Soluble epoxide hydrolase (C-terminal hydrolase domain) (sEH) (sEH)

Soluble epoxide hydrolase (sEH) is a homodimeric enzyme encoded by the EPHX2 gene, characterized by a unique bifunctional structure containing an N-terminal phosphatase domain and a C-terminal hydrolase domain (UniProt: P34913). The C-terminal hydrolase domain is the primary therapeutic focus, as it is responsible for the conversion of epoxyeicosatrienoic acids (EETs) into dihydroxyeicosatrienoic acids (DHETs) (PubMed: 25637251). EETs are crucial lipid mediators derived from arachidonic acid that exert anti-inflammatory, vasodilatory, and analgesic effects. Their rapid degradation by the sEH hydrolase domain limits their therapeutic potential in various tissues. Pharmacological inhibition of the C-terminal hydrolase domain stabilizes EET levels, offering a promising strategy for managing hypertension, heart failure, and chronic inflammatory conditions (PubMed: 30103345). Current drug development efforts, such as EC5026 and GSK2256294, are centered on small-molecule inhibitors that selectively target this domain to treat pain and cardiovascular disorders without interfering with the enzyme's phosphatase activity. By maintaining high levels of protective epoxides, these therapies modulate the resolution of inflammation and vascular tone. Clinical trials have explored sEH inhibitors for conditions ranging from chronic obstructive pulmonary disease to neuropathic pain.

Other names

Epoxide hydrolase 2EPHX2Cytosolic epoxide hydrolaseCEHEpoxide hydratase

Inhibition of the C-terminal hydrolase activity to prevent the degradation of bioactive epoxyeicosatrienoic acids (EETs) into less active diols (PubMed: 25637251).