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 language | English (US) |
|---|---|
| Pages (from-to) | 10637-10642 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 96 |
| Issue number | 19 |
| DOIs | |
| State | Published - Sep 14 1999 |
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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 journal › Article
}
TY - JOUR
T1 - Detoxification of environmental mutagens and carcinogens
T2 - Structure, mechanism, and evolution of liver epoxide hydrolase
AU - Argiriadi, Maria A.
AU - Morisseau, Christophe
AU - Hammock, Bruce D.
AU - Christianson, David W.
PY - 1999/9/14
Y1 - 1999/9/14
N2 - 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.
AB - 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.
KW - α
KW - β hydrolase
KW - Domain swapping
KW - Protein crystallography
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UR - http://www.scopus.com/inward/citedby.url?scp=0032849109&partnerID=8YFLogxK
U2 - 10.1073/pnas.96.19.10637
DO - 10.1073/pnas.96.19.10637
M3 - Article
C2 - 10485878
AN - SCOPUS:0032849109
VL - 96
SP - 10637
EP - 10642
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 19
ER -