15-deoxy-Δ^12,14-Prostaglandin J₂ inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism.

ABSTRACT: Human soluble epoxide hydrolase (hsEH) is an enzyme responsible for the inactivation of bioactive epoxy fatty acids, and its inhibition is emerging as a promising therapeutical strategy to target hypertension, cardiovascular disease, pain and insulin sensitivity. Here, we uncover the molecular bases of hsEH inhibition mediated by the endogenous 15-deoxy-Δ^12,14-Prostaglandin J₂ (15d-PGJ₂). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ₂ in the catalytic pocket, as well as by covalent locking of the same compound onto cysteine residues C423 and C522, remote to the active site. Biophysical characterisations allied with in silico investigations indicate that the covalent modification of the

SUBMITTER: Abis G 

PROVIDER: S-EPMC6525171 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature