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Molecular insight into mechanism and regulation of human soluble Epoxide Hydrolase (hsEH)

Guy’s Campus, London

15 Jan randall-seminar-abis-thumb-event Part of Randall Centre for Cell & Molecular Biophysics Seminar Series

Molecular insight into mechanism and regulation of human soluble Epoxide Hydrolase (hsEH)

Speaker: Dr Giancarlo Abis, Randall Centre for Cell & Molecular Biophysics

Host:  Sasi Conte

Abstract: Human Soluble Epoxide Hydrolase (hsEH) is an enzyme responsible for the inactivation of epoxy fatty acids with anti-inflammatory and vasoactive properties, whose bioavailability has been linked to cardiovascular and inflammatory diseases, nociception, and diabetes. Here, I will show our results that uncover the molecular bases of hsEH inhibition mediated by the prostaglandin 15dPGJ2, the first endogenous antagonist identified. Our findings reveal a dual inhibitory mechanism, whereby hsEH can be inhibited by reversible docking of 15dPGJ2 in the catalytic pocket, as well as by covalent locking of the same compound onto reactive cysteine residues remote to the enzyme 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. Our study provides novel insights into the molecular regulation of hsEH and paves the way for the development of new allosteric inhibitors to target hypertension and insulin sensitivity.


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