Biomolecular Interactions and Inhibition Kinetics of Human Soluble Epoxide Hydrolase by Tetrapeptide YMSV

Soluble epoxide hydrolase inhibition by tetrapeptide YMSV

Abstract

Soluble epoxide hydrolase (sEH) contributes to the pathophysiology of neurodegenerative diseases by decreasing the epoxyeicosatrienoic acids/dihydroeicosatrienoic acids ratio and influencing the anti-inflammatory system. Thus, sEH inhibition reduces systemic inflammation, particularly in the brain. This study investigated sEH inhibition by a tetrapeptide, YMSV, and its mechanism of action. Enzyme inhibition kinetics demonstrated that YMSV is a mixed-competitive inhibitor of sEH, with a half-maximal inhibitory concentration (IC₅₀) of 179.5 ± 0.92 µM. Secondary structural analysis of sEH by circular dichroism showed that YMSV decreased the α-helices by 7.7% and increased the β-sheets and random coils by 11.4% and 22%, respectively. Molecular docking simulation indicated that YMSV formed a hydrogen bond with the Asp333 residue of the hydrolase pocket of sEH in addition to the binding of non-active site residues. The findings provide new insights into the mechanism of sEH inhibition by YMSV and its potential as a peptide-based anti-depressant nutraceutical.