Xiao Ling, Chi Dehui, Sheng Guiju, Li Wenjuan, Lin Penghui, Liang Sicheng, Zhu Liangliang, Dong Peipei
School of Resources and Environment, Key Laboratory of Aqueous Environment Protection and Pollution Control of Yangtze River, Anqing Normal University Anqing 246133 China.
Department of Food Science and Technology, School of Life Science and Research Center of Aquatic Organism Conservation and Water Ecosystem Restoration, Anqing Normal University No. 1314, North Jixian Road Anqing 246133 China
RSC Adv. 2020 Jun 16;10(39):22966-22971. doi: 10.1039/d0ra02311f.
UDP-glucuronosyltransferases (UGTs) and β-glucuronidase (GUS) catalyze entirely distinct metabolism reactions. UGTs are responsible for the glucuronidation of a variety of drugs, endogenous and environmental chemicals, whereas GUS hydrolyzes glucuronides and liberates the parent substrates. Information on the overlap of ligand selectivity between UGT and GUS is essential for exploring the pharmacological or toxicological effects of the inhibitors of these two metabolic enzymes. This study is conducted to test whether UGTs and GUS share common ligands, by investigating the inhibitory effects towards GUS by a series of UGT typical substrates and inhibitors. Results showed that three typical ligands of UGTs, including two specific substrates (estradiol and trifluoperazine, E2 and TFP) and one selective inhibitor (magnolol, Mag), can inhibit the activity of GUS. Kinetic assays indicated that all the three UGT specific chemicals displayed competitive inhibition, with values of 31.4 (E2), 56.9 (TFP), and 16.6 μM (Mag). Docking studies further revealed that the three chemicals can enter the active sites of GUS by forming contacts with residues Glu-413, Trp-549, Asp-163, Tyr-472, Arg-562, or bound water. Our study indicates that ligand selectivity overlaps between UGTs and GUS, and some chemicals can act as co-inhibitors of these two metabolic enzymes. The pharmacological or toxicological effects of those co-inhibitors require further investigations.
尿苷二磷酸葡萄糖醛酸基转移酶（UGTs）和β-葡萄糖醛酸酶（GUS）催化完全不同的代谢反应。UGTs负责多种药物、内源性和环境化学物质的葡萄糖醛酸化，而GUS则水解葡萄糖醛酸酯并释放出母体底物。了解UGT和GUS之间配体选择性的重叠情况对于探索这两种代谢酶抑制剂的药理或毒理作用至关重要。本研究旨在通过研究一系列UGT典型底物和抑制剂对GUS的抑制作用，来测试UGTs和GUS是否共享共同配体。结果表明，UGTs的三种典型配体，包括两种特异性底物（雌二醇和三氟拉嗪，E2和TFP）和一种选择性抑制剂（厚朴酚，Mag），可以抑制GUS的活性。动力学分析表明，所有这三种UGT特异性化学物质均表现出竞争性抑制作用，其 值分别为31.4（E2）、56.9（TFP）和16.6 μM（Mag）。对接研究进一步揭示，这三种化学物质可通过与残基Glu-413、Trp-549、Asp-163、Tyr-472、Arg-562或结合水形成接触而进入GUS的活性位点。我们的研究表明，UGTs和GUS之间存在配体选择性重叠，一些化学物质可作为这两种代谢酶的共同抑制剂。这些共同抑制剂的药理或毒理作用需要进一步研究。
