HYES_RAT
ID HYES_RAT Reviewed; 554 AA.
AC P80299;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1994, sequence version 1.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Bifunctional epoxide hydrolase 2 {ECO:0000305};
DE Includes:
DE RecName: Full=Cytosolic epoxide hydrolase 2;
DE Short=CEH;
DE EC=3.3.2.10 {ECO:0000269|PubMed:8626766};
DE AltName: Full=Epoxide hydratase;
DE AltName: Full=Soluble epoxide hydrolase;
DE Short=SEH;
DE Includes:
DE RecName: Full=Lipid-phosphate phosphatase;
DE EC=3.1.3.76 {ECO:0000305|PubMed:12574508};
GN Name=Ephx2 {ECO:0000312|RGD:620732};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Liver;
RX PubMed=8349641; DOI=10.1016/s0021-9258(19)85377-2;
RA Knehr M., Thomas H., Arand M., Gebel T., Zeller H.-D., Oesch F.;
RT "Isolation and characterization of a cDNA encoding rat liver cytosolic
RT epoxide hydrolase and its functional expression in Escherichia coli.";
RL J. Biol. Chem. 268:17623-17627(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 450-554, AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=1743286; DOI=10.1016/0014-5793(91)81333-4;
RA Arand M., Knehr M., Thomas H., Zeller H.-D., Oesch F.;
RT "An impaired peroxisomal targeting sequence leading to an unusual
RT bicompartmental distribution of cytosolic epoxide hydrolase.";
RL FEBS Lett. 294:19-22(1991).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-333; TRP-334; GLU-433;
RP ASP-434; GLU-493; ASP-495; HIS-517; CYS-521; HIS-523; GLN-526; TRP-540 AND
RP LYS-542, AND ACTIVE SITE.
RX PubMed=8626766; DOI=10.1074/jbc.271.8.4223;
RA Arand M., Wagner H., Oesch F.;
RT "Asp333, Asp495, and His523 form the catalytic triad of rat soluble epoxide
RT hydrolase.";
RL J. Biol. Chem. 271:4223-4229(1996).
RN [4]
RP FUNCTION, PHOSPHATASE ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=12574508; DOI=10.1073/pnas.0437829100;
RA Cronin A., Mowbray S., Durk H., Homburg S., Fleming I., Fisslthaler B.,
RA Oesch F., Arand M.;
RT "The N-terminal domain of mammalian soluble epoxide hydrolase is a
RT phosphatase.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:1552-1557(2003).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY
RP REGULATION.
RX PubMed=21217101; DOI=10.1194/jlr.m009639;
RA Cronin A., Decker M., Arand M.;
RT "Mammalian soluble epoxide hydrolase is identical to liver hepoxilin
RT hydrolase.";
RL J. Lipid Res. 52:712-719(2011).
CC -!- FUNCTION: Bifunctional enzyme (PubMed:8626766, PubMed:12574508). The C-
CC terminal domain has epoxide hydrolase activity and acts on epoxides
CC (alkene oxides, oxiranes) and arene oxides (PubMed:8626766). Plays a
CC role in xenobiotic metabolism by degrading potentially toxic epoxides
CC (PubMed:8626766). Also determines steady-state levels of physiological
CC mediators (By similarity). The N-terminal domain has lipid phosphatase
CC activity, with the highest activity towards threo-9,10-phosphonooxy-
CC hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-
CC hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and
CC 12-phosphonooxy-octadec-9E-enoic acid (By similarity).
CC {ECO:0000250|UniProtKB:P34913, ECO:0000269|PubMed:12574508,
CC ECO:0000269|PubMed:8626766}.
CC -!- FUNCTION: Bifunctional enzyme (PubMed:8626766, PubMed:12574508). The C-
CC terminal domain has epoxide hydrolase activity and acts on epoxides
CC (alkene oxides, oxiranes) and arene oxides (PubMed:8626766). Plays a
CC role in xenobiotic metabolism by degrading potentially toxic epoxides
CC (By similarity). Also determines steady-state levels of physiological
CC mediators (By similarity). {ECO:0000250|UniProtKB:P34913,
CC ECO:0000269|PubMed:8626766}.
