Progress In Deciphering The Biological Role Of The Human Soluble Epoxide Hydrolase Phosphatase Activity

The soluble epoxide hydrolase (sEH) is a unique enzyme in that it has two enzymatic activities on two separate domains: a C‐terminal epoxide hydrolase (Cterm‐EH), and a N‐terminal phosphatase (Nterm‐phos). The Cterm‐EH has been reported to hydrolyze epoxy‐fatty acids, especially epoxy‐eicosatrienoic acids (EETs) that are endogenous regulators of blood pressure and inflammation. Thus, Cterm‐EH inhibition is novel pharmacological approach to treat hypertension, pain and inflammation. The N‐terminal domain function is still not well known. It was thought to only help stabilize the C‐terminal domain. However, we recently described its magnesium dependent phosphatase activity on some lipid phosphates. We will report our progress on determining the substrate selectivity of the Nterm‐phos, as well as novel as specific inhibitors for this activity. The results will be discussed in light of possible interaction between the two domains, and biological roles of both sEH activities. This work was supported in part by NIEHS Grant R37 ES02710, NIEHS SBRP Grant P42 ES04699, and NIEHS CEHS Grant P30 ES05707.