Detoxification of environmental mutagens and carcinogens: Structure, mechanism, and evolution of liver epoxide hydrolase

Maria A. Argiriadi, Christophe Morisseau, Bruce D. Hammock, David W. Christianson

Research output: Contribution to journalArticle

194 Scopus citations

Abstract

The crystal structure of recombinant murine liver cytosolic epoxide hydrolase (EC 3.3.2.3) has been determined at 2.8-Å 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 α/β 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.

Original languageEnglish (US)
Pages (from-to)10637-10642
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number19
DOIs
StatePublished - Sep 14 1999

    Fingerprint

Keywords

  • α
  • β hydrolase
  • Domain swapping
  • Protein crystallography

ASJC Scopus subject areas

  • Genetics
  • General

Cite this