CC -!- FUNCTION: Bifunctional enzyme (PubMed:8626766, PubMed:12574508). The N-
CC terminal domain has lipid phosphatase activity, with the highest
CC activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid,
CC followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-
CC phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic
CC acid (PubMed:12574508). Has phosphatase activity toward lyso-
CC glycerophospholipids with also some lower activity toward lysolipids of
CC sphingolipid and isoprenoid phosphates (By similarity).
CC {ECO:0000250|UniProtKB:P34913, ECO:0000269|PubMed:12574508}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an epoxide + H2O = an ethanediol; Xref=Rhea:RHEA:19037,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:32955, ChEBI:CHEBI:140594;
CC EC=3.3.2.10; Evidence={ECO:0000269|PubMed:8626766};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(9S,10S)-10-hydroxy-9-(phosphooxy)octadecanoate + H2O =
CC (9S,10S)-9,10-dihydroxyoctadecanoate + phosphate;
CC Xref=Rhea:RHEA:16537, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:58796, ChEBI:CHEBI:58797; EC=3.1.3.76;
CC Evidence={ECO:0000305|PubMed:12574508};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=8-hydroxy-(11S,12S)-epoxy-(5Z,9E,14Z)-eicosatrienoate + H2O =
CC (8,11R,12S)-trihydroxy-(5Z,9E,14Z)-eicosatrienoate;
CC Xref=Rhea:RHEA:50896, ChEBI:CHEBI:15377, ChEBI:CHEBI:78100,
CC ChEBI:CHEBI:132127; Evidence={ECO:0000269|PubMed:21217101};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50897;
CC Evidence={ECO:0000269|PubMed:21217101};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=10-hydroxy-(11S,12S)-epoxy- (5Z,8Z,14Z)-eicosatrienoate + H2O
CC = (10,11S,12R)-trihydroxy-(5Z,8Z,14Z)-eicosatrienoate;
CC Xref=Rhea:RHEA:50900, ChEBI:CHEBI:15377, ChEBI:CHEBI:78084,
CC ChEBI:CHEBI:78099; Evidence={ECO:0000269|PubMed:21217101};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50901;
CC Evidence={ECO:0000269|PubMed:21217101};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=12-phosphooxy-(9Z)-octadecenoate + H2O = 12-hydroxy-(9Z)-
CC octadecenoate + phosphate; Xref=Rhea:RHEA:45272, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:85141, ChEBI:CHEBI:85150;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45273;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=12-phosphooxy-(9E)-octadecenoate + H2O = 12-hydroxy-(9E)-
CC octadecenoate + phosphate; Xref=Rhea:RHEA:45276, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:85137, ChEBI:CHEBI:85152;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45277;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=12-(phosphooxy)octadecanoate + H2O = 12-hydroxyoctadecanoate +
CC phosphate; Xref=Rhea:RHEA:45280, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:84201, ChEBI:CHEBI:85134;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45281;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=8,9-epoxy-(5Z,11Z,14Z)-eicosatrienoate + H2O = 8,9-dihydroxy-
CC (5Z,11Z,14Z)-eicosatrienoate; Xref=Rhea:RHEA:44048,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:84025, ChEBI:CHEBI:84032;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:44049;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=11,12-epoxy-(5Z,8Z,14Z)-eicosatrienoate + H2O = 11,12-
CC dihydroxy-(5Z,8Z,14Z)-eicosatrienoate; Xref=Rhea:RHEA:44044,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:76625, ChEBI:CHEBI:84031;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:44045;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=14,15-epoxy-(5Z,8Z,11Z)-eicosatrienoate + H2O = 14,15-
CC dihydroxy-(5Z,8Z,11Z)-eicosatrienoate; Xref=Rhea:RHEA:44040,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:84024, ChEBI:CHEBI:84029;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:44041;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=9,10-epoxy-(12Z)-octadecenoate + H2O = 9,10-dihydroxy-(12Z)-
