VKOR1_RAT
ID VKOR1_RAT Reviewed; 161 AA.
AC Q6TEK4;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 123.
DE RecName: Full=Vitamin K epoxide reductase complex subunit 1;
DE EC=1.17.4.4 {ECO:0000269|PubMed:15640149, ECO:0000269|PubMed:23772386, ECO:0000269|PubMed:23928358};
DE AltName: Full=Vitamin K1 2,3-epoxide reductase subunit 1;
GN Name=Vkorc1;
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=14765194; DOI=10.1038/nature02214;
RA Rost S., Fregin A., Ivaskevicius V., Conzelmann E., Hoertnagel K.,
RA Pelz H.-J., Lappegard K., Seifried E., Scharrer I., Tuddenham E.G.D.,
RA Mueller C.R., Strom T.M., Oldenburg J.;
RT "Mutations in VKORC1 cause warfarin resistance and multiple coagulation
RT factor deficiency type 2.";
RL Nature 427:537-541(2004).
RN [2]
RP IDENTIFICATION.
RX PubMed=14765195; DOI=10.1038/nature02254;
RA Li T., Chang C.-Y., Jin D.-Y., Lin P.-J., Khvorova A., Stafford D.W.;
RT "Identification of the gene for vitamin K epoxide reductase.";
RL Nature 427:541-544(2004).
RN [3]
RP MUTAGENESIS OF CYS-132 AND CYS-135, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=15640149; DOI=10.1074/jbc.m413982200;
RA Wajih N., Sane D.C., Hutson S.M., Wallin R.;
RT "Engineering of a recombinant vitamin K-dependent (gamma)-carboxylation
RT system with enhanced (gamma)-carboxyglutamic acid forming capacity:
RT evidence for a functional CxxC redox center in the system.";
RL J. Biol. Chem. 280:10540-10547(2005).
RN [4]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP AND CHARACTERIZATION OF VARIANTS GLN-120; GLN-128; CYS-139; PHE-139 AND
RP SER-139.
RX PubMed=23772386; DOI=10.1016/j.fob.2013.02.001;
RA Matagrin B., Hodroge A., Montagut-Romans A., Andru J., Fourel I., Besse S.,
RA Benoit E., Lattard V.;
RT "New insights into the catalytic mechanism of vitamin K epoxide reductase
RT (VKORC1) - The catalytic properties of the major mutations of rVKORC1
RT explain the biological cost associated to mutations.";
RL FEBS Open Bio 3:144-150(2013).
RN [5]
RP TISSUE SPECIFICITY, CATALYTIC ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR
RP LOCATION, AND FUNCTION.
RX PubMed=23928358; DOI=10.1074/jbc.m113.457119;
RA Hammed A., Matagrin B., Spohn G., Prouillac C., Benoit E., Lattard V.;
RT "VKORC1L1, an enzyme rescuing the vitamin K 2,3-epoxide reductase activity
RT in some extrahepatic tissues during anticoagulation therapy.";
RL J. Biol. Chem. 288:28733-28742(2013).
RN [6]
RP VARIANTS GLN-120; GLN-128; CYS-139; PHE-139 AND SER-139, ACTIVITY
RP REGULATION, AND FUNCTION.
RX PubMed=15879509; DOI=10.1534/genetics.104.040360;
RA Pelz H.J., Rost S., Hunerberg M., Fregin A., Heiberg A.C., Baert K.,
RA MacNicoll A.D., Prescott C.V., Walker A.S., Oldenburg J., Muller C.R.;
RT "The genetic basis of resistance to anticoagulants in rodents.";
RL Genetics 170:1839-1847(2005).
