SEQUENCE SIMILARITY OF MAMMALIAN EPOXIDE HYDROLASES TO THE BACTERIAL HALOALKANE DEHALOGENASE AND OTHER RELATED PROTEINS - IMPLICATION FOR THE POTENTIAL CATALYTIC MECHANISM OF ENZYMATIC EPOXIDE HYDROLYSIS

Direct comparison of the amino acid sequences of microsomal and solubl e epoxide hydrolase superficially indicates that these enzymes are unr elated. Both proteins, however, share significant sequence similarity to a bacterial haloalkane dehalogenase that has earlier been shown to belong to the alp hydrolase fold family of enzymes. The catalytic mech anism for the dehalogenase has been elucidated in detail [Verschueren et al. (1993) Nature 363, 693-698] and proceeds via an ester intermedi ate where the substrate is covalently bound to the enzyme. From these observations we conclude (i) that microsomal and soluble epoxide hydro lase are distantly related enzymes that have evolved from a common anc estral protein together with the haloalkane dehalogenase and a variety of other proteins specified in the present paper, (ii) that these enz ymes most likely belong to the alpha/beta hydrolase fold family of enz ymes and (iii) that the enzymatic epoxide hydrolysis proceeds via a hy droxy ester intermediate, in contrast to the presently favoured base-c atalyzed direct attack of the epoxide by an activated water.