Reaction pathways and free energy profiles for cholinesterase-catalyzed hydrolysis of 6-monoacetylmorphine.
Reaction pathways and free energy profiles for cholinesterase-catalyzed hydrolysis of 6-monoacetylmorphine.
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DOI：
10.1039/c3ob42464b
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发表时间：
2014-04-14
影响因子：
3.2
通讯作者：
Zhan CG
中科院分区：
文献类型：
--
作者：
Qiao Y;Han K;Zhan CG
6-单乙酰吗啡（6-MAM）是海洛因最活跃的代谢产物，可迅速进入脑内发挥作用。在人体中负责将6-MAM代谢为效力较低的吗啡的主要酶是乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）。AChE和BChE催化的6-MAM水解为吗啡的详细反应途径进行了探索，第一次，在本研究中进行第一性原理量子力学/分子力学自由能计算。结果表明，两种酶的催化反应过程遵循相似的催化反应机理，每种酶的整个催化反应途径均由4个反应步骤组成。根据计算结果，与过渡态TS 2a/TS 2b相关的第二步反应是AChE/BChE催化水解反应的速率控制步骤，AChE催化水解反应的自由能垒（18.3 kcal/mol）比BChE催化水解反应的自由能垒（20.8 kcal/mol）低2.5 kcal/mol。的AChE和BChE催化的反应计算的自由能势垒是在良好的协议与实验推导的活化自由能（17.5和20.7千卡/摩尔的AChE和BChE催化的反应，分别）。进一步的结构分析表明，AChE的酰基口袋中的芳族残基Phe 295和Phe 297（对应于BChE中的Leu 286和Val 288）有助于降低TS 2a相对于TS 2b的能量。所获得的结构和机制的见解可能是有价值的，用于未来的合理设计的一种新的治疗海洛因滥用的治疗。
As the most active metabolite of heroin, 6-monoacetylmorphine (6-MAM) can penetrate into the brain for the rapid onset of heroin effects. The primary enzymes responsible for the metabolism of 6-MAM to the less potent morphine in humans are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The detailed reaction pathways for AChE- and BChE-catalyzed hydrolysis of 6-MAM to morphine have been explored, for the first time, in the present study by performing first-principles quantum mechanical/molecular mechanical free energy calculations. It has been demonstrated that the two enzymatic reaction processes follow the similar catalytic reaction mechanism, and the whole catalytic reaction pathway for each enzyme consists of four reaction steps. According to the calculated results, the second reaction step associated with the transition state TS2a/TS2b should be rate-determining for the AChE/BChE-catalyzed hydrolysis, and the free energy barrier calculated for the AChE-catalyzed hydrolysis (18.3 kcal/mol) is 2.5 kcal/mol lower than that for the BChE-catalyzed hydrolysis (20.8 kcal/mol). The free energy barriers calculated for the AChE- and BChE-catalyzed reactions are in good agreement with the experimentally derived activation free energies (17.5 and 20.7 kcal/mol for the AChE- and BChE-catalyzed reactions, respectively). Further structural analysis reveals that the aromatic residues Phe295 and Phe297 in the acyl pocket of AChE (corresponding to Leu286 and Val288 in BChE) contribute to the lower energy of TS2a relative to TS2b. The obtained structural and mechanistic insights could be valuable for use in future rational design of a novel therapeutic treatment of heroin abuse.
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影响因子：
15
作者：
Alexandrova, Anastassia N.;Roethlisberger, Daniela;Baker, David;Jorgensen, William L.
通讯作者：
Jorgensen, William L.
影响因子：
6.2
作者：
Danciulescu, C;Nick, B;Wortmann, FJ
通讯作者：
Wortmann, FJ
影响因子：
2.5
作者：
GOLDBERGER, BA;CONE, EJ;SMIALEK, JE
通讯作者：
SMIALEK, JE
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML