VKOR1_HUMAN
ID VKOR1_HUMAN Reviewed; 163 AA.
AC Q9BQB6; A6NIQ6; B2R4Z6; Q6UX90; Q7Z2R4;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Vitamin K epoxide reductase complex subunit 1;
DE EC=1.17.4.4 {ECO:0000269|PubMed:15879509, ECO:0000269|PubMed:16270630, ECO:0000269|PubMed:20978134, ECO:0000269|PubMed:22923610};
DE AltName: Full=Vitamin K1 2,3-epoxide reductase subunit 1;
GN Name=VKORC1; Synonyms=VKOR; ORFNames=MSTP134, MSTP576, UNQ308/PRO351;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION,
RP TISSUE SPECIFICITY, VARIANTS CMRES LEU-29; ALA-45; GLY-58 AND ARG-128, AND
RP VARIANT VKCFD2 TRP-98.
RC TISSUE=Kidney;
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 NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Aorta;
RA Liu B., Qin B.M., Sheng H., Zhao B., Liu Y.Q., Wang X.Y., Zhang Q.,
RA Song L., Lu H., Xu H.S., Zheng W.Y., Gong J., Wang Y.B., Liu Y.Q.,
RA Zhang C.N., Shi Y., Wang W., Zhang Z., Yang X., Han Y., Chen J.Z.,
RA Liu B.H., Hui R.T.;
RL Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 44-163 (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [10]
RP POTENTIAL REDOX-ACTIVE SITE.
RX PubMed=15276181; DOI=10.1016/j.tibs.2004.04.004;
RA Goodstadt L., Ponting C.P.;
RT "Vitamin K epoxide reductase: homology, active site and catalytic
RT mechanism.";
RL Trends Biochem. Sci. 29:289-292(2004).
RN [11]
RP MUTAGENESIS OF ARG-35; SER-56; LEU-120; LEU-128 AND TYR-139, CATALYTIC
RP ACTIVITY, ACTIVITY 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).
RN [12]
RP TOPOLOGY, AND SUBCELLULAR LOCATION.
RX PubMed=15716279; DOI=10.1074/jbc.m500765200;
RA Tie J.-K., Nicchitta C., von Heijne G., Stafford D.W.;
RT "Membrane topology mapping of vitamin K epoxide reductase by in vitro
RT translation/cotranslocation.";
RL J. Biol. Chem. 280:16410-16416(2005).
RN [13]
RP FUNCTION, POTENTIAL REDOX-ACTIVE SITE, CATALYTIC ACTIVITY, ACTIVITY
RP REGULATION, SUBCELLULAR LOCATION, MUTAGENESIS OF CYS-16; CYS-43; CYS-51;
RP SER-57; CYS-85; CYS-96; ARG-98; CYS-132; CYS-135 AND TYR-139, AND
RP CHARACTERIZATION OF VARIANT VKCFD2 TRP-98.
RX PubMed=16270630; DOI=10.1160/th05-02-0082;
RA Rost S., Fregin A., Hunerberg M., Bevans C.G., Muller C.R., Oldenburg J.;
RT "Site-directed mutagenesis of coumarin-type anticoagulant-sensitive VKORC1:
RT evidence that highly conserved amino acids define structural requirements
RT for enzymatic activity and inhibition by warfarin.";
RL Thromb. Haemost. 94:780-786(2005).
RN [14]
RP TOPOLOGY.
RX PubMed=20696932; DOI=10.1073/pnas.1009972107;
RA Schulman S., Wang B., Li W., Rapoport T.A.;
RT "Vitamin K epoxide reductase prefers ER membrane-anchored thioredoxin-like
RT redox partners.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:15027-15032(2010).
RN [15]
RP CATALYTIC ACTIVITY, FUNCTION, SUBCELLULAR LOCATION, TOPOLOGY, AND
RP MUTAGENESIS OF CYS-43 AND CYS-51.
