Detoxification of environmental mutagens and carcinogens: structure, mechanism, and evolution of liver epoxide hydrolase.
The crystal structure of recombinant murine liver cytosolic epoxide hydrolase (EC 3.3.2.3) has been determined at 2.8-A resolution. The binding of a nanomolar affinity inhibitor confirms the active site location in the C-terminal domain; this domain is similar to that of haloalkane dehalogenase and shares the alpha/beta hydrolase fold. A structure-based mechanism is proposed that illuminates the unique chemical strategy for the activation of endogenous and man-made epoxide substrates for hydrolysis and detoxification. Surprisingly, a vestigial active site is found in the N-terminal domain similar to that of another enzyme of halocarbon metabolism, haloacid dehalogenase. Although the vestigial active site does not participate in epoxide hydrolysis, the vestigial domain plays a critical structural role by stabilizing the dimer in a distinctive domain-swapped architecture. Given the genetic and structural relationships among these enzymes of xenobiotic metabolism, a structure-based evolutionary sequence is postulated.
Argiriadi
M A
MA
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA.
Morisseau
C
C
Hammock
B D
BD
Christianson
D W
DW
D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics*; D018360:Crystallography, X-Ray; D019281:Dimerization; D004851:Epoxide Hydrolases / Q000737:chemistry* / Q000235:genetics* / Q000493:pharmacokinetics*; D006867:Hydrolases / Q000737:chemistry; D006868:Hydrolysis; D008658:Inactivation, Metabolic; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009153:Mutagens / Q000493:pharmacokinetics*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D015262:Xenobiotics / Q000378:metabolism
D002273:Carcinogens; D009153:Mutagens; D011994:Recombinant Proteins; D015262:Xenobiotics; D006867:Hydrolases; D004851:Epoxide Hydrolases; C034507:2-haloacid dehalogenase