Epoxide hydrolase (also known as epoxide hydratase) functions in detoxication during drug metabolism. It converts epoxides to trans-dihydrodiols, which can be conjugated and excreted from the body. Epoxides result from the degradation of aromatic compounds. Deficiency in this enzyme in patients receiving aromatic-type anti-epileptic drugs such as phenytoin is reported to lead to DRESS syndrome.
Epoxides are significant as cytochrome P450 oxidase metabolites of unsaturated carbon-carbon bonds, but are also mutagenic. Epoxide hydrolase is present in large quantity on endoplasmic reticulum.
Mycobacterium tuberculosis, the major causative agent of tuberculosis, expresses at least six different forms of epoxide hydrolase (forms A-F). The structure of epoxide hydrolase B reveals that the enzyme is a monomer and contains an alpha/beta hydrolase fold. In addition to providing insights into the enzyme mechanism, this hydrolase currently serves as a platform for rational drug design of potent inhibitors. In particular, urea based inhibitors have been developed. These inhibitors directly target the catalytic cavity. It is hypothesized that the structure of epoxide hydrolase B may allow for drug design to inhibit all other Mycobacterium tuberculosis hydrolases as long as they contain similar alpha/beta folds.
The structure of hydrolase B contains a cap domain, which is hypothesized to regulate the active site of the hydrolase. Furthermore, Asp104, His333, and Asp302 form the catalytic triad of the protein and is critical to function of the protein.
At present, other structures of Mycobacterium tuberculosis hydrolase have not been solved.
Humans express the following four isozymes of epoxide hydrolase:
- ^ a b PDB 2E3J; Biswal BK, Morisseau C, Garen G, Cherney MM, Garen C, Niu C, Hammock BD, James MN. (September 2008). "The molecular structure of epoxide hydrolase B from Mycobacterium tuberculosis and its complex with a urea-based inhibitor.". J. Mol. Bio. 381 (4): 897–912. doi:10.1016/j.jmb.2008.06.030. PMID 18585390.; rendered via PyMOL