RX PubMed=20978134; DOI=10.1074/jbc.m110.172213;
RA Rishavy M.A., Usubalieva A., Hallgren K.W., Berkner K.L.;
RT "Novel insight into the mechanism of the vitamin K oxidoreductase (VKOR):
RT electron relay through Cys43 and Cys51 reduces VKOR to allow vitamin K
RT reduction and facilitation of vitamin K-dependent protein carboxylation.";
RL J. Biol. Chem. 286:7267-7278(2011).
RN [16]
RP SUBCELLULAR LOCATION, TOPOLOGY, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP AND FUNCTION.
RX PubMed=22923610; DOI=10.1074/jbc.m112.402941;
RA Tie J.K., Jin D.Y., Stafford D.W.;
RT "Human vitamin K epoxide reductase and its bacterial homologue have
RT different membrane topologies and reaction mechanisms.";
RL J. Biol. Chem. 287:33945-33955(2012).
RN [17]
RP 3D-STRUCTURE MODELING.
RX PubMed=24406068; DOI=10.1111/jth.12450;
RA Wu S., Tie J.K., Stafford D.W., Pedersen L.G.;
RT "Membrane topology for human vitamin K epoxide reductase.";
RL J. Thromb. Haemost. 12:112-114(2014).
RN [18]
RP VARIANTS CMRES THR-26; LEU-29; GLY-36; TYR-36; TRP-52; PHE-56; LEU-59;
RP CYS-59; GLY-66; MET-66; ALA-71; SER-77; TYR-77; ASN-123 AND HIS-139.
RX PubMed=20946155; DOI=10.1111/j.1538-7836.2010.04095.x;
RA Watzka M., Geisen C., Bevans C.G., Sittinger K., Spohn G., Rost S.,
RA Seifried E., Muller C.R., Oldenburg J.;
RT "Thirteen novel VKORC1 mutations associated with oral anticoagulant
RT resistance: insights into improved patient diagnosis and treatment.";
RL J. Thromb. Haemost. 9:109-118(2011).
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:14765194,
CC ECO:0000269|PubMed:14765195, ECO:0000269|PubMed:15879509,
CC ECO:0000269|PubMed:16270630, ECO:0000269|PubMed:20978134,
CC ECO:0000269|PubMed:22923610}.
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:15879509, ECO:0000269|PubMed:16270630,
CC ECO:0000269|PubMed:20978134, ECO:0000269|PubMed:22923610};
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:15879509, ECO:0000269|PubMed:16270630,
CC ECO:0000269|PubMed:20978134, ECO:0000269|PubMed:22923610};
CC -!- ACTIVITY REGULATION: Inhibited by warfarin (coumadin).
CC {ECO:0000269|PubMed:15879509, ECO:0000269|PubMed:16270630,
CC ECO:0000269|PubMed:22923610}.
CC -!- INTERACTION:
CC Q9BQB6; Q13323: BIK; NbExp=3; IntAct=EBI-6256462, EBI-700794;
CC Q9BQB6; Q7Z7G2: CPLX4; NbExp=3; IntAct=EBI-6256462, EBI-18013275;
CC Q9BQB6; Q96BA8: CREB3L1; NbExp=3; IntAct=EBI-6256462, EBI-6942903;
CC Q9BQB6; Q9Y282: ERGIC3; NbExp=3; IntAct=EBI-6256462, EBI-781551;
CC Q9BQB6; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-6256462, EBI-18304435;
CC Q9BQB6; Q96KR6: FAM210B; NbExp=3; IntAct=EBI-6256462, EBI-18938272;
CC Q9BQB6; Q5T7V8: GORAB; NbExp=3; IntAct=EBI-6256462, EBI-3917143;
CC Q9BQB6; Q8TDT2: GPR152; NbExp=3; IntAct=EBI-6256462, EBI-13345167;
CC Q9BQB6; Q9NQG1: MANBAL; NbExp=3; IntAct=EBI-6256462, EBI-3867271;
CC Q9BQB6; P15941-11: MUC1; NbExp=3; IntAct=EBI-6256462, EBI-17263240;
CC Q9BQB6; Q96TC7: RMDN3; NbExp=3; IntAct=EBI-6256462, EBI-1056589;
CC Q9BQB6; Q9NR31: SAR1A; NbExp=3; IntAct=EBI-6256462, EBI-3920694;
CC Q9BQB6; A0A0S2Z4U3: SDC3; NbExp=3; IntAct=EBI-6256462, EBI-10204280;
CC Q9BQB6; Q8TBB6: SLC7A14; NbExp=3; IntAct=EBI-6256462, EBI-5235586;