CC -!- FUNCTION: Involved in vitamin K metabolism. Catalytic subunit of the
CC vitamin K epoxide reductase (VKOR) complex which reduces inactive
CC vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for
CC the gamma-carboxylation of various proteins, including clotting
CC factors, and is required for normal blood coagulation, but also for
CC normal bone development. {ECO:0000269|PubMed:15640149,
CC ECO:0000269|PubMed:15879509, ECO:0000269|PubMed:23772386,
CC ECO:0000269|PubMed:23928358}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-disulfide + H2O + phylloquinone = 2,3-
CC epoxyphylloquinone + [protein]-dithiol; Xref=Rhea:RHEA:13817,
CC Rhea:RHEA-COMP:10593, Rhea:RHEA-COMP:10594, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15759, ChEBI:CHEBI:18067, ChEBI:CHEBI:29950,
CC ChEBI:CHEBI:50058; EC=1.17.4.4;
CC Evidence={ECO:0000269|PubMed:15640149, ECO:0000269|PubMed:23772386,
CC ECO:0000269|PubMed:23928358};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[protein]-disulfide + phylloquinol = [protein]-dithiol +
CC phylloquinone; Xref=Rhea:RHEA:57744, Rhea:RHEA-COMP:10593, Rhea:RHEA-
CC COMP:10594, ChEBI:CHEBI:18067, ChEBI:CHEBI:28433, ChEBI:CHEBI:29950,
CC ChEBI:CHEBI:50058; EC=1.17.4.4;
CC Evidence={ECO:0000269|PubMed:15640149, ECO:0000269|PubMed:23772386,
CC ECO:0000269|PubMed:23928358};
CC -!- ACTIVITY REGULATION: Inhibited by warfarin (coumadin).
CC {ECO:0000269|PubMed:15879509, ECO:0000269|PubMed:23772386,
CC ECO:0000269|PubMed:23928358}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:23772386, ECO:0000269|PubMed:23928358}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:23772386,
CC ECO:0000269|PubMed:23928358}.
CC -!- TISSUE SPECIFICITY: Highly expressed in liver. Detected at lower levels
CC in lung, kidney and testis. {ECO:0000269|PubMed:23928358}.
CC -!- DOMAIN: The number of transmembrane domains and the membrane topology
CC are controversial; supporting evidence is available both for models
CC with three transmembrane domains and four transmembrane domains.
CC {ECO:0000250}.
CC -!- MISCELLANEOUS: The location of two cysteine active-site residues within
CC a proposed transmembrane is consistent both with the known hydrophobic
CC environment of the thiol redox site of the enzyme and with the
CC lipophilicity of vitamin K and warfarin (coumadin).
CC -!- SIMILARITY: Belongs to the VKOR family. {ECO:0000305}.
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DR EMBL; AY423047; AAR82917.1; -; mRNA.
DR RefSeq; NP_976080.1; NM_203335.2.
DR AlphaFoldDB; Q6TEK4; -.
DR SMR; Q6TEK4; -.
DR STRING; 10116.ENSRNOP00000063977; -.
DR BindingDB; Q6TEK4; -.
DR ChEMBL; CHEMBL4105870; -.
DR GuidetoPHARMACOLOGY; 2645; -.
DR PaxDb; Q6TEK4; -.
DR PRIDE; Q6TEK4; -.
DR Ensembl; ENSRNOT00000073596; ENSRNOP00000063977; ENSRNOG00000050828.
DR GeneID; 309004; -.
DR KEGG; rno:309004; -.
DR UCSC; RGD:1303107; rat.
DR CTD; 79001; -.
DR RGD; 1303107; Vkorc1.
DR eggNOG; ENOG502S4E7; Eukaryota.
DR GeneTree; ENSGT00940000157421; -.
DR HOGENOM; CLU_105471_0_0_1; -.
DR InParanoid; Q6TEK4; -.
DR OMA; YVINFAL; -.
DR OrthoDB; 1611169at2759; -.
DR PhylomeDB; Q6TEK4; -.
DR TreeFam; TF328467; -.
DR BRENDA; 1.17.4.4; 5301.
DR Reactome; R-RNO-6806664; Metabolism of vitamin K.
DR PRO; PR:Q6TEK4; -.
DR Proteomes; UP000002494; Chromosome 1.
DR Bgee; ENSRNOG00000050828; Expressed in pancreas and 20 other tissues.
DR ExpressionAtlas; Q6TEK4; baseline and differential.
DR Genevisible; Q6TEK4; 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:RGD.
DR GO; GO:0048038; F:quinone binding; IEA:UniProtKB-KW.
