DB code: D00539

RLCP classification 1.35.30000.63 : Hydrolysis
CATH domain 3.40.-.- :
3.40.50.1820 : Rossmann fold Catalytic domain
E.C. 3.3.2.10
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
3.40.50.1820 : Rossmann fold S00544 S00344 S00517 S00525 S00526 S00720 S00723 S00724 S00725 S00919 S00057 S00374 S00345 S00347 S00348 S00346 S00350 S00352 S00353 S00355 S00356 S00358 D00189 D00210 T00253

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq MEROPS Pfam
P34914 Epoxide hydrolase 2
EC 3.3.2.10
Soluble epoxide hydrolase
SEH
Epoxide hydratase
Cytosolic epoxide hydrolase
CEH
NP_001258332.1 (Protein)
NM_001271403.1 (DNA/RNA sequence)
NP_031966.2 (Protein)
NM_007940.4 (DNA/RNA sequence)
S33.973 (Serine)
PF00561 (Abhydrolase_1)
PF13419 (HAD_2)
[Graphical View]

KEGG enzyme name
soluble epoxide hydrolase
epoxide hydrase (ambiguous)
epoxide hydratase (ambiguous)
arene-oxide hydratase (ambiguous)
aryl epoxide hydrase (ambiguous)
trans-stilbene oxide hydrolase
sEH
cytosolic epoxide hydrolase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P34914 HYES_MOUSE An epoxide + H(2)O = a glycol. Homodimer. Cytoplasm. Peroxisome. Magnesium (By similarity).

KEGG Pathways
Map code Pathways E.C.
MAP00590 Arachidonic acid metabolism
MAP00625 Tetrachloroethene degradation

Compound table
Substrates Products Intermediates
KEGG-id C00722 C01782 C00001 C01380 C01666
E.C.
Compound Epoxide Arene oxide H2O Glycol Arene diol
Type carbohydrate aromatic ring (only carbon atom),carbohydrate H2O carbohydrate aromatic ring (only carbon atom),carbohydrate
ChEBI 2817
 2817
 		15377
 15377
 		30742
 30742
PubChem 104944
 104944
 		22247451
 962
 22247451
 962
 		174
 174
1cqzA01 Unbound Unbound Unbound Unbound
1cqzB01 Unbound Unbound Unbound Unbound
1cr6A01 Unbound Unbound Unbound Unbound
1cr6B01 Unbound Unbound Unbound Unbound
1ek1A01 Unbound Unbound Unbound Unbound
1ek1B01 Unbound Unbound Unbound Unbound
1ek2A01 Unbound Unbound Unbound Unbound
1ek2B01 Unbound Unbound Unbound Unbound
1cqzA02 Unbound Unbound Unbound Unbound
1cqzB02 Unbound Unbound Unbound Unbound
1cr6A02 Analogue:CPU Unbound Unbound Unbound
1cr6B02 Analogue:CPU Unbound Unbound Unbound
1ek1A02 Analogue:CIU Unbound Unbound Unbound
1ek1B02 Analogue:CIU Unbound Unbound Unbound
1ek2A02 Analogue:CDU Unbound Unbound Unbound
1ek2B02 Analogue:CDU Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
literature [13], [14], [15], [16] & [17]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1cqzA01
1cqzB01
1cr6A01
1cr6B01
1ek1A01
1ek1B01
1ek2A01
1ek2B01
1cqzA02 ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1cqzB02 ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1cr6A02 ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1cr6B02 ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1ek1A02 ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1ek1B02 ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1ek2A02 ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1ek2B02 ASP 333;TYR 381;TYR 465;ASP 495;HIS 523

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[2]
Fig.3 2
[3]
Fig.2, p.4228-4229 2
[4]
Fig.6, p.14655-14657 2
[6]
Fig.6, p.2909-2911
[9]
Fig.1 2
[10]
Scheme 6, p.150-152 2
[11]
Fig.4, p.79-83 2
[12]
Fig.8, p.14583-14585
[13]
Fig.3, p.10638-10639
[14]
Fig.4, p.115-116 2
[15]
p.15269
[16]
Fig.1, p.23085-23087 2
[17]
p.5609-5612
[20]
Fig.1, p.332-335
[21]
Scheme 1 2
[22]
Fig.1, p.552-553 2
[23]
Scheme 2 3
[24]
Fig.9, p.225-226 3