CC Q9BQB6; O15393-2: TMPRSS2; NbExp=3; IntAct=EBI-6256462, EBI-12345267;
CC Q9BQB6; Q19QW4: ORF7a; Xeno; NbExp=2; IntAct=EBI-6256462, EBI-25489066;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:14765194, ECO:0000269|PubMed:15716279,
CC ECO:0000269|PubMed:16270630, ECO:0000269|PubMed:20978134,
CC ECO:0000269|PubMed:22923610}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:14765194, ECO:0000269|PubMed:15716279,
CC ECO:0000269|PubMed:16270630, ECO:0000269|PubMed:20978134,
CC ECO:0000269|PubMed:22923610}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=MST576;
CC IsoId=Q9BQB6-1; Sequence=Displayed;
CC Name=2; Synonyms=MST134;
CC IsoId=Q9BQB6-2; Sequence=VSP_013363;
CC Name=3;
CC IsoId=Q9BQB6-3; Sequence=VSP_043407;
CC -!- TISSUE SPECIFICITY: Expressed at highest levels in fetal and adult
CC liver, followed by fetal heart, kidney, and lung, adult heart, and
CC pancreas. {ECO:0000269|PubMed:14765194}.
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 (PubMed:15716279 and PubMed:22923610)
CC and four transmembrane domains (PubMed:20696932 and PubMed:20978134).
CC According to PubMed:15716279 and PubMed:22923610 the N-terminus of the
CC protein is in the endoplasmic reticulum lumen, while the C-terminus is
CC in the cytosol, which is in favor of three transmembrane domains.
CC According to PubMed:20696932, both N-terminus and C-terminus are in the
CC cytosol, indicating the presence of four transmembrane domains.
CC Besides, the 3D-structure of a bacterial ortholog shows four
CC transmembrane domains. Moreover, proteins that reside in the
CC endoplasmic reticulum lumen can catalyze the reduction of the active
CC site cysteines, possibly via Cys-43 and Cys-51 (PubMed:20696932 and
CC PubMed:20978134), but less efficiently than the synthetic compound
CC dithiothreitol (in vitro). Location of Cys-43 and Cys-51 in the
CC endoplasmic reticulum lumen would be in agreement with four
CC transmembrane domains. Again, these data are controversial, and papers
CC do not agree on the effects of mutating Cys-43 and Cys-51, probably
CC because of differences in the assay systems.
CC -!- DISEASE: Combined deficiency of vitamin K-dependent clotting factors 2
CC (VKCFD2) [MIM:607473]: VKCFD leads to a bleeding tendency that is
CC usually reversed by oral administration of vitamin K.
CC {ECO:0000269|PubMed:14765194, ECO:0000269|PubMed:16270630}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Coumarin resistance (CMRES) [MIM:122700]: A condition
CC characterized by partial or complete resistance to warfarin or other 4-
CC hydroxycoumarin derivatives. These drugs are used as anti-coagulants
CC for the prevention of thromboembolic diseases in subjects with deep
CC vein thrombosis, atrial fibrillation, or mechanical heart valve
CC replacement. {ECO:0000269|PubMed:14765194,
CC ECO:0000269|PubMed:20946155}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
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}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAQ88821.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/vkorc1/";
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DR EMBL; AY423044; AAR82914.1; -; mRNA.
DR EMBL; AY521634; AAS01052.1; -; mRNA.