DR GO; GO:0047058; F:vitamin-K-epoxide reductase (warfarin-insensitive) activity; IDA:RGD.
DR GO; GO:0047057; F:vitamin-K-epoxide reductase (warfarin-sensitive) activity; ISO:RGD.
DR GO; GO:0007596; P:blood coagulation; ISS:UniProtKB.
DR GO; GO:0060348; P:bone development; ISS:UniProtKB.
DR GO; GO:0017187; P:peptidyl-glutamic acid carboxylation; ISS:UniProtKB.
DR GO; GO:0050820; P:positive regulation of coagulation; ISO:RGD.
DR GO; GO:0030193; P:regulation of blood coagulation; IMP:RGD.
DR GO; GO:0046677; P:response to antibiotic; IDA:RGD.
DR GO; GO:0014070; P:response to organic cyclic compound; IDA:RGD.
DR GO; GO:0010243; P:response to organonitrogen compound; IDA:RGD.
DR GO; GO:0042373; P:vitamin K metabolic process; ISS:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; ISO:RGD.
DR CDD; cd12917; VKOR_euk; 1.
DR Gene3D; 1.20.1440.130; -; 1.
DR InterPro; IPR012932; VKOR.
DR InterPro; IPR038354; VKOR_sf.
DR InterPro; IPR042406; VKORC1/VKORC1L1.
DR PANTHER; PTHR14519; PTHR14519; 1.
DR Pfam; PF07884; VKOR; 1.
DR SMART; SM00756; VKc; 1.
PE 1: Evidence at protein level;
KW Disulfide bond; Endoplasmic reticulum; Membrane; Oxidoreductase; Quinone;
KW Redox-active center; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..161
FT /note="Vitamin K epoxide reductase complex subunit 1"
FT /id="PRO_0000191670"
FT TOPO_DOM 1..10
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 11..31
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 32..74
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 75..94
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 95..100
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 101..123
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 124..126
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 127..149
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 150..161
FT /note="Lumenal"
FT /evidence="ECO:0000250"
FT DISULFID 132..135
FT /note="Redox-active"
FT VARIANT 120
FT /note="L -> Q (identified in warfarin-resistant animals;
FT strongly reduces enzyme activity; abolishes inhibition by
FT warfarin)"
FT /evidence="ECO:0000269|PubMed:15879509,
FT ECO:0000269|PubMed:23772386"
FT VARIANT 128
FT /note="L -> Q (identified in warfarin-resistant animals;
FT moderately reduces enzyme activity; decreases inhibition by
FT warfarin)"
FT /evidence="ECO:0000269|PubMed:15879509,
FT ECO:0000269|PubMed:23772386"
FT VARIANT 139
FT /note="Y -> C (identified in warfarin-resistant animals;
FT strongly reduces enzyme activity; abolishes inhibition by
FT warfarin)"
FT /evidence="ECO:0000269|PubMed:15879509,
FT ECO:0000269|PubMed:23772386"
FT VARIANT 139
FT /note="Y -> F (identified in warfarin-resistant animals;
FT strongly reduces enzyme activity; abolishes inhibition by
FT warfarin)"
FT /evidence="ECO:0000269|PubMed:15879509,
FT ECO:0000269|PubMed:23772386"
FT VARIANT 139
FT /note="Y -> S (identified in warfarin-resistant animals;
FT strongly reduces enzyme activity; abolishes inhibition by
FT warfarin)"
FT /evidence="ECO:0000269|PubMed:15879509,
FT ECO:0000269|PubMed:23772386"
FT MUTAGEN 132
FT /note="C->S: Loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:15640149"
FT MUTAGEN 135
FT /note="C->S: Loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:15640149"
SQ SEQUENCE 161 AA; 17783 MW; BBCE9897B00807DD CRC64;
MGTTWRSPGR LRLALCLAGL ALSLYALHVK AARARNEDYR ALCDVGTAIS CSRVFSSRWG
RGFGLVEHVL GADSILNQSN SIFGCMFYTI QLLLGCLRGR WASILLILSS LVSVAGSLYL
AWILFFVLYD FCIVCITTYA INAGLMLLSF QKVPEHKVKK P
