EzCatDB: D00539
Related links:    PDB-formatted query search system Fasta-formatted query search system Fasta-formatted query search system

DB codeD00539
RLCP classification1.35.30000.63 : Hydrolysis
CATH domainDomain 13.40.-.-
Domain 23.40.50.1820 : Rossmann foldCatalytic domain
E.C.3.3.2.10

CATH domainRelated DB codes (homologues)
3.40.50.1820 : Rossmann foldS00544,S00344,S00517,S00525,S00526,S00720,S00723,S00724,S00725,S00919,S00057,S00374,S00345,S00347,S00348,S00346,S00350,S00352,S00353,S00355,S00356,S00358,D00189,D00210,T00253

Enzyme Name
UniProtKBKEGG

P34914
Protein nameEpoxide hydrolase 2soluble epoxide hydrolase
epoxide hydrase (ambiguous)
epoxide hydratase (ambiguous)
arene-oxide hydratase (ambiguous)
aryl epoxide hydrase (ambiguous)
trans-stilbene oxide hydrolase
sEH
cytosolic epoxide hydrolase
SynonymsEC 3.3.2.10
Soluble epoxide hydrolase
SEH
Epoxide hydratase
Cytosolic epoxide hydrolase
CEH
RefSeqNP_001258332.1 (Protein)
NM_001271403.1 (DNA/RNA sequence)
NP_031966.2 (Protein)
NM_007940.4 (DNA/RNA sequence)
MEROPSS33.973 (Serine)
PfamPF00561 (Abhydrolase_1)
PF13419 (HAD_2)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00590Arachidonic acid metabolism
MAP00625Tetrachloroethene degradation

UniProtKB:Accession NumberP34914
Entry nameHYES_MOUSE
ActivityAn epoxide + H(2)O = a glycol.
SubunitHomodimer.
Subcellular locationCytoplasm. Peroxisome.
CofactorMagnesium (By similarity).

Compound table: links to PDB-related databases & PoSSuM

SubstratesProducts
KEGG-idC00722C01782C00001C01380C01666
CompoundEpoxideArene oxideH2OGlycolArene diol
Typecarbohydratearomatic ring (only carbon atom),carbohydrateH2Ocarbohydratearomatic ring (only carbon atom),carbohydrate
ChEBI
2817
15377
30742

PubChem
104944
962
22247451
174

             
1cqzA01UnboundUnbound UnboundUnbound
1cqzB01UnboundUnbound UnboundUnbound
1cr6A01UnboundUnbound UnboundUnbound
1cr6B01UnboundUnbound UnboundUnbound
1ek1A01UnboundUnbound UnboundUnbound
1ek1B01UnboundUnbound UnboundUnbound
1ek2A01UnboundUnbound UnboundUnbound
1ek2B01UnboundUnbound UnboundUnbound
1cqzA02UnboundUnbound UnboundUnbound
1cqzB02UnboundUnbound UnboundUnbound
1cr6A02Analogue:CPUUnbound UnboundUnbound
1cr6B02Analogue:CPUUnbound UnboundUnbound
1ek1A02Analogue:CIUUnbound UnboundUnbound
1ek1B02Analogue:CIUUnbound UnboundUnbound
1ek2A02Analogue:CDUUnbound UnboundUnbound
1ek2B02Analogue:CDUUnbound UnboundUnbound

Active-site residues
resource
literature [13], [14], [15], [16] & [17]
pdbCatalytic residues
         
1cqzA01 
1cqzB01 
1cr6A01 
1cr6B01 
1ek1A01 
1ek1B01 
1ek2A01 
1ek2B01 
1cqzA02ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1cqzB02ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1cr6A02ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1cr6B02ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1ek1A02ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1ek1B02ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1ek2A02ASP 333;TYR 381;TYR 465;ASP 495;HIS 523
1ek2B02ASP 333;TYR 381;TYR 465;ASP 495;HIS 523