CC octadecenoate; Xref=Rhea:RHEA:44032, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:84023, ChEBI:CHEBI:84027;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:44033;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-tetradecanoyl-sn-glycerol 3-phosphate + H2O = 1-
CC tetradecanoyl-sn-glycerol + phosphate; Xref=Rhea:RHEA:53592,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:72683,
CC ChEBI:CHEBI:75536; Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53593;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-octadecanoyl-sn-glycero-3-phosphate + H2O = 1-octadecanoyl-
CC sn-glycerol + phosphate; Xref=Rhea:RHEA:53596, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:74565, ChEBI:CHEBI:75550;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53597;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phosphate +
CC H2O = 1-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycerol + phosphate;
CC Xref=Rhea:RHEA:53600, ChEBI:CHEBI:15377, ChEBI:CHEBI:34071,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:74938;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53601;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-hexadecanoyl-sn-glycero-3-phosphate + H2O = 1-hexadecanoyl-
CC sn-glycerol + phosphate; Xref=Rhea:RHEA:53604, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:57518, ChEBI:CHEBI:75542;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53605;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-(9Z-octadecenoyl)-sn-glycero-3-phosphate + H2O = 1-(9Z-
CC octadecenoyl)-sn-glycerol + phosphate; Xref=Rhea:RHEA:39835,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:74544,
CC ChEBI:CHEBI:75757; Evidence={ECO:0000250|UniProtKB:P34913};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39836;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(8S,9R)-epoxy-(5Z,11Z,14Z)-eicosatrienoate + H2O = (8S,9S)-
CC dihydroxy-(5Z,11Z,14Z)-eicosatrienoate; Xref=Rhea:RHEA:53972,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:131974, ChEBI:CHEBI:138002;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53973;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(11S,12R)-epoxy-(5Z,8Z,14Z)-eicosatrienoate + H2O = (11R,12R)-
CC dihydroxy-(5Z,8Z,14Z)-eicosatrienoate; Xref=Rhea:RHEA:53980,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:131969, ChEBI:CHEBI:138004;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53981;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(11S,12R)-epoxy-(5Z,8Z,14Z)-eicosatrienoate + H2O = (11S,12S)-
CC dihydroxy-(5Z,8Z,14Z)-eicosatrienoate; Xref=Rhea:RHEA:53984,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:131969, ChEBI:CHEBI:138005;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53985;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(14S,15R)-epoxy-(5Z,8Z,11Z)-eicosatrienoate + H2O = (14R,15R)-
CC dihydroxy-(5Z,8Z,11Z)-eicosatrienoate; Xref=Rhea:RHEA:53992,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:131964, ChEBI:CHEBI:138003;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53993;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(14S,15R)-epoxy-(5Z,8Z,11Z)-eicosatrienoate + H2O = (14S,15S)-
CC dihydroxy-(5Z,8Z,11Z)-eicosatrienoate; Xref=Rhea:RHEA:53996,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:131964, ChEBI:CHEBI:138006;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53997;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(11R,12S)-epoxy-(5Z,8Z,14Z)-eicosatrienoate + H2O = (11S,12S)-
CC dihydroxy-(5Z,8Z,14Z)-eicosatrienoate; Xref=Rhea:RHEA:54004,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:131970, ChEBI:CHEBI:138005;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54005;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(11R,12S)-epoxy-(5Z,8Z,14Z)-eicosatrienoate + H2O = (11R,12R)-
