Gok Muslum, Cicek Cigdem, Sari Suat, Bodur Ebru
Department of Biochemistry, Faculty of Medicine, Mugla Sitki Kocman University, 48000, Mugla, Turkey.
Department of Biochemistry, Faculty of Medicine, Yuksek Ihtisas University, 06520, Ankara, Turkey.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 21. doi: 10.1007/s00210-025-04065-3.
Butyrylcholinesterase is an abundant detoxification enzyme in human serum that is mainly synthesized in the liver. It plays a crucial role in the hydrolysis of a variety of choline esters and xenobiotics, and there is emerging evidence that it is also involved in lipid metabolism. In this study, the inhibitory effects of the major unsaturated fatty acids - arachidonic acid (AA), linoleic acid (LA), oleic acid (OA), and alpha-linolenic acid (α-LA) - on human BChE are investigated using enzyme kinetics experiments and molecular modeling analyses. These fatty acids, integral components of membrane phospholipids, differ in chain length and degree of unsaturation, which influence their inhibitory effect on BChE. Our results showed that AA had the highest IC₅₀ value of 611 µM against BChE, followed by OA, α-LA, and LA. All fatty acids showed noncompetitive inhibition, in contrast to AA, which displayed uncompetitive inhibition. Inhibitory constants (Ki) showed that OA had the strongest binding affinity due to its lowest Ki value of 321.4 µM, followed by AA, α-LA, and LA. Molecular modeling supported the in vitro results. The fatty acids were predicted to bind to a newly proposed allosteric site on BChE. Our results demonstrate that the number and position of double bonds in the alkenyl chains of fatty acids significantly influence their interactions with BChE, providing new insights into how dietary lipids regulate the enzyme. This study offers a foundation for further exploration of BChE's role in lipid metabolism and its implications for neurodegenerative and metabolic diseases.
丁酰胆碱酯酶是人体血清中一种丰富的解毒酶，主要在肝脏中合成。它在多种胆碱酯和外源性物质的水解中起关键作用，并且越来越多的证据表明它也参与脂质代谢。在本研究中，使用酶动力学实验和分子模拟分析研究了主要不饱和脂肪酸——花生四烯酸（AA）、亚油酸（LA）、油酸（OA）和α-亚麻酸（α-LA）——对人丁酰胆碱酯酶的抑制作用。这些脂肪酸是膜磷脂的组成成分，在链长和不饱和度上有所不同，这会影响它们对丁酰胆碱酯酶的抑制作用。我们的结果表明，AA对丁酰胆碱酯酶的IC₅₀值最高，为611 μM，其次是OA、α-LA和LA。与显示非竞争性抑制的AA不同，所有脂肪酸均显示非竞争性抑制。抑制常数（Ki）表明，OA由于其最低的Ki值321.4 μM而具有最强的结合亲和力，其次是AA、α-LA和LA。分子模拟支持了体外实验结果。预测这些脂肪酸会结合到丁酰胆碱酯酶上新提出的变构位点上。我们的结果表明，脂肪酸烯基链中双键的数量和位置显著影响它们与丁酰胆碱酯酶的相互作用，为膳食脂质如何调节该酶提供了新的见解。这项研究为进一步探索丁酰胆碱酯酶在脂质代谢中的作用及其对神经退行性疾病和代谢性疾病的影响奠定了基础。
