InterPro: IPR000639 Epoxide hydrolase-like

The alpha/beta hydrolase fold is common to a number of hydrolytic enzymes of widely differing phylogenetic origin and catalytic function. The core of each enzyme is an alpha/beta-sheet (rather than a barrel), containing 8 strands connected by helices [1]. The enzymes are believed to have diverged from a common ancestor, preserving the arrangement of the catalytic residues. All have a catalytic triad, the elements of which are borne on loops, which are the best conserved structural features of the fold. The epoxide hydrolases (EH) add water to epoxides, forming the corresponding diol. On the basis of sequence similarity, it has been proposed that the mammalian soluble EHs contain 2 evolutionarily distinct domains, the N-terminal domain is similar to bacterial haloacid dehalogenase, while the C-terminal domain is similar to soluble plant EH, microsomal EH, and bacterial haloalkane dehalogenase (HLD) [2]. The mechanism of HLD, established by X-ray crystallographic analysis of an HDL-substrate intermediate [3], involves nucleophilic attack of Asp-124 on the halogen-substituted terminal carbon of the substrate, forming a covalently-bound ester intermediate. The Asp-260/His-289 pair activate a water molecule that hydrolyses the ester intermediate to release the product. The similarity of EH to HLD is important for deducing a catalytic mechanism for EH. Mutagenesis experiments on murine soluble EH confirmed the crucial role of nucleophile Asp-333 and His-523 in the catalytic mechanism and the importance of conserved His-263 and His-332 [4].