References
[1]
Resource
Comments
Medline ID
PubMed ID 7713895
Journal J Biol Chem
Year 1995
Volume 270
Pages 7968-74
Authors Pinot F, Grant DF, Beetham JK, Parker AG, Borhan B, Landt S, Jones AD, Hammock BD
Title Molecular and biochemical evidence for the involvement of the Asp-333-His-523 pair in the catalytic mechanism of soluble epoxide hydrolase.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 7592938
Journal J Biol Chem
Year 1995
Volume 270
Pages 26923-30
Authors Borhan B, Jones AD, Pinot F, Grant DF, Kurth MJ, Hammock BD
Title Mechanism of soluble epoxide hydrolase. Formation of an alpha-hydroxy ester-enzyme intermediate through Asp-333.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 8626766
Journal J Biol Chem
Year 1996
Volume 271
Pages 4223-9
Authors Arand M, Wagner H, Oesch F
Title Asp333, Asp495, and His523 form the catalytic triad of rat soluble epoxide hydrolase.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 9169427
Journal J Biol Chem
Year 1997
Volume 272
Pages 14650-7
Authors Rink R, Fennema M, Smids M, Dehmel U, Janssen DB
Title Primary structure and catalytic mechanism of the epoxide hydrolase from Agrobacterium radiobacter AD1.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 9485441
Journal Biochemistry
Year 1998
Volume 37
Pages 2897-904
Authors Laughlin LT, Tzeng HF, Lin S, Armstrong RN
Title Mechanism of microsomal epoxide hydrolase. Semifunctional site-specific mutants affecting the alkylation half-reaction.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 9485442
Journal Biochemistry
Year 1998
Volume 37
Pages 2905-11
Authors Tzeng HF, Laughlin LT, Armstrong RN
Title Semifunctional site-specific mutants affecting the hydrolytic half-reaction of microsomal epoxide hydrolase.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 9578475
Journal Eur J Biochem
Year 1998
Volume 253
Pages 173-83
Authors Misawa E, Chan Kwo Chion CK, Archer IV, Woodland MP, Zhou NY, Carter SF, Widdowson DA, Leak DJ
Title Characterisation of a catabolic epoxide hydrolase from a Corynebacterium sp.
Related PDB
Related UniProtKB
[8]
Resource
Comments catalysis
Medline ID
PubMed ID 9854022
Journal Biochem J
Year 1999
Volume 337
Pages 37-43
Authors Arand M, Muller F, Mecky A, Hinz W, Urban P, Pompon D, Kellner R, Oesch F
Title Catalytic triad of microsomal epoxide hydrolase: replacement of Glu404 with Asp leads to a strongly increased turnover rate.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 9922181
Journal Biochemistry
Year 1998
Volume 37
Pages 18119-27
Authors Rink R, Janssen DB
Title Kinetic mechanism of the enantioselective conversion of styrene oxide by epoxide hydrolase from Agrobacterium radiobacter AD1.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 9933984
Journal Adv Biochem Eng Biotechnol
Year 1999
Volume 63
Pages 145-67
Authors Orru RV, Archelas A, Furstoss R, Faber K
Title Epoxide hydrolases and their synthetic applications.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 10065366
Journal Drug Metab Rev
Year 1999
Volume 31
Pages 71-86
Authors Armstrong RN
Title Kinetic and chemical mechanism of epoxide hydrolase.
Related PDB
Related UniProtKB
[12]
Resource
Comments X-ray crystallography (2.1 Angstroms)
Medline ID
PubMed ID 10329649
Journal J Biol Chem
Year 1999
Volume 274
Pages 14579-86
Authors Nardini M, Ridder IS, Rozeboom HJ, Kalk KH, Rink R, Janssen DB, Dijkstra BW
Title The x-ray structure of epoxide hydrolase from Agrobacterium radiobacter AD1. An enzyme to detoxify harmful epoxides.
Related PDB 1ehy
Related UniProtKB
[13]
Resource
Comments X-ray crystallography (2.8 Angstroms)
Medline ID
PubMed ID 10485878
Journal Proc Natl Acad Sci U S A
Year 1999
Volume 96
Pages 10637-42
Authors Argiriadi MA, Morisseau C, Hammock BD, Christianson DW
Title Detoxification of environmental mutagens and carcinogens: structure, mechanism, and evolution of liver epoxide hydrolase.
Related PDB 1cqz 1cr6
Related UniProtKB
[14]
Resource
Comments X-ray crystallography (1.8 Angstroms)
Medline ID
PubMed ID 10673439
Journal Structure Fold Des
Year 2000
Volume 8
Pages 111-22
Authors Zou J, Hallberg BM, Bergfors T, Oesch F, Arand M, Mowbray SL, Jones TA
Title Structure of Aspergillus niger epoxide hydrolase at 1.8 A resolution: implications for the structure and function of the mammalian microsomal class of epoxide hydrolases.
Related PDB 1qo7
Related UniProtKB
[15]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 10747889
Journal J Biol Chem
Year 2000
Volume 275