CC dihydroxy-(5Z,8Z,14Z)-eicosatrienoate; Xref=Rhea:RHEA:54000,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:131970, ChEBI:CHEBI:138004;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54001;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(8S,9R)-epoxy-(5Z,11Z,14Z)-eicosatrienoate + H2O = (8R,9R)-
CC dihydroxy-(5Z,11Z,14Z)-eicosatrienoate; Xref=Rhea:RHEA:54016,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:131974, ChEBI:CHEBI:138008;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54017;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(14R,15S)-epoxy-(5Z,8Z,11Z)-eicosatrienoate + H2O = (14R,15R)-
CC dihydroxy-(5Z,8Z,11Z)-eicosatrienoate; Xref=Rhea:RHEA:53976,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:131965, ChEBI:CHEBI:138003;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53977;
CC Evidence={ECO:0000250|UniProtKB:P34914};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P34913};
CC -!- ACTIVITY REGULATION: Inhibited by 1-(1-acetylpiperidin-4-yl)-3-(4-
CC (trifl uoromethoxy)phenyl)urea (TPAU), 1-cyclohexyl-3-dodecylurea
CC (CDU), 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), 1-((3S, 5S,
CC 7S)-adamantan-1-yl)-3-(5-(2-(2-ethoxyethoxy) ethoxy)pentyl)urea (AEPU),
CC N-adamantyl-N[']-cyclohexyl urea (ACU), 4-(((1S, 4S)-4-(3-((3S, 5S,
CC 7S)-adamantan-1-yl) ureido)cyclohexyl)oxy)benzoic acid (c-AUCB), 4-
CC (((1R, 4R)-4-(3-((3S, 5S, 7S)-adamantan-1-
CC yl)ureido)cyclohexyl)oxy)benzoic acid (t-AUCB), 4-(((1R, 4R)-4-(3-
CC (4(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid (t-TAUCB)
CC and to a lesser extent by 8-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido)
CC octanoic acid (AUOA) (PubMed:21217101). Phosphatase activity is
CC inhibited by dodecyl-phosphate, phospholipids such as phospho-
CC lysophosphatidic acids and fatty acids such as palmitic acid and lauric
CC acid (By similarity). {ECO:0000250|UniProtKB:P34913,
CC ECO:0000269|PubMed:21217101}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.235 mM for p-nitrophenyl phosphate
CC {ECO:0000269|PubMed:12574508};
CC KM=4.6 uM for 8-hydroxy-(11S,12S)-epoxy-(5Z,9E,14Z)-eicosatrienoate
CC {ECO:0000269|PubMed:21217101};
CC KM=14.7 uM for 10-hydroxy-(11S,12S)-epoxy- (5Z,8Z,14Z)-
CC eicosatrienoate {ECO:0000269|PubMed:21217101};
CC Vmax=1450 nmol/min/mg enzyme {ECO:0000269|PubMed:12574508};
CC Vmax=1739 nmol/min/mg enzyme with 8-hydroxy-(11S,12S)-epoxy-
CC (5Z,9E,14Z)-eicosatrienoate as substrate
CC {ECO:0000269|PubMed:21217101};
CC Vmax=550 nmol/min/mg enzyme with 10-hydroxy-(11S,12S)-
CC epoxy- (5Z,8Z,14Z)-eicosatrienoate as substrate
CC {ECO:0000269|PubMed:21217101};
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Peroxisome.
CC -!- INDUCTION: By compounds that cause peroxisome proliferation such as
CC clofibrate, tiadenol and fenofibrate.
CC -!- DOMAIN: The N-terminal domain has phosphatase activity. The C-terminal
CC domain has epoxide hydrolase activity.
CC -!- PTM: The covalent modification of cysteine by 15-deoxy-Delta12,14-
CC prostaglandin-J2 is autocatalytic and reversible. It may occur as an
CC alternative to other cysteine modifications, such as S-nitrosylation
CC and S-palmitoylation (By similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the AB hydrolase superfamily. Epoxide hydrolase
CC family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; X65083; CAA46211.1; -; mRNA.
DR EMBL; X60328; CAA42898.1; -; mRNA.
DR PIR; A47503; A47503.
DR RefSeq; NP_075225.1; NM_022936.1.
DR AlphaFoldDB; P80299; -.
DR SMR; P80299; -.
DR STRING; 10116.ENSRNOP00000023385; -.
DR BindingDB; P80299; -.
DR ChEMBL; CHEMBL5669; -.
DR GuidetoPHARMACOLOGY; 2970; -.
DR SwissLipids; SLP:000001643; -.
DR ESTHER; ratno-hyes; Epoxide_hydrolase.
DR MEROPS; S33.973; -.
DR CarbonylDB; P80299; -.
DR iPTMnet; P80299; -.
DR PhosphoSitePlus; P80299; -.
DR PaxDb; P80299; -.
DR PRIDE; P80299; -.
