Bruce Hammock

Date: May 24, 2002

Epoxide hydrolases add water to three membered cyclic ethers known as epoxides converting them to the corresponding diols. Since some epoxides are among the most potent known mutagens, toxins and carcinogens there has long been an interest in their degradation by both the soluble and microsomal epoxide hydrolases in liver and other tissues.

The enzymes appear to be wide spread among many organisms including insects and plants and clearly are involved in xenobiotic or foreign compound metabolism. The cloning and expression of the enzyme led to a novel theory for their evolution predicting that they actually are members of the alpha/beta hydrolase fold as are esterases and lipases. This hypothesis suggested that the catalytic mechanism accepted for the last 20 years is incorrect.

A series of experiments including peptide chemistry, heavy water experiments with electrical ionization and electrospray mass spectrophotometry and site directed mutagenesis suggest that the enzyme acts in a two step process involving attack on the substrate by a catalytic aspartic acid. Recent evidence suggests that the soluble epoxide hydrolase may have an additional role in the biosynthesis of biologically active members of the arachidonic acid cascade and the enzyme has been clearly implicated in the biological activation of the endogenous lipid termed leukotoxin that is suggested to be involved in the commonly fatal adult respiratory distress syndrome.

Since the soluble epoxide hydrolase can be induced by a variety of pharmaceuticals, agricultural chemicals and industrial products, and inhibited by some agricultural chemicals, it represents a target of action of environmental chemicals. Interestingly, this research in environmental chemistry has led to a new class of compounds that could be useful in inhibition of high blood pressure, vascular inflammation, and atherosclerosis.