HYEP_RAT
ID HYEP_RAT Reviewed; 455 AA.
AC P07687;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-APR-1988, sequence version 1.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=Epoxide hydrolase 1 {ECO:0000305};
DE EC=3.3.2.9 {ECO:0000269|PubMed:9854022};
DE AltName: Full=Epoxide hydratase;
DE AltName: Full=Microsomal epoxide hydrolase;
DE Short=mEH {ECO:0000305};
GN Name=Ephx1 {ECO:0000312|RGD:2557}; Synonyms=Eph-1;
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 [GENOMIC DNA].
RX PubMed=3032949; DOI=10.1016/s0021-9258(18)45663-3;
RA Falany C.N., McQuiddy P., Kasper C.B.;
RT "Structure and organization of the microsomal xenobiotic epoxide hydrolase
RT gene.";
RL J. Biol. Chem. 262:5924-5930(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3755318; DOI=10.1016/0003-9861(86)90408-x;
RA Porter T.D., Beck T.W., Kasper C.B.;
RT "Complementary DNA and amino acid sequence of rat liver microsomal,
RT xenobiotic epoxide hydrolase.";
RL Arch. Biochem. Biophys. 248:121-129(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pituitary;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP SUBCELLULAR LOCATION, AND TOPOLOGY.
RX PubMed=9245728; DOI=10.1006/bbrc.1997.7044;
RA Holler R., Arand M., Mecky A., Oesch F., Friedberg T., Meckey A.;
RT "The membrane anchor of microsomal epoxide hydrolase from human, rat, and
RT rabbit displays an unexpected membrane topology.";
RL Biochem. Biophys. Res. Commun. 236:754-759(1997).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR
RP LOCATION, ACTIVE SITE, AND MUTAGENESIS OF ASP-226; GLU-388; GLU-404;
RP GLU-410 AND HIS-431.
RX PubMed=9854022; DOI=10.1042/bj3370037;
RA Arand M., Mueller F., Mecky A., Hinz W., Urban P., Pompon D., Kellner R.,
RA Oesch F.;
RT "Catalytic triad of microsomal epoxide hydrolase: replacement of Glu404
RT with Asp leads to a strongly increased turnover rate.";
RL Biochem. J. 337:37-43(1999).
RN [6]
RP METHYLATION AT ARG-295, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=15047867; DOI=10.1091/mbc.e04-02-0101;
RA Wu C.C., MacCoss M.J., Mardones G., Finnigan C., Mogelsvang S.,
RA Yates J.R. III, Howell K.E.;
RT "Organellar proteomics reveals Golgi arginine dimethylation.";
RL Mol. Biol. Cell 15:2907-2919(2004).
CC -!- FUNCTION: Biotransformation enzyme that catalyzes the hydrolysis of
CC arene and aliphatic epoxides to less reactive and more water soluble
CC dihydrodiols by the trans addition of water. May play a role in the
CC metabolism of endogenous lipids such as epoxide-containing fatty acids.
CC Metabolizes the abundant endocannabinoid 2-arachidonoylglycerol (2-AG)
CC to free arachidonic acid (AA) and glycerol (By similarity).
