Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction
Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction
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人羧酸酯酶催化可卡因水解机制 1：原酸酯中间体减缓反应
DOI：
10.3390/molecules24224057
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发表时间：
2019-11
期刊：
影响因子：
4.6
通讯作者：
Zhaoyong Yang
中科院分区：
文献类型：
--
作者：
Maocai Yan;Zhen Zhang;Zhaoming Liu;Chunyan Zhang;Jingchang Zhang;Shuai Fan;Zhaoyong Yang
人羧酸酯酶1 （Human carboxylesterase 1, hCES1）是人体内主要的羧酸酯酶，在包括脂质和药物在内的多种物质的代谢中起着重要作用，因此越来越受到脂质代谢、药代动力学、药物-药物相互作用、药前活化等领域的关注。本研究以可卡因为模型底物，采用量子力学计算方法研究了hCES1的催化水解机理。我们的研究结果支持酯酶催化水解机制的四步理论，其中酰化阶段和去酰化阶段都包括两个过渡态和一个四面体中间体。本文还分析了S221、H468和E354催化三元组的作用和配合关系。此外，在hces1催化的可卡因水解反应中发现了正酯中间体，显著提高了自由能势垒，减缓了反应速度。基于这一发现，我们提出具有β-氨基羧酸酯结构的hCES1底物可能在hCES1催化水解中形成正构酯中间体，从而延长其体内半衰期。因此，本研究有助于阐明hCES1的催化机制，阐明其催化过程的重要细节，进而为hCES1底物的代谢和药物设计提供重要见解。
Human carboxylesterase 1 (hCES1) is a major carboxylesterase in the human body and plays important roles in the metabolism of a wide variety of substances, including lipids and drugs, and therefore is attracting more and more attention from areas including lipid metabolism, pharmacokinetics, drug–drug interactions, and prodrug activation. In this work, we studied the catalytic hydrolysis mechanism of hCES1 by the quantum mechanics computation method, using cocaine as a model substrate. Our results support the four-step theory of the esterase catalytic hydrolysis mechanism, in which both the acylation stage and the deacylation stage include two transition states and a tetrahedral intermediate. The roles and cooperation of the catalytic triad, S221, H468, and E354, were also analyzed in this study. Moreover, orthoester intermediates were found in hCES1-catalyzed cocaine hydrolysis reaction, which significantly elevate the free energy barrier and slow down the reaction. Based on this finding, we propose that hCES1 substrates with β-aminocarboxylester structure might form orthoester intermediates in hCES1-catalyzed hydrolysis, and therefore prolong their in vivo half-life. Thus, this study helps to clarify the catalytic mechanism of hCES1 and elucidates important details of its catalytic process, and furthermore, provides important insights into the metabolism of hCES1 substrates and drug designing.
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过渡态理论
影响因子：
--
作者：
A. Lasaga
通讯作者：
A. Lasaga
影响因子：
5.6
作者：
Fleming, CD;Bencharit, S;Redinbo, MR
通讯作者：
Redinbo, MR
影响因子：
2.9
作者：
Aranda, J.;Cerqueira, N. M. F. S. A.;Ramos, M. J.
通讯作者：
Ramos, M. J.
DOI：
10.1002/wcms.1173
发表时间：
2014-09
期刊：
Wiley Interdisciplinary Reviews: Computational Molecular Science
影响因子：
--
作者：
K. Świderek;I. Tuñón;V. Moliner
通讯作者：
K. Świderek;I. Tuñón;V. Moliner
影响因子：
4.4
作者：
Cancès, E;Mennucci, B;Tomasi, J
通讯作者：
Tomasi, J