DR GeneID; 65030; -.
DR KEGG; rno:65030; -.
DR UCSC; RGD:620732; rat.
DR CTD; 2053; -.
DR RGD; 620732; Ephx2.
DR eggNOG; KOG3085; Eukaryota.
DR eggNOG; KOG4178; Eukaryota.
DR InParanoid; P80299; -.
DR OrthoDB; 616687at2759; -.
DR PhylomeDB; P80299; -.
DR BRENDA; 3.3.2.10; 5301.
DR Reactome; R-RNO-2142670; Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET).
DR Reactome; R-RNO-9018682; Biosynthesis of maresins.
DR Reactome; R-RNO-9033241; Peroxisomal protein import.
DR SABIO-RK; P80299; -.
DR PRO; PR:P80299; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0005777; C:peroxisome; IDA:RGD.
DR GO; GO:0033885; F:10-hydroxy-9-(phosphonooxy)octadecanoate phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0004301; F:epoxide hydrolase activity; IDA:UniProtKB.
DR GO; GO:0016787; F:hydrolase activity; IBA:GO_Central.
DR GO; GO:0042577; F:lipid phosphatase activity; ISS:UniProtKB.
DR GO; GO:0052642; F:lysophosphatidic acid phosphatase activity; ISS:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IMP:RGD.
DR GO; GO:0016791; F:phosphatase activity; IDA:RGD.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0015643; F:toxic substance binding; ISO:RGD.
DR GO; GO:0042632; P:cholesterol homeostasis; ISO:RGD.
DR GO; GO:0016311; P:dephosphorylation; ISO:RGD.
DR GO; GO:0097176; P:epoxide metabolic process; IDA:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IMP:RGD.
DR GO; GO:0043651; P:linoleic acid metabolic process; IMP:RGD.
DR GO; GO:0046839; P:phospholipid dephosphorylation; ISS:UniProtKB.
DR GO; GO:0045777; P:positive regulation of blood pressure; IMP:RGD.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:RGD.
DR GO; GO:0002539; P:prostaglandin production involved in inflammatory response; IMP:RGD.
DR GO; GO:0090181; P:regulation of cholesterol metabolic process; ISO:RGD.
DR GO; GO:0009636; P:response to toxic substance; IEA:UniProtKB-KW.
DR GO; GO:0019233; P:sensory perception of pain; IMP:RGD.
DR GO; GO:0046272; P:stilbene catabolic process; ISO:RGD.
DR Gene3D; 1.10.150.240; -; 1.
DR Gene3D; 3.40.50.1000; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR000073; AB_hydrolase_1.
DR InterPro; IPR000639; Epox_hydrolase-like.
DR InterPro; IPR036412; HAD-like_sf.
DR InterPro; IPR006439; HAD-SF_hydro_IA.
DR InterPro; IPR011945; HAD-SF_ppase_IA/epoxid_hydro_N.
DR InterPro; IPR041492; HAD_2.
DR InterPro; IPR023214; HAD_sf.
DR InterPro; IPR023198; PGP-like_dom2.
DR Pfam; PF00561; Abhydrolase_1; 1.
DR Pfam; PF13419; HAD_2; 1.
DR PRINTS; PR00111; ABHYDROLASE.
DR PRINTS; PR00412; EPOXHYDRLASE.
DR SUPFAM; SSF53474; SSF53474; 1.
DR SUPFAM; SSF56784; SSF56784; 1.
DR TIGRFAMs; TIGR02247; HAD-1A3-hyp; 1.
DR TIGRFAMs; TIGR01509; HAD-SF-IA-v3; 1.
