Discovery of a new function of human butyrylcholinesterase and the catalytic activity of its natural variants toward homocysteine thiolactone hydrolysis.

IF 5.4
Chemico-biological interactions Pub Date : 2025-10-22 Epub Date: 2025-07-29 DOI:10.1016/j.cbi.2025.111683
Xiabin Chen, Xiaoxuan Li, Huan Liu, Jianzhuang Yao, Yishuang Li, Hualing Li, Zelin Wu, Yun Zhang, Tingjun Hou, Jiye Wang, Shurong Hou
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Abstract

Abnormal activity level of human butyrylcholinesterase (BChE) was detected in patients with cardiovascular disease and neurodegenerative disorders, however, the specific role of BChE in the pathology of these diseases are not known yet. Homocysteine thiolactone (HTL) is a toxic thioester metabolite of homocysteine in conditions of hyperhomocysteinemia (HHcy). Experimental evidences suggest that HTL and resultant N-Hcy proteins that disrupt normal protein function, are associated with the pathology of HHcy-related complications such as cardiovascular diseases. Given the abundance of BChE in the blood and its esterase capacity, it is worthy to investigate the hydrolytic ability of BChE and its genetic polymorphism effects towards the endogenous toxic HTL in order to delineate its function in the complex disease network. In this study, human BChE and acetylcholinesterase were examined for their ability in HTL hydrolysis, and BChE demonstrates higher catalytic efficiency than reported serum paraoxonase 1. Furthermore, the catalytic mechanism uncovered by Quantum mechanics/Molecular mechanics molecular dynamics method helps to understand and substantiate the function of BChE in HTL metabolism. Six frequent BChE nonsynonymous coding single nucleotide polymorphisms (SNPs) variants were recombinantly produced and their catalytic activity was assessed. Differential catalytic efficiency toward HTL was observed among these variants, suggesting their distinct metabolic capability in vivo. These findings highlight the potential protection role of BChE against HTL-induced toxicity, and pave a way for future investigation into BChE's contribution in HTL metabolism and the possible correlation between specific BChE SNPs and susceptibility for developing HTL-associated diseases.

人丁基胆碱酯酶新功能的发现及其天然变体对同型半胱氨酸硫内酯水解的催化活性。
人丁基胆碱酯酶(BChE)在心血管疾病和神经退行性疾病患者中检测到异常的活性水平,但BChE在这些疾病的病理中的具体作用尚不清楚。同型半胱氨酸硫内酯(HTL)是高同型半胱氨酸血症(HHcy)条件下同型半胱氨酸的有毒硫酯代谢物。实验证据表明,HTL和由此产生的破坏正常蛋白质功能的N-Hcy蛋白与hhcy相关并发症(如心血管疾病)的病理有关。鉴于BChE在血液中的丰度及其酯酶能力,研究BChE对内源性毒性HTL的水解能力及其遗传多态性效应,以阐明其在复杂疾病网络中的功能是值得的。在这项研究中,我们检测了人BChE和乙酰胆碱酯酶(AChE)水解HTL的能力,BChE表现出比报道的血清对氧磷酶1 (PON1)更高的催化效率。此外,量子力学/分子力学(QM/MM)分子动力学(MD)方法揭示的催化机制有助于理解和证实BChE在HTL代谢中的作用。重组产生了6个常见的BChE非同义编码单核苷酸多态性(snp)变体,并评估了它们的催化活性。在这些变体中观察到对HTL的不同催化效率,表明它们在体内具有不同的代谢能力。这些发现强调了BChE对HTL诱导毒性的潜在保护作用,并为进一步研究BChE在HTL代谢中的作用以及特定BChE snp与HTL相关疾病易感性之间的可能相关性铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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