaminecontainingdrugs AT kaixu importanceofhabstractioninthefinalstepofnitrosoalkaneformationinthemechanismbasedinactivationofcytochromep450byaminecontainingdrugs |
_version_ |
1725902346628628480 |