PMID- 15096040
OWN - NLM
STAT- MEDLINE
DCOM- 20040817
LR  - 20161124
IS  - 0006-2960 (Print)
IS  - 0006-2960 (Linking)
VI  - 43
IP  - 16
DP  - 2004 Apr 27
TI  - Structure of human epoxide hydrolase reveals mechanistic inferences on 
      bifunctional catalysis in epoxide and phosphate ester hydrolysis.
PG  - 4716-23
AB  - The X-ray crystal structure of human soluble epoxide hydrolase (sEH) has been 
      determined at 2.6 A resolution, revealing a domain-swapped quaternary structure 
      identical to that observed for the murine enzyme [Argiriadi, M. A., Morisseau, 
      C., Hammock, B. D., and Christianson, D. W. (1999) Proc. Natl. Acad. Sci. U.S.A. 
      96, 10637-10642]. As with the murine enzyme, the epoxide hydrolytic mechanism of 
      the human enzyme proceeds through an alkyl-enzyme intermediate with Asp-333 in 
      the C-terminal domain. The structure of the human sEH complex with 
      N-cyclohexyl-N'-(iodophenyl)urea (CIU) has been determined at 2.35 A resolution. 
      Tyr-381 and Tyr-465 donate hydrogen bonds to the alkylurea carbonyl group of CIU, 
      consistent with the proposed roles of these residues as proton donors in the 
      first step of catalysis. The N-terminal domain of mammalian sEH contains a 15 A 
      deep cleft, but its biological function is unclear. Recent experiments 
      demonstrate that the N-terminal domain of human sEH catalyzes the metal-dependent 
      hydrolysis of phosphate esters [Cronin, A., Mowbray, S., Durk, H., Homburg, S., 
      Fleming, I., Fisslthaler, B., Oesch, F., and Arand, M. (2003) Proc. Natl. Acad. 
      Sci. U.S.A. 100, 1552-1557; Newman, J. W., Morisseau, C., Harris, T. R., and 
      Hammock, B. D. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 1558-1563]. The binding 
      of Mg(2+)-HPO4(2-) to the N-terminal domain of human sEH in its CIU complex 
      reveals structural features relevant to those of the enzyme-substrate complex in 
      the phosphatase reaction.
FAU - Gomez, German A
AU  - Gomez GA
AD  - Roy and Diana Vagelos Laboratories, Department of Chemistry, University of 
      Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.
FAU - Morisseau, Christophe
AU  - Morisseau C
FAU - Hammock, Bruce D
AU  - Hammock BD
FAU - Christianson, David W
AU  - Christianson DW
LA  - eng
SI  - PDB/1S8O
SI  - PDB/1VJ5
GR  - GM63106/GM/NIGMS NIH HHS/United States
GR  - P42 ES04699/ES/NIEHS NIH HHS/United States
GR  - R37 ES02710/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Epoxy Compounds)
RN  - 0 (Esters)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Organophosphonates)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Stearic Acids)
RN  - 4ELV7Z65AP (stearic acid)
RN  - EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Catalysis
MH  - Catalytic Domain
MH  - Crystallography, X-Ray
MH  - Enzyme Inhibitors/chemistry
MH  - Epoxide Hydrolases/antagonists & inhibitors/*chemistry
MH  - Epoxy Compounds/chemistry
MH  - Esters
MH  - Humans
MH  - Hydrolysis
MH  - Mice
MH  - Multienzyme Complexes/antagonists & inhibitors/*chemistry
MH  - Organophosphonates/*chemistry
MH  - Phenylurea Compounds/chemistry
MH  - Phosphoric Monoester Hydrolases/antagonists & inhibitors/chemistry
MH  - Solubility
MH  - Stearic Acids/chemistry
MH  - Substrate Specificity
EDAT- 2004/04/21 05:00
MHDA- 2004/08/18 05:00
CRDT- 2004/04/21 05:00
PHST- 2004/04/21 05:00 [pubmed]
PHST- 2004/08/18 05:00 [medline]
PHST- 2004/04/21 05:00 [entrez]
AID - 10.1021/bi036189j [doi]
PST - ppublish
SO  - Biochemistry. 2004 Apr 27;43(16):4716-23. doi: 10.1021/bi036189j.