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 27-MAR-2024, entry version 174. 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 {ECO:0000303|PubMed:14765194, GN ECO:0000312|HGNC:HGNC:23663}; GN Synonyms=VKOR {ECO:0000303|PubMed:20978134}; GN 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 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 SUBCELLULAR LOCATION. 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, AND MUTAGENESIS OF RP 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, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND RP 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] {ECO:0007744|PDB:6WV3, ECO:0007744|PDB:6WV4, ECO:0007744|PDB:6WV5, ECO:0007744|PDB:6WV6, ECO:0007744|PDB:6WV7, ECO:0007744|PDB:6WVH} RP X-RAY CRYSTALLOGRAPHY (1.99 ANGSTROMS) OF 4-155 IN COMPLEX WITH WARFARIN RP AND VITAMIN K, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, RP SUBCELLULAR LOCATION, REDOX-ACTIVE SITES, AND MUTAGENESIS OF ASN-80 AND RP TYR-139. RX PubMed=33154105; DOI=10.1126/science.abc5667; RA Liu S., Li S., Shen G., Sukumar N., Krezel A.M., Li W.; RT "Structural basis of antagonizing the vitamin K catalytic cycle for RT anticoagulation."; RL Science 371:0-0(2021). RN [19] 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, ECO:0000269|PubMed:33154105}. 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 ECO:0000269|PubMed:33154105}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:13819; CC Evidence={ECO:0000269|PubMed:15879509, ECO:0000269|PubMed:16270630, CC ECO:0000269|PubMed:20978134, ECO:0000269|PubMed:22923610, CC ECO:0000269|PubMed:33154105}; 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 ECO:0000269|PubMed:33154105}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:57746; CC Evidence={ECO:0000269|PubMed:15879509, ECO:0000269|PubMed:16270630, CC ECO:0000269|PubMed:20978134, ECO:0000269|PubMed:22923610, CC ECO:0000269|PubMed:33154105}; CC -!- ACTIVITY REGULATION: Inhibited by warfarin (coumadin) (PubMed:15879509, CC PubMed:16270630, PubMed:22923610, PubMed:33154105). Warfarin locks CC VKORC1 in both redox states into the closed conformation CC (PubMed:33154105). Inhibited by warfarin analogs phenindione, CC brodifacoum and chlorophacinone (PubMed:33154105). CC {ECO:0000269|PubMed:15879509, ECO:0000269|PubMed:16270630, CC ECO:0000269|PubMed:22923610, ECO:0000269|PubMed:33154105}. 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:20696932, CC ECO:0000269|PubMed:20978134, ECO:0000269|PubMed:22923610, CC ECO:0000269|PubMed:33154105}. 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: Partially oxidized VKORC1 forms a cysteine adduct with CC substrates, vitamin K 2,3-epoxide, inducing a closed conformation, CC juxtaposing all cysteines (S-S or SH) for unimpeded electron transfer CC (PubMed:33154105). VKOR becomes fully oxidized with an open CC conformation that releases reaction products, vitamin K quinone, or CC hydroquinone (PubMed:33154105). Cys-132 and Cys-135 constitute the CC catalytic redox-active center (PubMed:33154105). Cys-43 and Cys-51 are CC the cysteine pair that mediates transfer of reducing equivalents during CC catalysis (PubMed:33154105). {ECO:0000269|PubMed:33154105}. 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 -!- 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/"; 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; 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; 141. DR IntAct; Q9BQB6; 62. 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; 9606-ENSP00000378426; -. DR PeptideAtlas; Q9BQB6; -. DR ProteomicsDB; 78652; -. [Q9BQB6-1] DR ProteomicsDB; 78653; -. [Q9BQB6-2] DR ProteomicsDB; 78654; -. [Q9BQB6-3] DR Pumba; Q9BQB6; -. DR Antibodypedia; 50916; 140 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 AGR; HGNC:23663; -. 