DR EMBL; AF176924; AAQ13668.1; -; mRNA.
DR EMBL; AY466113; AAR28759.1; -; mRNA.
DR EMBL; AY587020; AAS83106.1; -; Genomic_DNA.
DR EMBL; AK289790; BAF82479.1; -; mRNA.
DR EMBL; AK312005; BAG34943.1; -; mRNA.
DR EMBL; AC135050; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471192; EAW52167.1; -; Genomic_DNA.
DR EMBL; CH471192; EAW52168.1; -; Genomic_DNA.
DR EMBL; BC002911; AAH02911.1; -; mRNA.
DR EMBL; AY358456; AAQ88821.1; ALT_INIT; mRNA.
DR CCDS; CCDS10703.1; -. [Q9BQB6-1]
DR CCDS; CCDS10704.1; -. [Q9BQB6-3]
DR RefSeq; NP_001298240.1; NM_001311311.1.
DR RefSeq; NP_076869.1; NM_024006.5. [Q9BQB6-1]
DR RefSeq; NP_996560.1; NM_206824.2. [Q9BQB6-3]
DR PDB; 6WV3; X-ray; 2.20 A; A=3-155.
DR PDB; 6WV4; X-ray; 3.01 A; A=3-155.
DR PDB; 6WV5; X-ray; 2.80 A; A=3-155.
DR PDB; 6WV6; X-ray; 2.70 A; A=3-155.
DR PDB; 6WV7; X-ray; 2.48 A; A/B=3-155.
DR PDB; 6WVH; X-ray; 1.99 A; A/B=3-155.
DR PDBsum; 6WV3; -.
DR PDBsum; 6WV4; -.
DR PDBsum; 6WV5; -.
DR PDBsum; 6WV6; -.
DR PDBsum; 6WV7; -.
DR PDBsum; 6WVH; -.
DR AlphaFoldDB; Q9BQB6; -.
DR SMR; Q9BQB6; -.
DR BioGRID; 122472; 137.
DR IntAct; Q9BQB6; 61.
DR MINT; Q9BQB6; -.
DR STRING; 9606.ENSP00000378426; -.
DR BindingDB; Q9BQB6; -.
DR ChEMBL; CHEMBL1930; -.
DR DrugBank; DB01418; Acenocoumarol.
DR DrugBank; DB00266; Dicoumarol.
DR DrugBank; DB09332; Kappadione.
DR DrugBank; DB00170; Menadione.
DR DrugBank; DB00498; Phenindione.
DR DrugBank; DB00946; Phenprocoumon.
DR DrugBank; DB01022; Phylloquinone.
DR DrugBank; DB00682; Warfarin.
DR DrugCentral; Q9BQB6; -.
DR GuidetoPHARMACOLOGY; 2645; -.
DR MoonDB; Q9BQB6; Predicted.
DR iPTMnet; Q9BQB6; -.
DR PhosphoSitePlus; Q9BQB6; -.
DR SwissPalm; Q9BQB6; -.
DR BioMuta; VKORC1; -.
DR DMDM; 62511226; -.
DR EPD; Q9BQB6; -.
DR jPOST; Q9BQB6; -.
DR MassIVE; Q9BQB6; -.
DR MaxQB; Q9BQB6; -.
DR PaxDb; Q9BQB6; -.
DR PeptideAtlas; Q9BQB6; -.
DR PRIDE; Q9BQB6; -.
DR ProteomicsDB; 78652; -. [Q9BQB6-1]
DR ProteomicsDB; 78653; -. [Q9BQB6-2]
DR ProteomicsDB; 78654; -. [Q9BQB6-3]
DR Antibodypedia; 50916; 135 antibodies from 22 providers.
DR DNASU; 79001; -.
