人羧酸酯酶1扩展活性位点的保守质子化模式及其对酶催化的影响。

IF 5.3 2区 化学 Q1 CHEMISTRY, MEDICINAL
Zijian Huang, Zelin Wu, Suitian Lai, Xiabin Chen* and Junjun Liu*, 
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引用次数: 0

摘要

人羧酸酯酶1 (hCES1)是一种重要的丝氨酸水解酶,在人体代谢过程中起着广泛的作用。其催化中心与b型羧酸酯酶/脂肪酶家族中的胆碱酯酶(AChE和BChE)具有结构相似性,具有催化三联体和氧阴离子孔等标志性元素。先前对AChE和BChE的研究表明,扩展活性位点内的质子化谷氨酸残基对于形成以水为中心的氢键网络至关重要,从而稳定催化三元组。然而,与胆碱酯酶相比,hCES1催化三联体周围的氢键网络更为复杂,含有额外的谷氨酸残基。这些谷氨酸的质子化状态及其在酶催化中的确切作用尚不清楚,需要进一步研究。本研究通过常规分子动力学模拟、恒pH分子动力学模拟和热力学积分计算,系统地研究了hCES1扩展活性位点内关键谷氨酸残基的质子化状态及其对功能的影响。我们的研究结果表明,E220和E246的质子化对于维持水中心氢键网络的稳定性至关重要,从而稳定催化三联体并确保催化效率。相反,这些残基的去质子化会引起静电斥力,从而破坏氢键网络并扰乱催化三元组。此外,结构分析和序列比对表明,这种以水为中心的延伸活性位点及其相关的质子化模式代表了整个b型羧酸酯酶/脂肪酶家族的保守结构基序,而不是hCES1所独有的。这些发现为hCES1的催化机制提供了新的见解,并为具有类似催化结构的丝氨酸水解酶的工程设计奠定了理论基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Conserved Protonation Pattern in the Extended Active Site of Human Carboxylesterase 1 and Its Impact on Enzyme Catalysis

Conserved Protonation Pattern in the Extended Active Site of Human Carboxylesterase 1 and Its Impact on Enzyme Catalysis

Human carboxylesterase 1 (hCES1), a crucial serine hydrolase, plays extensive roles in human metabolic processes. Its catalytic center exhibits structural similarities to cholinesterases (AChE and BChE) from the Type-B carboxylesterase/lipase family, featuring hallmark elements such as the catalytic triad and oxyanion hole. Previous studies on AChE and BChE have demonstrated that a protonated glutamate residue within the extended active site is essential for forming a water-centered hydrogen bond network that stabilizes the catalytic triad. However, the hydrogen bond network surrounding hCES1’s catalytic triad is more complex, incorporating additional glutamate residues compared to cholinesterases. The protonation states of these glutamates and their precise roles in enzymatic catalysis remain unclear, necessitating further investigation. In this study, we systematically investigated the protonation states of key glutamate residues within hCES1’s extended active site and their functional impacts using conventional molecular dynamics simulations, constant pH molecular dynamics simulations, and thermodynamic integration calculations. Our results reveal that protonation of E220 and E246 is critical for maintaining the stability of the water-centered hydrogen bond network, thereby stabilizing the catalytic triad and ensuring catalytic efficiency. Conversely, deprotonation of these residues induces electrostatic repulsion that disrupts the hydrogen bond network and disorders the catalytic triad. Moreover, structural analysis and sequence alignment indicate that this water-centered extended active site and its associated protonation pattern represent a conserved structural motif across the Type-B carboxylesterase/lipase family, rather than being unique to hCES1. These findings provide novel insights into the catalytic mechanism of hCES1 and establish a theoretical foundation for engineering serine hydrolases with analogous catalytic architectures.

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来源期刊
CiteScore
9.80
自引率
10.70%
发文量
529
审稿时长
1.4 months
期刊介绍: The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery. Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field. As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.
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