CC {ECO:0000250|UniProtKB:P07099, ECO:0000269|PubMed:9854022}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cis-stilbene oxide + H2O = (1R,2R)-hydrobenzoin;
CC Xref=Rhea:RHEA:23900, ChEBI:CHEBI:15377, ChEBI:CHEBI:50004,
CC ChEBI:CHEBI:50014; EC=3.3.2.9; Evidence={ECO:0000269|PubMed:9854022};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23901;
CC Evidence={ECO:0000305|PubMed:9854022};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-(4-methoxyphenyl)-N-methyl-N-[(3-methyloxetan-3-
CC yl)methyl]methanamine + H2O = 2-{[(4-
CC methoxybenzyl)(methyl)amino]methyl}-2-methylpropane-1,3-diol;
CC Xref=Rhea:RHEA:55764, ChEBI:CHEBI:15377, ChEBI:CHEBI:139161,
CC ChEBI:CHEBI:139164; EC=3.3.2.9;
CC Evidence={ECO:0000269|PubMed:9854022};
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:P07099};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:44049;
CC Evidence={ECO:0000250|UniProtKB:P07099};
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:P07099};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:44045;
CC Evidence={ECO:0000250|UniProtKB:P07099};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol + H2O =
CC (5Z,8Z,11Z,14Z)-eicosatetraenoate + glycerol + H(+);
CC Xref=Rhea:RHEA:26132, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17754, ChEBI:CHEBI:32395, ChEBI:CHEBI:52392;
CC Evidence={ECO:0000250|UniProtKB:P07099};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:26133;
CC Evidence={ECO:0000250|UniProtKB:P07099};
CC -!- ACTIVITY REGULATION: Inhibited by 10-hydroxystearamide and methoxy-
CC arachidonyl fluorophosphate. {ECO:0000250|UniProtKB:P07099}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=87.5 uM for styrene 7,8-oxide {ECO:0000269|PubMed:9854022};
CC KM=6.8 uM for 9,10-epoxystearic acid {ECO:0000269|PubMed:9854022};
CC Vmax=365 nmol/min/mg enzyme with styrene 7,8-oxide as substrate
CC {ECO:0000269|PubMed:9854022};
CC Vmax=10 nmol/min/mg enzyme with 9,10-epoxystearic acid as substrate
CC {ECO:0000269|PubMed:9854022};
CC -!- SUBCELLULAR LOCATION: Microsome membrane {ECO:0000269|PubMed:9854022};
CC Single-pass type III membrane protein {ECO:0000269|PubMed:9245728}.
CC Endoplasmic reticulum membrane {ECO:0000305}; Single-pass type III
CC membrane protein {ECO:0000269|PubMed:9245728}.
CC -!- SIMILARITY: Belongs to the peptidase S33 family. {ECO:0000305}.
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DR EMBL; M15345; AAA41585.1; -; Genomic_DNA.
DR EMBL; M15339; AAA41585.1; JOINED; Genomic_DNA.
DR EMBL; M15340; AAA41585.1; JOINED; Genomic_DNA.
DR EMBL; M15341; AAA41585.1; JOINED; Genomic_DNA.
DR EMBL; M15342; AAA41585.1; JOINED; Genomic_DNA.
DR EMBL; M15343; AAA41585.1; JOINED; Genomic_DNA.
DR EMBL; M15344; AAA41585.1; JOINED; Genomic_DNA.
DR EMBL; M26125; AAA42350.1; -; mRNA.
DR EMBL; BC061568; AAH61568.1; -; mRNA.
DR PIR; A26732; A26081.
DR RefSeq; NP_001029262.1; NM_001034090.3.
DR RefSeq; NP_036976.2; NM_012844.3.
DR AlphaFoldDB; P07687; -.
DR SMR; P07687; -.
DR IntAct; P07687; 3.
DR STRING; 10116.ENSRNOP00000004780; -.
DR ChEMBL; CHEMBL2299; -.
DR ESTHER; ratno-hyep; Epoxide_hydrolase.
DR MEROPS; S33.971; -.
DR iPTMnet; P07687; -.
DR PhosphoSitePlus; P07687; -.
DR jPOST; P07687; -.
DR PaxDb; P07687; -.
DR PRIDE; P07687; -.
DR Ensembl; ENSRNOT00000004780; ENSRNOP00000004780; ENSRNOG00000003515.
DR GeneID; 25315; -.
DR KEGG; rno:25315; -.
DR UCSC; RGD:2557; rat.
DR CTD; 2052; -.
DR RGD; 2557; Ephx1.
DR eggNOG; KOG2565; Eukaryota.
DR GeneTree; ENSGT00390000002210; -.
DR InParanoid; P07687; -.
DR OMA; SAARFYW; -.
DR OrthoDB; 898504at2759; -.
DR PhylomeDB; P07687; -.
DR TreeFam; TF313813; -.
DR BRENDA; 3.3.2.9; 5301.
DR Reactome; R-RNO-211945; Phase I - Functionalization of compounds.
DR SABIO-RK; P07687; -.
DR PRO; PR:P07687; -.
DR Proteomes; UP000002494; Chromosome 13.
DR Bgee; ENSRNOG00000003515; Expressed in liver and 19 other tissues.
DR Genevisible; P07687; RN.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0033961; F:cis-stilbene-oxide hydrolase activity; IMP:UniProtKB.
DR GO; GO:0019899; F:enzyme binding; IPI:RGD.
DR GO; GO:0004301; F:epoxide hydrolase activity; IDA:RGD.