DR Ensembl; ENST00000319788.11; ENSP00000326135.7; ENSG00000167397.15. [Q9BQB6-2]
DR Ensembl; ENST00000354895.4; ENSP00000346969.4; ENSG00000167397.15. [Q9BQB6-3]
DR Ensembl; ENST00000394975.3; ENSP00000378426.2; ENSG00000167397.15. [Q9BQB6-1]
DR GeneID; 79001; -.
DR KEGG; hsa:79001; -.
DR MANE-Select; ENST00000394975.3; ENSP00000378426.2; NM_024006.6; NP_076869.1.
DR UCSC; uc002eas.4; human. [Q9BQB6-1]
DR CTD; 79001; -.
DR DisGeNET; 79001; -.
DR GeneCards; VKORC1; -.
DR HGNC; HGNC:23663; VKORC1.
DR HPA; ENSG00000167397; Tissue enhanced (liver).
DR MalaCards; VKORC1; -.
DR MIM; 122700; phenotype.
DR MIM; 607473; phenotype.
DR MIM; 608547; gene.
DR neXtProt; NX_Q9BQB6; -.
DR OpenTargets; ENSG00000167397; -.
DR Orphanet; 98434; Hereditary combined deficiency of vitamin K-dependent clotting factors.
DR Orphanet; 413684; Prediction of resistance to vitamin K antagonists.
DR Orphanet; 413674; Prediction of toxicity or dose selection of vitamin K antagonists.
DR PharmGKB; PA133787052; -.
DR VEuPathDB; HostDB:ENSG00000167397; -.
DR eggNOG; ENOG502S4E7; Eukaryota.
DR GeneTree; ENSGT00940000157421; -.
DR HOGENOM; CLU_1749017_0_0_1; -.
DR InParanoid; Q9BQB6; -.
DR OMA; YVINFAL; -.
DR OrthoDB; 1611169at2759; -.
DR PhylomeDB; Q9BQB6; -.
DR TreeFam; TF328467; -.
DR BioCyc; MetaCyc:HS15548-MON; -.
DR BRENDA; 1.17.4.4; 2681.
DR PathwayCommons; Q9BQB6; -.
DR Reactome; R-HSA-6806664; Metabolism of vitamin K.
DR SignaLink; Q9BQB6; -.
DR SIGNOR; Q9BQB6; -.
DR BioGRID-ORCS; 79001; 9 hits in 1081 CRISPR screens.
DR ChiTaRS; VKORC1; human.
DR GeneWiki; VKORC1; -.
DR GenomeRNAi; 79001; -.
DR Pharos; Q9BQB6; Tclin.
DR PRO; PR:Q9BQB6; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q9BQB6; protein.
DR Bgee; ENSG00000167397; Expressed in stromal cell of endometrium and 97 other tissues.
DR ExpressionAtlas; Q9BQB6; baseline and differential.
DR Genevisible; Q9BQB6; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0048038; F:quinone binding; IEA:UniProtKB-KW.
DR GO; GO:0047058; F:vitamin-K-epoxide reductase (warfarin-insensitive) activity; IEA:Ensembl.
DR GO; GO:0047057; F:vitamin-K-epoxide reductase (warfarin-sensitive) activity; IDA:UniProtKB.
DR GO; GO:0007596; P:blood coagulation; IMP:UniProtKB.
DR GO; GO:0060348; P:bone development; ISS:UniProtKB.
DR GO; GO:0017187; P:peptidyl-glutamic acid carboxylation; IMP:UniProtKB.
DR GO; GO:0050820; P:positive regulation of coagulation; IEA:Ensembl.
DR GO; GO:0030193; P:regulation of blood coagulation; IEA:Ensembl.
DR GO; GO:0046677; P:response to antibiotic; IEA:Ensembl.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0010243; P:response to organonitrogen compound; IEA:Ensembl.
DR GO; GO:0042373; P:vitamin K metabolic process; IDA:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; IMP:UniProtKB.