PE 1: Evidence at protein level;
KW Acetylation; Aromatic hydrocarbons catabolism; Cytoplasm; Detoxification;
KW Direct protein sequencing; Hydrolase; Lipid metabolism; Lipoprotein;
KW Magnesium; Metal-binding; Multifunctional enzyme; Peroxisome;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1..554
FT /note="Bifunctional epoxide hydrolase 2"
FT /id="PRO_0000084114"
FT DOMAIN 257..530
FT /note="AB hydrolase-1"
FT /evidence="ECO:0000255"
FT REGION 1..224
FT /note="Phosphatase"
FT REGION 233..554
FT /note="Epoxide hydrolase"
FT MOTIF 552..554
FT /note="Microbody targeting signal"
FT /evidence="ECO:0000255"
FT ACT_SITE 333
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:8626766"
FT ACT_SITE 465
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P34913"
FT ACT_SITE 523
FT /note="Proton acceptor"
FT /evidence="ECO:0000269|PubMed:8626766"
FT BINDING 9
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P34913"
FT BINDING 11
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P34913"
FT BINDING 123..124
FT /ligand="phosphate"
FT /ligand_id="ChEBI:CHEBI:43474"
FT /evidence="ECO:0000250|UniProtKB:P34913"
FT BINDING 185
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P34913"
FT BINDING 381
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P34913"
FT MOD_RES 55
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT MOD_RES 176
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT MOD_RES 176
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT MOD_RES 191
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT MOD_RES 215
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT MOD_RES 368
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT MOD_RES 420
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT MOD_RES 454
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT MOD_RES 504
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT MOD_RES 553
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:P34914"
FT LIPID 521
FT /note="S-(15-deoxy-Delta12,14-prostaglandin J2-9-
FT yl)cysteine"
FT /evidence="ECO:0000250"
FT MUTAGEN 332
FT /note="H->Q: Reduces epoxide hydrolase activity by 95%."
FT MUTAGEN 333
FT /note="D->G: Loss of epoxide hydrolase activity."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 334
FT /note="W->F: Slight reduction of epoxide hydrolase
FT activity."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 433
FT /note="E->Q,K: Slight loss of epoxide hydrolase activity."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 434
FT /note="D->Y: Slight loss of epoxide hydrolase activity."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 493
FT /note="E->Q,K: No effect."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 495
FT /note="D->H: Loss of epoxide hydrolase activity."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 517
FT /note="H->Y: Reduces epoxide hydrolase activity by 50%.
FT Loss of activity; when associated with Y-521."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 521
FT /note="C->Y: Loss of epoxide hydrolase activity; when
FT associated with Y-517."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 523
FT /note="H->D,N,Y: Loss of epoxide hydrolase activity."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 526
FT /note="Q->H: Reduces epoxide hydrolase activity by 80%;
FT when associated with T-542."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 540
FT /note="W->L,S: Reduces epoxide hydrolase activity by 95%."
FT /evidence="ECO:0000269|PubMed:8626766"
FT MUTAGEN 542
FT /note="K->T: Reduces epoxide hydrolase activity by 80%;
FT when associated with H-526."
FT /evidence="ECO:0000269|PubMed:8626766"
SQ SEQUENCE 554 AA; 62340 MW; 145FDCA53F582138 CRC64;
MALRVAAFDL DGVLALPSIA GVLRHTEEAL ALPRDFLLGA FQMKFPEGPT EQLMKGKITF
SQWVPLMDES CRKSSKACGA SLPENFSISE IFSQAMAARS INRPMLQAAA ALKKKGFTTC
IVTNNWLDDS DKRDILAQMM CELSQHFDFL IESCQVGMIK PEPQIYKFVL DTLKAKPNEV
VFLDDFGSNL KPARDMGMVT ILVRDTASAL RELEKVTGTQ FPEAPLPVPC SPNDVSHGYV
TVKPGIRLHF VEMGSGPAIC LCHGFPESWF SWRYQIPALA QAGFRVLAID MKGYGDSSSP
PEIEEYAMEL LCEEMVTFLN KLGIPQAVFI GHDWAGVLVW NMALFHPERV RAVASLNTPL
MPPNPEVSPM EVIRSIPVFN YQLYFQEPGV AEAELEKNMS RTFKSFFRTS DDMGLLTVNK
ATEMGGILVG TPEDPKVSKI TTEEEIEYYI QQFKKSGFRG PLNWYRNTER NWKWSCKALG
RKILVPALMV TAEKDIVLRP EMSKNMENWI PFLKRGHIED CGHWTQIEKP AEVNQILIKW
LKTEIQNPSV TSKI
