15-deoxy-Δ12,14-Prostaglandin J2 inhibits human soluble epoxide hydrolase by a dual orthosteric and allosteric mechanism

• Published in: Communications biology Vol. 2; no. 1
• Main Authors: Abis, Giancarlo, Charles, Rebecca L., Kopec, Jolanta, Yue, Wyatt W., Atkinson, R. Andrew, Bui, Tam T. T., Lynham, Steven, Popova, Simona, Sun, Yin-Biao, Fraternali, Franca, Eaton, Philip, Conte, Maria R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-05-2019; Nature Publishing Group
• Subjects: 101/6; 631/535/1266; 631/57/2272; 82; 82/16; 82/58; 82/80; 82/83; Allosteric properties; Biochemistry; Biochemistry, Molecular Biology; Biology; Biomedical and Life Sciences; Biophysics; Cardiovascular diseases; Enzymes; Epoxide hydrolase; Fatty acids; Insulin; Life Sciences
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-019-0426-2

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 J
2
(15d-PGJ
2
). Our data reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15d-PGJ
2
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 reactive cysteines may be part of a hitherto undiscovered allosteric regulatory mechanism of the enzyme. This study provides insights into the molecular modes of inhibition of hsEH epoxy-hydrolytic activity and paves the way for the development of new allosteric inhibitors.
Giancarlo Abis et al. show that 15-deoxy-Δ12,14-Prostaglandin J2 inhibits the human soluble epoxide hydrolase by reversibly binding its catalytic pocket or by covalently binding reactive cysteines far from the active site. Inhibitors targeting these allosteric sites might prove to be useful therapeutic strategies.