These isozymes are known (mEH and sEH) or presumed (EH3 and EH4) to share a common structure that includes containing an Alpha/beta hydrolase fold and a common reaction mechanism wherein they add water to epoxides to form vicinal cis (see (cis-trans isomerism); see (epoxide#Olefin (alkene) oxidation using organic peroxides and metal catalysts)) diol products.
mEH is widely expressed in virtually all mammalian cells as an endoplasmic reticulum-bound (i.e. microsomal-bound) enzyme with its C terminal catalytic domain facing the cytoplasm; in some tissues, however, mEH has been found bound to the cell surface plasma membrane with its catalytic domain facing the extracellular space.
[3][4] mEH also metabolizes certain epoxides of polyunsaturated fatty acids such as the epoxyeicosatrienoic acids (EETs) but its activity in doing this is far less than that of sEH; mEH therefore may play a minor role, compared to sEH, in limiting the bioactivity of these cell signaling compounds (see microsomal epoxide hydrolase).
[3] sEH is widely expressed in mammalian cells as a cytosolic enzyme where it primarily serves the function of converting epoxyeicosatrienoic acids (EETs), epoxyeicosatetraenoic acids (EQAs), and epoxydocosapentaenoic acids (DPAs) to their corresponding diols, thereby limiting or ending their cell signaling actions; in this capacity, sEH appears to play a critical in vivo role in limiting the effects of these epoxides in animal models and possibly humans.
Human EH3 is a recently characterized protein with epoxy hydrolase activity for metabolizing epoxyeicosatrienoic acids (EETs) and vernolic acids (leukotoxins) to their corresponding diols; in these capacities they may thereby limit the cell signaling activity of the EETs and contribute to the toxicity of the leukotoxins.
[10] The gene for EH4, EPHX4, is projected to encode an epoxide hydrolase closely related in amino acid sequence and structure to mEH, sEH, and EH3.
[11][12][13] (Cholesterol epoxide hydrolase or ChEH), is located in the endoplasmic reticulum and to a lesser extent plasma membrane of various cell types but most highly express in liver.
In addition to providing insights into the enzyme mechanism, this hydrolase currently serves as a platform for rational drug design of potent inhibitors.