PMID- 10485878
OWN - NLM
STAT- MEDLINE
DCOM- 19991014
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 19
DP  - 1999 Sep 14
TI  - Detoxification of environmental mutagens and carcinogens: structure, mechanism,
      and evolution of liver epoxide hydrolase.
PG  - 10637-42
AB  - 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.
FAU - Argiriadi, M A
AU  - Argiriadi MA
AD  - Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
      Pennsylvania, Philadelphia, PA 19104-6323, USA.
FAU - Morisseau, C
AU  - Morisseau C
FAU - Hammock, B D
AU  - Hammock BD
FAU - Christianson, D W
AU  - Christianson DW
LA  - eng
SI  - PDB/1CQZ
SI  - PDB/1CR6
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Carcinogens)
RN  - 0 (Mutagens)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Xenobiotics)
RN  - EC 3.- (Hydrolases)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - EC 3.8.1.2 (2-haloacid dehalogenase)
SB  - IM
MH  - Animals
MH  - Carcinogens/*pharmacokinetics
MH  - Crystallography, X-Ray
MH  - Dimerization
MH  - Epoxide Hydrolases/*chemistry/*genetics/*pharmacokinetics
MH  - Hydrolases/chemistry
MH  - Hydrolysis
MH  - *Inactivation, Metabolic
MH  - Liver/*enzymology
MH  - Mice
MH  - Models, Chemical
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutagens/*pharmacokinetics
MH  - Protein Conformation
MH  - Protein Structure, Tertiary
MH  - Recombinant Proteins/chemistry
MH  - Xenobiotics/metabolism
PMC - PMC17935
EDAT- 1999/09/15 00:00
MHDA- 1999/09/15 00:01
CRDT- 1999/09/15 00:00
PHST- 1999/09/15 00:00 [pubmed]
PHST- 1999/09/15 00:01 [medline]
PHST- 1999/09/15 00:00 [entrez]
AID - 10.1073/pnas.96.19.10637 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10637-42. doi:
      10.1073/pnas.96.19.10637.