Pages 15265-70
Authors Argiriadi MA, Morisseau C, Goodrow MH, Dowdy DL, Hammock BD, Christianson DW
Title Binding of alkylurea inhibitors to epoxide hydrolase implicates active site tyrosines in substrate activation.
Related PDB 1ek1 1ek2
Related UniProtKB
[16]
Resource
Comments catalysis
Medline ID
PubMed ID 10806198
Journal J Biol Chem
Year 2000
Volume 275
Pages 23082-8
Authors Yamada T, Morisseau C, Maxwell JE, Argiriadi MA, Christianson DW, Hammock BD
Title Biochemical evidence for the involvement of tyrosine in epoxide activation during the catalytic cycle of epoxide hydrolase.
Related PDB
Related UniProtKB
[17]
Resource
Comments catalysis
Medline ID
PubMed ID 10820034
Journal Biochemistry
Year 2000
Volume 39
Pages 5600-13
Authors Rink R, Kingma J, Lutje Spelberg JH, Janssen DB
Title Tyrosine residues serve as proton donor in the catalytic mechanism of epoxide hydrolase from Agrobacterium radiobacter.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 10862610
Journal J Biol Chem
Year 2000
Volume 275
Pages 28873-81
Authors Sandberg M, Hassett C, Adman ET, Meijer J, Omiecinski CJ
Title Identification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 11092551
Journal Bioorg Med Chem
Year 2000
Volume 8
Pages 2663-73
Authors Nakagawa Y, Wheelock CE, Morisseau C, Goodrow MH, Hammock BG, Hammock BD
Title 3-D QSAR analysis of inhibition of murine soluble epoxide hydrolase (MsEH) by benzoylureas, arylureas, and their analogues.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 11139132
Journal Drug Metab Rev
Year 2000
Volume 32
Pages 327-38
Authors Armstrong RN, Cassidy CS
Title New structural and chemical insight into the catalytic mechanism of epoxide hydrolases.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID 11457071
Journal J Am Chem Soc
Year 2001
Volume 123
Pages 3350-7
Authors Lau EY, Newby ZE, Bruice TC
Title A theoretical examination of the acid-catalyzed and noncatalyzed ring-opening reaction of an oxirane by nucleophilic addition of acetate. Implications to epoxide hydrolases.
Related PDB
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 11849937
Journal Curr Opin Biotechnol
Year 2001
Volume 12
Pages 552-8
Authors Steinreiber A, Faber K
Title Microbial epoxide hydrolases for preparative biotransformations.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 12465965
Journal J Am Chem Soc
Year 2002
Volume 124
Pages 14558-70
Authors Schiott B, Bruice TC
Title Reaction mechanism of soluble epoxide hydrolase: insights from molecular dynamics simulations.
Related PDB
Related UniProtKB
[24]
Resource
Comments
Medline ID
PubMed ID 12369917
Journal Curr Protein Pept Sci
Year 2000
Volume 1
Pages 209-35
Authors Holmquist M
Title Alpha/Beta-hydrolase fold enzymes: structures, functions and mechanisms.
Related PDB
Related UniProtKB
[25]
Resource
Comments
Medline ID
PubMed ID 12767152
Journal J Chem Inf Comput Sci
Year 2003
Volume 43
Pages 934-40
Authors Funar-Timofei S, Suzuki T, Paier JA, Steinreiber A, Faber K, Fabian WM
Title Quantitative structure-activity relationships for the enantioselectivity of oxirane ring-opening catalyzed by epoxide hydrolases.
Related PDB
Related UniProtKB
[26]
Resource
Comments
Medline ID
PubMed ID 12869654
Journal Mol Pharmacol
Year 2003
Volume 64
Pages 482-90
Authors Przybyla-Zawislak BD, Srivastava PK, Vazquez-Matias J, Mohrenweiser HW, Maxwell JE, Hammock BD, Bradbury JA, Enayetallah AE, Zeldin DC, Grant DF
Title Polymorphisms in human soluble epoxide hydrolase.
Related PDB
Related UniProtKB

Comments
The E.C. was transferred from 3.3.2.3 to 3.3.2.10.
This enzyme belongs to the Alpha/Beta hydrolase superfamily. Moreover, this enzyme is homologous to counterpart enzymes from fungi and bacteria (S00352 in EzCATDB).
Although this enzyme binds magnesium ion, it is not involved in catalysis.
According to the literature [13], [14], & [15], the catalysis proceeds through an SN2-like reaction.
In the first step, Asp333 (PDB 1cqz) makes a nucleophilic attack on the epoxide to form a "glycol-monoester intermediate", whilst Tyr465 and Tyr381 (PDB 1cqz) stablize the negative charged oxygen atom in the transition-state, and act as a general acid catalyst to facilitate the epoxide ring opening, by protonating to the epoxide oxygen.
In the second step, the glycol-monoester intermediate is hydrolyzed by a water molecule, which is activated through proton abstraction by the His523/Asp495 (PDB 1cqz) charge-relay system.

Created Updated
2002-07-04 2009-04-08