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 3D-structure; Alternative splicing; Disease variant; Disulfide bond;
KW Endoplasmic reticulum; Membrane; Oxidoreductase; Quinone;
KW Redox-active center; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..163
FT /note="Vitamin K epoxide reductase complex subunit 1"
FT /id="PRO_0000191668"
FT TOPO_DOM 1..8
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 9..29
FT /note="Helical"
FT /evidence="ECO:0000305"
FT TOPO_DOM 30..74
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 75..95
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 101..123
FT /note="Helical"
FT /evidence="ECO:0000305"
FT TOPO_DOM 124..126
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 127..149
FT /note="Helical"
FT /evidence="ECO:0000305"
FT TOPO_DOM 150..163
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT DISULFID 132..135
FT /note="Redox-active"
FT VAR_SEQ 59..163
FT /note="WGRGFGLVEHVLGQDSILNQSNSIFGCIFYTLQLLLGCLRTRWASVLMLLSS
FT LVSLAGSVYLAWILFFVLYDFCIVCITTYAINVSLMWLSFRKVQEPQGKAKRH -> LP
FT ADTLGLCPDAAELPGVSRWFCLPGLDPVLRAL (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043407"
FT VAR_SEQ 95..163
FT /note="GCLRTRWASVLMLLSSLVSLAGSVYLAWILFFVLYDFCIVCITTYAINVSLM
FT WLSFRKVQEPQGKAKRH -> DGVSPCCPGWSQAICLPQPPKVLGGLQALPADTLGLCP
FT DAAELPGVSRWFCLPGLDPVLRAL (in isoform 2)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_013363"
FT VARIANT 26
FT /note="A -> T (in CMRES; dbSNP:rs770703948)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065785"
FT VARIANT 29
FT /note="V -> L (in CMRES; dbSNP:rs104894539)"
FT /evidence="ECO:0000269|PubMed:14765194,
FT ECO:0000269|PubMed:20946155"
FT /id="VAR_021821"
FT VARIANT 36
FT /note="D -> G (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065786"
FT VARIANT 36
FT /note="D -> Y (in CMRES; dbSNP:rs61742245)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065787"
FT VARIANT 45
FT /note="V -> A (in CMRES; dbSNP:rs104894540)"
FT /evidence="ECO:0000269|PubMed:14765194"
FT /id="VAR_021822"
FT VARIANT 52
FT /note="S -> W (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065788"
FT VARIANT 56
FT /note="S -> F (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065789"
FT VARIANT 58
FT /note="R -> G (in CMRES; dbSNP:rs104894541)"
FT /evidence="ECO:0000269|PubMed:14765194"
FT /id="VAR_021823"
FT VARIANT 59
FT /note="W -> C (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065790"
FT VARIANT 59
FT /note="W -> L (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065791"
FT VARIANT 66
FT /note="V -> G (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065792"
FT VARIANT 66
FT /note="V -> M (in CMRES; dbSNP:rs72547529)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065793"
FT VARIANT 71
FT /note="G -> A (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065794"
FT VARIANT 77
FT /note="N -> S (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065795"
FT VARIANT 77
FT /note="N -> Y (in CMRES; dbSNP:rs755767348)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065796"
FT VARIANT 98
FT /note="R -> W (in VKCFD2; strongly reduced enzyme activity;
FT dbSNP:rs72547528)"
FT /evidence="ECO:0000269|PubMed:14765194,
FT ECO:0000269|PubMed:16270630"
FT /id="VAR_021824"
FT VARIANT 123
FT /note="I -> N (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065797"
FT VARIANT 128
FT /note="L -> R (in CMRES; dbSNP:rs104894542)"
FT /evidence="ECO:0000269|PubMed:14765194"
FT /id="VAR_021825"
FT VARIANT 139
FT /note="Y -> H (in CMRES)"
FT /evidence="ECO:0000269|PubMed:20946155"
FT /id="VAR_065798"
FT MUTAGEN 16
FT /note="C->A,S: Reduces enzyme activity by about 80%."
FT /evidence="ECO:0000269|PubMed:16270630"
FT MUTAGEN 35
FT /note="R->P: Nearly abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:15879509"
FT MUTAGEN 43
FT /note="C->A,S: Reduces enzyme activity."
