DICP OpenIR
Subject Area物理化学
Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin
Qiao, Yan1,2; Han, Keli1; Zhan, Chang-Guo2; Han KL(韩克利); CHANG-GUO ZHAN
Source PublicationBIOCHEMISTRY
2013-09-17
DOI10.1021/bi400709v
Volume52Issue:37Pages:6467-6479
Indexed BySCI
Cooperation Status
SubtypeArticle
Department11
Funding Project1101
Contribution Rank待补充
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
Funding Organization1,1 ; 1,1 ; 1,1 ; 1,1
WOS SubjectBiochemistry & Molecular Biology
WOS Research AreaBiochemistry & Molecular Biology
WOS KeywordAB-INITIO QM/MM ; MOLECULAR-DYNAMICS SIMULATIONS ; RATE-DETERMINING STEP ; REACTION-MECHANISM ; DIACETYLMORPHINE HEROIN ; COCAINE ESTERASE ; ENZYME-REACTIONS ; FORCE-FIELD ; HUMAN-SERUM ; WILD-TYPE
AbstractThe pharmacological function of heroin requires an activation process that transforms heroin into 6-monoacetylmorphine (6-MAM), which is the most active form. The primary enzyme responsible for this activation process in human plasma is butyrylcholinesterase (BChE). The detailed reaction pathway of the activation process via BChE-catalyzed hydrolysis has been explored computationally, for the first time, in this study via molecular dynamics simulation and first-principles quantum mechanical/molecular mechanical free energy calculations. It has been demonstrated that the whole reaction process includes acylation and deacylation stages. The acylation consists of two reaction steps, i.e., the nucleophilic attack on the carbonyl carbon of the 3-acetyl group of heroin by the hydroxyl oxygen of the Ser198 side chain and the dissociation of 6-MAM. The deacylation also consists of two reaction steps, i.e., the nucleophilic attack on the carbonyl carbon of the acyl enzyme intermediate by a water molecule and the dissociation of the acetic acid from Ser198. The calculated free energy profile reveals that the second transition state (TS2) should be rate-determining. The structural analysis reveals that the oxyanion hole of BChE plays an important role in the stabilization of rate-determining TS2. The free energy barrier (15.9 +/- 0.2 or 16.1 +/- 0.2 kcal/mol) calculated for the rate-determining step is in good agreement with the experimentally derived activation free energy (similar to 16.2 kcal/mol), suggesting that the mechanistic insights obtained from this computational study are reliable. The obtained structural and mechanistic insights could be valuable for use in the future rational design of a novel therapeutic treatment of heroin abuse.
Language英语
Funding Organization1,1 ; 1,1 ; 1,1 ; 1,1
URL查看原文
WOS IDWOS:000330099600017
Citation statistics
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/119469
Collection中国科学院大连化学物理研究所
Corresponding AuthorHan KL(韩克利); CHANG-GUO ZHAN
Affiliation1.Chinese Acad Sci, Dalian Inst Chem Phys, State Key Lab Mol React Dynam, Dalian 116023, Peoples R China
2.Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, Lexington, KY 40536 USA
Recommended Citation
GB/T 7714
Qiao, Yan,Han, Keli,Zhan, Chang-Guo,et al. Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin[J]. BIOCHEMISTRY,2013,52(37):6467-6479.
APA Qiao, Yan,Han, Keli,Zhan, Chang-Guo,韩克利,&CHANG-GUO ZHAN.(2013).Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin.BIOCHEMISTRY,52(37),6467-6479.
MLA Qiao, Yan,et al."Fundamental Reaction Pathway and Free Energy Profile for Butyrylcholinesterase-Catalyzed Hydrolysis of Heroin".BIOCHEMISTRY 52.37(2013):6467-6479.
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