PMID- 12574508
OWN - NLM
STAT- MEDLINE
DCOM- 20030401
LR  - 20181113
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 100
IP  - 4
DP  - 2003 Feb 18
TI  - The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase.
PG  - 1552-7
AB  - The mammalian soluble epoxide hydrolase (sEH) is an enzyme with multiple 
      functions, being implicated in detoxification of xenobiotic epoxides as well as 
      in regulation of physiological processes such as blood pressure. The enzyme is a 
      homodimer, in which each subunit is composed of two domains. The 35-kDa 
      C-terminal domain has an alpha/beta hydrolase fold and harbors the catalytic 
      center for the EH activity. The 25-kDa N-terminal domain has a different 
      alpha/beta fold and belongs to the haloacid dehalogenase superfamily of enzymes. 
      The catalytic properties of the enzyme reported so far can all be explained by 
      the action of the C-terminal domain alone. The function of the N-terminal domain, 
      other than in structural stabilization of the dimer, has therefore remained 
      unclear. By structural comparison of this domain to other haloacid dehalogenase 
      family members, we identified a putative active site containing all necessary 
      components for phosphatase activity. Subsequently, we found rat sEH hydrolyzed 
      4-nitrophenyl phosphate with a rate constant of 0.8 s(-1) and a K(m) of 0.24 mM. 
      Recombinant human sEH lacking the C-terminal domain also displayed phosphatase 
      activity. Presence of a phosphatase substrate did not affect epoxide turnover nor 
      did epoxides affect dephosphorylation by the intact enzyme, indicating both 
      catalytic sites act independently. The enzyme was unable to hydrolyze 
      4-nitrophenyl sulfate, suggesting its role in xenobiotic metabolism does not 
      extend beyond phosphates. Thus, we propose this domain participates instead in 
      the regulation of the physiological functions associated with sEH.
FAU - Cronin, Annette
AU  - Cronin A
AD  - Institute of Pharmacology and Toxicology, University of Wurzburg, Versbacher 
      Strasse 9, D-97078 Wurzburg, Germany.
FAU - Mowbray, Sherry
AU  - Mowbray S
FAU - Durk, Heike
AU  - Durk H
FAU - Homburg, Shirli
AU  - Homburg S
FAU - Fleming, Ingrid
AU  - Fleming I
FAU - Fisslthaler, Beate
AU  - Fisslthaler B
FAU - Oesch, Franz
AU  - Oesch F
FAU - Arand, Michael
AU  - Arand M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030206
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 (DNA Primers)
RN  - 0 (Recombinant Proteins)
RN  - EC 3.- (Hydrolases)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - EC 3.8.1.2 (2-haloacid dehalogenase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - DNA Primers
MH  - Epoxide Hydrolases/chemistry/genetics/*metabolism
MH  - Humans
MH  - Hydrolases/chemistry
MH  - Male
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Phosphoric Monoester Hydrolases/chemistry
MH  - Rats
MH  - Rats, Inbred F344
MH  - Recombinant Proteins/chemistry/genetics/metabolism
MH  - Sequence Homology, Amino Acid
MH  - Solubility
PMC - PMC149870
EDAT- 2003/02/08 04:00
MHDA- 2003/04/02 05:00
PMCR- 2003/08/18
CRDT- 2003/02/08 04:00
PHST- 2003/02/08 04:00 [pubmed]
PHST- 2003/04/02 05:00 [medline]
PHST- 2003/02/08 04:00 [entrez]
PHST- 2003/08/18 00:00 [pmc-release]
AID - 0437829100 [pii]
AID - 7829 [pii]
AID - 10.1073/pnas.0437829100 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1552-7. doi: 
      10.1073/pnas.0437829100. Epub 2003 Feb 6.