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A thiol redox sensor in soluble epoxide hydrolase enables oxidative activation by intra-protein disulfide bond formation

Charles, RL; Abis, G; Fernandez, BF; Guttzeit, S; Buccafusca, R; Conte, MR; Eaton, P; (2021) A thiol redox sensor in soluble epoxide hydrolase enables oxidative activation by intra-protein disulfide bond formation. Redox Biology , Article 102107. 10.1016/j.redox.2021.102107. (In press). Green open access

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Abstract

Soluble epoxide hydrolase (sEH), an enzyme that broadly regulates the cardiovascular system, hydrolyses epoxyeicosatrienoic acids (EETs) to their corresponding dihydroxyeicosatrienoic acids (DHETs). We previously showed that endogenous lipid electrophiles adduct within the catalytic domain, inhibiting sEH to lower blood pressure in angiotensin II-induced hypertensive mice. As angiotensin II increases vascular H_{2}O_{2}, we explored sEH redox regulation by this oxidant and how this integrates with inhibition by lipid electrophiles to regulate vasotone. Kinetics analyses revealed that H_{2}O_{2} not only increased the specific activity of sEH but increased its affinity for substrate and increased its catalytic efficiency. This oxidative activation was mediated by formation of an intra-disulfide bond between C262 and C264, as determined by mass spectrometry and substantiated by biotin-phenylarsinate and thioredoxin-trapping mutant assays. C262S/264S sEH mutants were resistant to peroxide-induced activation, corroborating the disulfide-activation mechanism. The physiological impact of sEH redox state was determined in isolated arteries and the effect of the pro-oxidant vasopressor angiotensin II on arterial sEH redox state and vasodilatory EETs indexed in mice. Angiotensin II induced the activating intra-disulfide in sEH, causing a decrease in plasma EET/DHET ratios that is consistent with the pressor response to this hormone. Although sEH C262–C264 disulfide formation enhances hydrolysis of vasodilatory EETs, this modification also sensitized sEH to inhibition by lipid electrophiles. This explains why angiotensin II decreases EETs and increases blood pressure, but when lipid electrophiles are also present, that EETs are increased and blood pressure lowered.

Type: Article
Title: A thiol redox sensor in soluble epoxide hydrolase enables oxidative activation by intra-protein disulfide bond formation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.redox.2021.102107
Publisher version: https://doi.org/10.1016/j.redox.2021.102107
Language: English
Additional information: © 2021 Published by Elsevier B.V. under a Creative Commons license (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Redox regulation, Oxidation, Angiotensin II, Disulfide, Soluble epoxide hydrolase
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10133383
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