DR GO; GO:0019369; P:arachidonic acid metabolic process; ISS:UniProtKB.
DR GO; GO:0019439; P:aromatic compound catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0006725; P:cellular aromatic compound metabolic process; ISO:RGD.
DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IEP:RGD.
DR GO; GO:0071310; P:cellular response to organic substance; IEP:RGD.
DR GO; GO:0034312; P:diol biosynthetic process; IDA:RGD.
DR GO; GO:0097176; P:epoxide metabolic process; IDA:UniProtKB.
DR GO; GO:0001889; P:liver development; IEP:RGD.
DR GO; GO:0014070; P:response to organic cyclic compound; ISO:RGD.
DR GO; GO:0009636; P:response to toxic substance; IEA:UniProtKB-KW.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR000639; Epox_hydrolase-like.
DR InterPro; IPR010497; Epoxide_hydro_N.
DR InterPro; IPR016292; Epoxide_hydrolase.
DR Pfam; PF06441; EHN; 1.
DR PIRSF; PIRSF001112; Epoxide_hydrolase; 1.
DR PRINTS; PR00412; EPOXHYDRLASE.
DR SUPFAM; SSF53474; SSF53474; 1.
PE 1: Evidence at protein level;
KW Acetylation; Aromatic hydrocarbons catabolism; Detoxification;
KW Endoplasmic reticulum; Hydrolase; Lipid metabolism; Membrane; Methylation;
KW Microsome; Reference proteome; Signal-anchor; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..455
FT /note="Epoxide hydrolase 1"
FT /id="PRO_0000080859"
FT TRANSMEM 1..21
FT /note="Helical; Signal-anchor for type III membrane
FT protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 22..455
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:9245728"
FT ACT_SITE 226
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:9854022"
FT ACT_SITE 374
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P34913"
FT ACT_SITE 431
FT /note="Proton acceptor"
FT /evidence="ECO:0000305|PubMed:9854022"
FT MOD_RES 295
FT /note="Dimethylated arginine"
FT /evidence="ECO:0000269|PubMed:15047867"
FT MOD_RES 439
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9D379"
FT MUTAGEN 226
FT /note="D->G,N,S: Loss of catalytic activity and loss of
FT covalent substrate binding."
FT /evidence="ECO:0000269|PubMed:9854022"
FT MUTAGEN 388
FT /note="E->A: Slight decrease in catalytic activity."
FT /evidence="ECO:0000269|PubMed:9854022"
FT MUTAGEN 404
FT /note="E->A: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:9854022"
FT MUTAGEN 404
FT /note="E->D: Increases catalytic activity."
FT /evidence="ECO:0000269|PubMed:9854022"
FT MUTAGEN 410
FT /note="E->A: Slight decrease in catalytic activity."
FT /evidence="ECO:0000269|PubMed:9854022"
FT MUTAGEN 431
FT /note="H->Q: Loss of catalytic activity and severe
FT reduction in substrate binding."
FT /evidence="ECO:0000269|PubMed:9854022"
FT CONFLICT 348..389
FT /note="Missing (in Ref. 1; AAA41585)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 455 AA; 52582 MW; 437A15BBCD6861FA CRC64;
MWLELVLASL LGFVIYWFVS RDKEETLPLG DGWWGPGSKP SAKEDESIRP FKVETSDEEI
KDLHQRIDRF RASPPLEGSR FHYGFNSNYM KKVVSYWRNE FDWRKQVEIL NQYPHFKTKI
EGLDIHFIHV KPPQLPSGRT PKPLLMVHGW PGSFYEFYKI IPLLTDPKSH GLSDEHVFEV
ICPSIPGYGY SEASSKKGLN SVATARIFYK LMTRLGFQKF YIQGGDWGSL ICTNMAQMVP
NHVKGLHLNM AFISRSFYTM TPLLGQRFGR FLGYTEKDIE LLYPYKEKVF YSIMRESGYL
HIQATKPDTV GCALNDSPVG LAAYILEKFS TWTKSEYREL EDGGLERKFS LDDLLVNIMI
YWTTGTIVSS QRYYKENLGQ GIMVHKHEGM KVFVPTGFSA FPSELLHAPE KWVKVKYPKL
ISYSYMERGG HFAAFEEPKL LAQDIRKFVS LAELQ