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[2]Fig.32
[3]Fig.2, p.4228-42292
[4]Fig.6, p.14655-146572
[6]Fig.6, p.2909-2911
[9]Fig.12
[10]Scheme 6, p.150-1522
[11]Fig.4, p.79-832
[12]Fig.8, p.14583-14585
[13]Fig.3, p.10638-10639
[14]Fig.4, p.115-1162
[15]p.15269
[16]Fig.1, p.23085-230872
[17]p.5609-5612
[20]Fig.1, p.332-335
[21]Scheme 12
[22]Fig.1, p.552-5532
[23]Scheme 23
[24]Fig.9, p.225-2263

references
[1]
PubMed ID7713895
JournalJ Biol Chem
Year1995
Volume270
Pages7968-74
AuthorsPinot F, Grant DF, Beetham JK, Parker AG, Borhan B, Landt S, Jones AD, Hammock BD
TitleMolecular and biochemical evidence for the involvement of the Asp-333-His-523 pair in the catalytic mechanism of soluble epoxide hydrolase.
[2]
PubMed ID7592938
JournalJ Biol Chem
Year1995
Volume270
Pages26923-30
AuthorsBorhan B, Jones AD, Pinot F, Grant DF, Kurth MJ, Hammock BD
TitleMechanism of soluble epoxide hydrolase. Formation of an alpha-hydroxy ester-enzyme intermediate through Asp-333.
[3]
PubMed ID8626766
JournalJ Biol Chem
Year1996
Volume271
Pages4223-9
AuthorsArand M, Wagner H, Oesch F
TitleAsp333, Asp495, and His523 form the catalytic triad of rat soluble epoxide hydrolase.
[4]
PubMed ID9169427
JournalJ Biol Chem
Year1997
Volume272
Pages14650-7
AuthorsRink R, Fennema M, Smids M, Dehmel U, Janssen DB
TitlePrimary structure and catalytic mechanism of the epoxide hydrolase from Agrobacterium radiobacter AD1.
[5]
PubMed ID9485441
JournalBiochemistry
Year1998
Volume37
Pages2897-904
AuthorsLaughlin LT, Tzeng HF, Lin S, Armstrong RN
TitleMechanism of microsomal epoxide hydrolase. Semifunctional site-specific mutants affecting the alkylation half-reaction.
[6]
PubMed ID9485442
JournalBiochemistry
Year1998
Volume37
Pages2905-11
AuthorsTzeng HF, Laughlin LT, Armstrong RN
TitleSemifunctional site-specific mutants affecting the hydrolytic half-reaction of microsomal epoxide hydrolase.
[7]
PubMed ID9578475
JournalEur J Biochem
Year1998
Volume253
Pages173-83
AuthorsMisawa E, Chan Kwo Chion CK, Archer IV, Woodland MP, Zhou NY, Carter SF, Widdowson DA, Leak DJ
TitleCharacterisation of a catabolic epoxide hydrolase from a Corynebacterium sp.
[8]
Commentscatalysis
PubMed ID9854022
JournalBiochem J
Year1999
Volume337
Pages37-43
AuthorsArand M, Muller F, Mecky A, Hinz W, Urban P, Pompon D, Kellner R, Oesch F
TitleCatalytic triad of microsomal epoxide hydrolase: replacement of Glu404 with Asp leads to a strongly increased turnover rate.
[9]
PubMed ID9922181
JournalBiochemistry
Year1998
Volume37
Pages18119-27
AuthorsRink R, Janssen DB
TitleKinetic mechanism of the enantioselective conversion of styrene oxide by epoxide hydrolase from Agrobacterium radiobacter AD1.
[10]
PubMed ID9933984
JournalAdv Biochem Eng Biotechnol
Year1999
Volume63
Pages145-67
AuthorsOrru RV, Archelas A, Furstoss R, Faber K
TitleEpoxide hydrolases and their synthetic applications.
[11]
PubMed ID10065366
JournalDrug Metab Rev
Year1999
Volume31
Pages71-86
AuthorsArmstrong RN
TitleKinetic and chemical mechanism of epoxide hydrolase.
[12]
CommentsX-ray crystallography (2.1 Angstroms)
PubMed ID10329649
JournalJ Biol Chem
Year1999
Volume274
Pages14579-86
AuthorsNardini M, Ridder IS, Rozeboom HJ, Kalk KH, Rink R, Janssen DB, Dijkstra BW
TitleThe x-ray structure of epoxide hydrolase from Agrobacterium radiobacter AD1. An enzyme to detoxify harmful epoxides.
Related PDB1ehy
[13]
CommentsX-ray crystallography (2.8 Angstroms)
PubMed ID10485878
JournalProc Natl Acad Sci U S A
Year1999
Volume96
Pages10637-42
AuthorsArgiriadi MA, Morisseau C, Hammock BD, Christianson DW
TitleDetoxification of environmental mutagens and carcinogens: structure, mechanism, and evolution of liver epoxide hydrolase.