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 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; CVSTYVI; -. DR OrthoDB; 68850at2759; -. DR PhylomeDB; Q9BQB6; -. DR TreeFam; TF328467; -. DR BioCyc; MetaCyc:HS15548-MONOMER; -. 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 1164 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 99 other cell types or tissues. DR ExpressionAtlas; Q9BQB6; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProt. DR GO; GO:0048038; F:quinone binding; IEA:UniProtKB-KW. DR GO; GO:0047058; F:vitamin-K-epoxide reductase (warfarin-insensitive) activity; IDA:UniProt. 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: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; VKOR domain; 1. DR InterPro; IPR012932; VKOR. DR InterPro; IPR038354; VKOR_sf. DR InterPro; IPR042406; VKORC1/VKORC1L1. DR PANTHER; PTHR14519:SF0; VITAMIN K EPOXIDE REDUCTASE COMPLEX SUBUNIT 1; 1. DR PANTHER; PTHR14519; VITAMIN K EPOXIDE REDUCTASE COMPLEX, SUBUNIT 1; 1. DR Pfam; PF07884; VKOR; 1. DR SMART; SM00756; VKc; 1. DR Genevisible; Q9BQB6; HS. 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..9 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:33154105" FT TRANSMEM 10..29 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:33154105, FT ECO:0007744|PDB:6WV3, ECO:0007744|PDB:6WV4, FT ECO:0007744|PDB:6WV5, ECO:0007744|PDB:6WV6, FT ECO:0007744|PDB:6WV7, ECO:0007744|PDB:6WVH" FT TOPO_DOM 30..80 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:33154105" FT TRANSMEM 81..95 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:33154105, FT ECO:0007744|PDB:6WV3, ECO:0007744|PDB:6WV4, FT ECO:0007744|PDB:6WV5, ECO:0007744|PDB:6WV6, FT ECO:0007744|PDB:6WV7, ECO:0007744|PDB:6WVH" FT TOPO_DOM 96..100 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:33154105" FT TRANSMEM 101..128 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:33154105, FT ECO:0007744|PDB:6WV3, ECO:0007744|PDB:6WV4, FT ECO:0007744|PDB:6WV5, ECO:0007744|PDB:6WV6, FT ECO:0007744|PDB:6WV7, ECO:0007744|PDB:6WVH" FT TOPO_DOM 129..131 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:33154105" FT TRANSMEM 132..153 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:33154105, FT ECO:0007744|PDB:6WV3, ECO:0007744|PDB:6WV4, FT ECO:0007744|PDB:6WV5, ECO:0007744|PDB:6WV6, FT ECO:0007744|PDB:6WV7, ECO:0007744|PDB:6WVH" FT TOPO_DOM 154..163 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:33154105" FT BINDING 80 FT /ligand="(S)-warfarin" FT /ligand_id="ChEBI:CHEBI:87744" FT /evidence="ECO:0000269|PubMed:33154105, FT ECO:0007744|PDB:6WV3, ECO:0007744|PDB:6WV4" FT BINDING 135 FT /ligand="phylloquinone" FT /ligand_id="ChEBI:CHEBI:18067" FT /evidence="ECO:0000305|PubMed:33154105, FT ECO:0007744|PDB:6WV5" FT BINDING 139 FT /ligand="(S)-warfarin" FT /ligand_id="ChEBI:CHEBI:87744" FT /evidence="ECO:0000269|PubMed:33154105, FT ECO:0007744|PDB:6WV3, ECO:0007744|PDB:6WV4" FT BINDING 139 FT /ligand="phylloquinone" FT /ligand_id="ChEBI:CHEBI:18067" FT /evidence="ECO:0000305|PubMed:33154105, FT ECO:0007744|PDB:6WV5" FT DISULFID 43..51 FT /note="Redox-active" FT /evidence="ECO:0000269|PubMed:33154105, FT ECO:0007744|PDB:6WV4, ECO:0007744|PDB:6WV5" FT DISULFID 132..135 FT /note="Redox-active" FT /evidence="ECO:0000269|PubMed:33154105, FT ECO:0000305|PubMed:15276181, ECO:0000305|PubMed:16270630, FT ECO:0007744|PDB:6WV4, ECO:0007744|PDB:6WV5" 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 80 FT /note="N->A: Decreased vitamin K epoxide reductase FT activity." FT /evidence="ECO:0000269|PubMed:33154105" 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->A: Decreased vitamin K epoxide reductase FT activity." FT /evidence="ECO:0000269|PubMed:33154105" 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 //