The role of unsaturated fatty acids in modulating human butyrylcholinesterase activity: insights from kinetics and molecular docking

• DOI: 10.1007/s00210-025-04065-3
• Publication Date: 2025-03-22T21:24:29Z
• Authors: Muslum Gok; Cigdem Cicek; Suat Sari; Ebru Bodur

Abstract 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.

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