Structure of Aspergillus niger epoxide hydrolase at 1.8 angstrom resolution: implications for the structure and function of the mammalian microsomal class of epoxide hydrolases

Background: Epoxide hydrolases have important roles in the:defense of cells against potentially harmful epoxides. Conversion of epoxides into less tox ic and more easily excreted diets is a universally successful strategy. A n umber of microorganisms employ the same chemistry to process epoxides for u se as carbon sources. Results: The X-ray structure of the epoxide hydrolase from Aspergillus nige r was-determined at 3.5 Angstrom resolution using the multiwavelength anoma lous dispersion (MAD) method, and then refined at 1.8 Angstrom resolution. There is a dimer consisting of two 44 kDa subunits in the asymmetric unit. Each subunit consists of an alpha/beta hydrolase fold, and a primarily heli cal lid over the active site; The dimer interface includes lid-lid interact ions as well as contributions from an N-terminal meander, The active site c ontains a classical catalytic triad,and two tyrosines and a glutamic acid r esidue that are likely to assist in catalysis. Conclusions: The Aspergillus enzyme provides the first structure of an epox ide hydrolase with strong relationships to the most important enzyme of hum an epoxide metabolism, the microsomal epoxide hydrolase, Differences in act ive-site residues, especially in components that assist in epoxide ring ope ning and hydrolysis of the enzyme-substrate intermediate, might explain why -the fungal enzyme attains the greater speeds necessary for an effective me tabolic enzyme. The N-terminal domain that is characteristic of microsomal epoxide hydrolases corresponds to a meander that is critical for dimer form ation in the Aspergillus enzyme.