Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Food Funct. 2024 May 20;15(10):5287-5299. doi: 10.1039/d4fo00538d.
Catechol--methyltransferase (COMT) plays a central role in the metabolic inactivation of endogenous neurotransmitters and xenobiotic drugs and hormones having catecholic structures. Its inhibitors are used in clinical practice to treat Parkinson's disease. In this study, a fluorescence-based visualization inhibitor screening method was developed to assess the inhibition activity on COMT both and in living cells. Following the screening of 94 natural products, Pu-erh tea extract exhibited the most potent inhibitory effect on COMT with an IC value of 0.34 μg mL. experiments revealed that Pu-erh tea extract substantially hindered COMT-mediated levodopa metabolism in rats, resulting in a significant increase in levodopa levels and a notable decrease in 3--methyldopa in plasma. Subsequently, the chemical components of Pu-erh tea were analyzed using UHPLC-Q-Exactive Orbitrap HRMS, identifying 24 major components. Among them, epigallocatechin gallate, gallocatechin gallate, epicatechin gallate, and catechin gallate exhibited potent inhibition of COMT activity with IC values from 93.7 nM to 125.8 nM and were the main bioactive constituents in Pu-erh tea responsible for its COMT inhibition effect. Inhibition kinetics analyses and docking simulations revealed that these compounds competitively inhibit COMT-mediated -methylation at the catechol site. Overall, this study not only explained how Pu-erh tea catechins inhibit COMT, suggesting Pu-erh tea as a potential dietary intervention for Parkinson's disease, but also introduced a new strategy for discovering COMT inhibitors more effectively.
儿茶酚-O-甲基转移酶（COMT）在代谢内源性神经递质以及具有儿茶酚结构的外源性药物和激素方面起着核心作用。其抑制剂被用于临床治疗帕金森病。在本研究中，建立了一种基于荧光的可视化抑制剂筛选方法，以评估 COMT 的抑制活性和在活细胞中的抑制活性。在筛选了 94 种天然产物后，普洱茶叶提取物对 COMT 的抑制作用最强，IC 值为 0.34μg/mL。实验表明，普洱茶叶提取物显著抑制了 COMT 介导的左旋多巴在大鼠体内的代谢，导致左旋多巴水平显著升高，血浆中 3--甲基多巴显著减少。随后，使用 UHPLC-Q-Exactive Orbitrap HRMS 分析了普洱茶叶的化学成分，鉴定出 24 种主要成分。其中，表没食子儿茶素没食子酸酯、没食子儿茶素没食子酸酯、表儿茶素没食子酸酯和儿茶素没食子酸酯对 COMT 活性具有较强的抑制作用，IC 值范围为 93.7nM 至 125.8nM，是普洱茶叶中主要的生物活性成分，负责其对 COMT 的抑制作用。抑制动力学分析和对接模拟表明，这些化合物竞争性地抑制 COMT 介导的儿茶酚部位的 -甲基化。总的来说，这项研究不仅解释了普洱茶叶儿茶素如何抑制 COMT，提示普洱茶叶可能是治疗帕金森病的一种潜在饮食干预方法，而且还引入了一种更有效地发现 COMT 抑制剂的新策略。
