Executive Summary : | Sterols, polyunsaturated fatty acids, sphingolipids and epoxy lipids are key lipid signaling molecules that aggravate complex cellular events. Of particular interest is in epoxy lipids and xenobiotic epoxides. Human epoxide hydrolases (EHs) regulate the cellular levels of endogenous epoxides and their metabolites. Microsomal EH1 mainly detoxifies a broad array of carcinogenic xenobiotic epoxides. In Indian population, varied gene polymorphisms of EH1 are associated with susceptibility to various types of cancer and hereditary diseases. While endogenous epoxy lipids, epoxyeicosatrienoic acids (EETs) obtained from arachidonic acid metabolism are transformed to less toxic dihydroeicosatrienoic acid (DHETs) by the microsomal EH3 and the soluble EH2. The balance of epoxy lipids and the respective dihydroxylated lipids governs the lipid signalling and the cascade of cellular events there off. Therefore, EH2 and EH3 led to a plausible drug target for hypertension, cardiovascular disease, and type II diabetes. Soluble EH2 is explored for its structural and biochemical characterization, and for design of inhibitors. However, there are open questions to understand the origin of proton relay pathways and rate limiting step in the catalytic cycle that assist in design of isoform specific (EH1-EH3) inhibitors. Scarcity of the X-ray crystal structure of the membrane-bound proteins (EH1 and EH3) further hampered the elucidation of mechanism of action and the drug design for these enzymes. To address the detoxification, the origin of substrate selectivity and distinct epoxide hydrolase activity of EH1 and EH3 isozymes, a systematic atomistic and molecular level elucidation of structure and reaction mechanisms are proposed using multiscale modeling. This computational approach explains the enzymatic action and its physiological role, which brings in novel transition state analogues and avenues for the drug targets of cancer and metabolic disorders. |