FT /evidence="ECO:0000269|PubMed:16270630,
FT ECO:0000269|PubMed:20978134"
FT MUTAGEN 51
FT /note="C->A,S: Reduces enzyme activity."
FT /evidence="ECO:0000269|PubMed:16270630,
FT ECO:0000269|PubMed:20978134"
FT MUTAGEN 56
FT /note="S->P: Nearly abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:15879509"
FT MUTAGEN 57
FT /note="S->A: Nearly abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:16270630"
FT MUTAGEN 85
FT /note="C->A: Reduces enzyme activity by about 25%."
FT /evidence="ECO:0000269|PubMed:16270630"
FT MUTAGEN 85
FT /note="C->S: Reduces enzyme activity by about 75%."
FT /evidence="ECO:0000269|PubMed:16270630"
FT MUTAGEN 96
FT /note="C->A,S: Reduces enzyme activity by about 70%."
FT /evidence="ECO:0000269|PubMed:16270630"
FT MUTAGEN 98
FT /note="R->D,E: Reduces enzyme activity by about 80%.
FT Decreases inhibition by warfarin."
FT /evidence="ECO:0000269|PubMed:16270630"
FT MUTAGEN 98
FT /note="R->K: No effect on enzyme activity. Decreases
FT inhibition by warfarin."
FT /evidence="ECO:0000269|PubMed:16270630"
FT MUTAGEN 120
FT /note="L->Q: Decreases enzyme activity moderately.
FT Decreases inhibition by warfarin."
FT /evidence="ECO:0000269|PubMed:15879509"
FT MUTAGEN 128
FT /note="L->Q,S: Decreases enzyme activity by about 80%.
FT Decreases inhibition by warfarin."
FT /evidence="ECO:0000269|PubMed:15879509"
FT MUTAGEN 132
FT /note="C->S: Nearly abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:16270630"
FT MUTAGEN 135
FT /note="C->S: Nearly abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:16270630"
FT MUTAGEN 139
FT /note="Y->C,G,S: Decreases enzyme activity moderately.
FT Strongly decreases inhibition by warfarin."
FT /evidence="ECO:0000269|PubMed:15879509,
FT ECO:0000269|PubMed:16270630"
FT MUTAGEN 139
FT /note="Y->F: No effect on enzyme activity. Strongly
FT decreases inhibition by warfarin."
FT /evidence="ECO:0000269|PubMed:15879509,
FT ECO:0000269|PubMed:16270630"
FT HELIX 10..15
FT /evidence="ECO:0007829|PDB:6WVH"
FT HELIX 19..35
FT /evidence="ECO:0007829|PDB:6WVH"
FT STRAND 44..46
FT /evidence="ECO:0007829|PDB:6WVH"
FT HELIX 51..56
FT /evidence="ECO:0007829|PDB:6WVH"
FT HELIX 58..60
FT /evidence="ECO:0007829|PDB:6WVH"
FT HELIX 62..64
FT /evidence="ECO:0007829|PDB:6WVH"
FT HELIX 67..70
FT /evidence="ECO:0007829|PDB:6WVH"
FT HELIX 80..95
FT /evidence="ECO:0007829|PDB:6WVH"
FT HELIX 100..126
FT /evidence="ECO:0007829|PDB:6WVH"
FT HELIX 133..154
FT /evidence="ECO:0007829|PDB:6WVH"
SQ SEQUENCE 163 AA; 18235 MW; 2F00526A6C561D5A CRC64;
MGSTWGSPGW VRLALCLTGL VLSLYALHVK AARARDRDYR ALCDVGTAIS CSRVFSSRWG
RGFGLVEHVL GQDSILNQSN SIFGCIFYTL QLLLGCLRTR WASVLMLLSS LVSLAGSVYL
AWILFFVLYD FCIVCITTYA INVSLMWLSF RKVQEPQGKA KRH
