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

193 Citations (Scopus)

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

Environmental Carcinogens
Epoxide Hydrolases
Mutagens
Catalytic Domain
haloalkane dehalogenase
Epoxy Compounds
mouse EPHX1 protein
Liver
Hydrolysis
Hydrolases
Xenobiotics
Enzymes

Keywords

  • α
  • β hydrolase
  • Domain swapping
  • Protein crystallography

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Detoxification of environmental mutagens and carcinogens : Structure, mechanism, and evolution of liver epoxide hydrolase. / Argiriadi, Maria A.; Morisseau, Christophe; Hammock, Bruce D.; Christianson, David W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 19, 14.09.1999, p. 10637-10642.

Research output: Contribution to journalArticle

Argiriadi, Maria A. ; Morisseau, Christophe ; Hammock, Bruce D. ; Christianson, David W. / Detoxification of environmental mutagens and carcinogens : Structure, mechanism, and evolution of liver epoxide hydrolase. In: Proceedings of the National Academy of Sciences of the United States of America. 1999 ; Vol. 96, No. 19. pp. 10637-10642.
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