Related PDB1cqz,1cr6
[14]
CommentsX-ray crystallography (1.8 Angstroms)
PubMed ID10673439
JournalStructure Fold Des
Year2000
Volume8
Pages111-22
AuthorsZou J, Hallberg BM, Bergfors T, Oesch F, Arand M, Mowbray SL, Jones TA
TitleStructure 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 PDB1qo7
[15]
CommentsX-ray crystallography
PubMed ID10747889
JournalJ Biol Chem
Year2000
Volume275
Pages15265-70
AuthorsArgiriadi MA, Morisseau C, Goodrow MH, Dowdy DL, Hammock BD, Christianson DW
TitleBinding of alkylurea inhibitors to epoxide hydrolase implicates active site tyrosines in substrate activation.
Related PDB1ek1,1ek2
[16]
Commentscatalysis
PubMed ID10806198
JournalJ Biol Chem
Year2000
Volume275
Pages23082-8
AuthorsYamada T, Morisseau C, Maxwell JE, Argiriadi MA, Christianson DW, Hammock BD
TitleBiochemical evidence for the involvement of tyrosine in epoxide activation during the catalytic cycle of epoxide hydrolase.
[17]
Commentscatalysis
PubMed ID10820034
JournalBiochemistry
Year2000
Volume39
Pages5600-13
AuthorsRink R, Kingma J, Lutje Spelberg JH, Janssen DB
TitleTyrosine residues serve as proton donor in the catalytic mechanism of epoxide hydrolase from Agrobacterium radiobacter.
[18]
PubMed ID10862610
JournalJ Biol Chem
Year2000
Volume275
Pages28873-81
AuthorsSandberg M, Hassett C, Adman ET, Meijer J, Omiecinski CJ
TitleIdentification and functional characterization of human soluble epoxide hydrolase genetic polymorphisms.
[19]
PubMed ID11092551
JournalBioorg Med Chem
Year2000
Volume8
Pages2663-73
AuthorsNakagawa Y, Wheelock CE, Morisseau C, Goodrow MH, Hammock BG, Hammock BD
Title3-D QSAR analysis of inhibition of murine soluble epoxide hydrolase (MsEH) by benzoylureas, arylureas, and their analogues.
[20]
PubMed ID11139132
JournalDrug Metab Rev
Year2000
Volume32
Pages327-38
AuthorsArmstrong RN, Cassidy CS
TitleNew structural and chemical insight into the catalytic mechanism of epoxide hydrolases.
[21]
PubMed ID11457071
JournalJ Am Chem Soc
Year2001
Volume123
Pages3350-7
AuthorsLau EY, Newby ZE, Bruice TC
TitleA theoretical examination of the acid-catalyzed and noncatalyzed ring-opening reaction of an oxirane by nucleophilic addition of acetate. Implications to epoxide hydrolases.
[22]
PubMed ID11849937
JournalCurr Opin Biotechnol
Year2001
Volume12
Pages552-8
AuthorsSteinreiber A, Faber K
TitleMicrobial epoxide hydrolases for preparative biotransformations.
[23]
PubMed ID12465965
JournalJ Am Chem Soc
Year2002
Volume124
Pages14558-70
AuthorsSchiott B, Bruice TC
TitleReaction mechanism of soluble epoxide hydrolase: insights from molecular dynamics simulations.
[24]
PubMed ID12369917
JournalCurr Protein Pept Sci
Year2000
Volume1
Pages209-35
AuthorsHolmquist M
TitleAlpha/Beta-hydrolase fold enzymes: structures, functions and mechanisms.
[25]
PubMed ID12767152
JournalJ Chem Inf Comput Sci
Year2003
Volume43
Pages934-40
AuthorsFunar-Timofei S, Suzuki T, Paier JA, Steinreiber A, Faber K, Fabian WM
TitleQuantitative structure-activity relationships for the enantioselectivity of oxirane ring-opening catalyzed by epoxide hydrolases.
[26]
PubMed ID12869654
JournalMol Pharmacol
Year2003
Volume64
Pages482-90
AuthorsPrzybyla-Zawislak BD, Srivastava PK, Vazquez-Matias J, Mohrenweiser HW, Maxwell JE, Hammock BD, Bradbury JA, Enayetallah AE, Zeldin DC, Grant DF
TitlePolymorphisms in human soluble epoxide hydrolase.

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.

createdupdated
2002-07-042009-04-08


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
© Biotechnology Research Institute for Drug Discovery, AIST, 2015-2016 All Rights Reserved.
© Computational Biology Research Center, AIST, 2004-2016 All Rights Reserved.