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Protein

Vitamin K epoxide reductase complex subunit 1

Gene

VKORC1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Involved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development.6 Publications

Miscellaneous

The location of two cysteine active-site residues within a proposed transmembrane is consistent both with the known hydrophobic environment of the thiol redox site of the enzyme and with the lipophilicity of vitamin K and warfarin (coumadin).

Catalytic activityi

Phylloquinone + oxidized dithiothreitol + H2O = 2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol.4 Publications

Enzyme regulationi

Inhibited by warfarin (coumadin).3 Publications

GO - Molecular functioni

  • quinone binding Source: UniProtKB-KW
  • vitamin-K-epoxide reductase (warfarin-sensitive) activity Source: UniProtKB

GO - Biological processi

  • blood coagulation Source: UniProtKB
  • bone development Source: UniProtKB
  • drug metabolic process Source: UniProtKB
  • peptidyl-glutamic acid carboxylation Source: UniProtKB
  • vitamin K metabolic process Source: UniProtKB

Keywordsi

Molecular functionOxidoreductase

Enzyme and pathway databases

BioCyciMetaCyc:HS15548-MONOMER
BRENDAi1.1.4.1 2681
ReactomeiR-HSA-6806664 Metabolism of vitamin K

Protein family/group databases

MoonDBiQ9BQB6 Predicted

Names & Taxonomyi

Protein namesi
Recommended name:
Vitamin K epoxide reductase complex subunit 1 (EC:1.17.4.44 Publications)
Alternative name(s):
Vitamin K1 2,3-epoxide reductase subunit 1
Gene namesi
Name:VKORC1
Synonyms:VKOR
ORF Names:MSTP134, MSTP576, UNQ308/PRO351
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

EuPathDBiHostDB:ENSG00000167397.14
HGNCiHGNC:23663 VKORC1
MIMi608547 gene
neXtProtiNX_Q9BQB6

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 8LumenalSequence analysis8
Transmembranei9 – 29HelicalCuratedAdd BLAST21
Topological domaini30 – 74CytoplasmicSequence analysisAdd BLAST45
Transmembranei75 – 95HelicalSequence analysisAdd BLAST21
Transmembranei101 – 123HelicalCuratedAdd BLAST23
Topological domaini124 – 126LumenalCurated3
Transmembranei127 – 149HelicalCuratedAdd BLAST23
Topological domaini150 – 163CytoplasmicCuratedAdd BLAST14

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Involvement in diseasei

Combined deficiency of vitamin K-dependent clotting factors 2 (VKCFD2)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionVKCFD leads to a bleeding tendency that is usually reversed by oral administration of vitamin K.
See also OMIM:607473
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02182498R → W in VKCFD2; strongly reduced enzyme activity. 2 PublicationsCorresponds to variant dbSNP:rs72547528EnsemblClinVar.1
Coumarin resistance (CMRES)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA condition characterized by partial or complete resistance to warfarin or other 4-hydroxycoumarin derivatives. These drugs are used as anti-coagulants for the prevention of thromboembolic diseases in subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement.
See also OMIM:122700
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06578526A → T in CMRES. 1 Publication1
Natural variantiVAR_02182129V → L in CMRES. 2 PublicationsCorresponds to variant dbSNP:rs104894539EnsemblClinVar.1
Natural variantiVAR_06578636D → G in CMRES. 1 Publication1
Natural variantiVAR_06578736D → Y in CMRES. 1 PublicationCorresponds to variant dbSNP:rs61742245EnsemblClinVar.1
Natural variantiVAR_02182245V → A in CMRES. 1 PublicationCorresponds to variant dbSNP:rs104894540EnsemblClinVar.1
Natural variantiVAR_06578852S → W in CMRES. 1 Publication1
Natural variantiVAR_06578956S → F in CMRES. 1 Publication1
Natural variantiVAR_02182358R → G in CMRES. 1 PublicationCorresponds to variant dbSNP:rs104894541EnsemblClinVar.1
Natural variantiVAR_06579059W → C in CMRES. 1 Publication1
Natural variantiVAR_06579159W → L in CMRES. 1 Publication1
Natural variantiVAR_06579266V → G in CMRES. 1 Publication1
Natural variantiVAR_06579366V → M in CMRES. 1 PublicationCorresponds to variant dbSNP:rs72547529Ensembl.1
Natural variantiVAR_06579471G → A in CMRES. 1 Publication1
Natural variantiVAR_06579577N → S in CMRES. 1 Publication1
Natural variantiVAR_06579677N → Y in CMRES. 1 PublicationCorresponds to variant dbSNP:rs755767348Ensembl.1
Natural variantiVAR_065797123I → N in CMRES. 1 Publication1
Natural variantiVAR_021825128L → R in CMRES. 1 PublicationCorresponds to variant dbSNP:rs104894542EnsemblClinVar.1
Natural variantiVAR_065798139Y → H in CMRES. 1 Publication1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi16C → A or S: Reduces enzyme activity by about 80%. 1 Publication1
Mutagenesisi35R → P: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi43C → A or S: Reduces enzyme activity. 2 Publications1
Mutagenesisi51C → A or S: Reduces enzyme activity. 2 Publications1
Mutagenesisi56S → P: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi57S → A: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi85C → A: Reduces enzyme activity by about 25%. 1 Publication1
Mutagenesisi85C → S: Reduces enzyme activity by about 75%. 1 Publication1
Mutagenesisi96C → A or S: Reduces enzyme activity by about 70%. 1 Publication1
Mutagenesisi98R → D or E: Reduces enzyme activity by about 80%. Decreases inhibition by warfarin. 1 Publication1
Mutagenesisi98R → K: No effect on enzyme activity. Decreases inhibition by warfarin. 1 Publication1
Mutagenesisi120L → Q: Decreases enzyme activity moderately. Decreases inhibition by warfarin. 1 Publication1
Mutagenesisi128L → Q or S: Decreases enzyme activity by about 80%. Decreases inhibition by warfarin. 1 Publication1
Mutagenesisi132C → S: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi135C → S: Nearly abolishes enzyme activity. 1 Publication1
Mutagenesisi139Y → C, G or S: Decreases enzyme activity moderately. Strongly decreases inhibition by warfarin. 2 Publications1
Mutagenesisi139Y → F: No effect on enzyme activity. Strongly decreases inhibition by warfarin. 2 Publications1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi79001
MalaCardsiVKORC1
MIMi122700 phenotype
607473 phenotype
OpenTargetsiENSG00000167397
Orphaneti98434 Hereditary combined deficiency of vitamin K-dependent clotting factors
413684 Resistance to vitamin K antagonists
413674 Vitamin K antagonists toxicity or dose selection
PharmGKBiPA133787052

Chemistry databases

ChEMBLiCHEMBL1930
DrugBankiDB01418 Acenocoumarol
DB00266 Dicoumarol
DB00170 Menadione
DB00498 Phenindione
DB00946 Phenprocoumon
DB00682 Warfarin
GuidetoPHARMACOLOGYi2645

Polymorphism and mutation databases

BioMutaiVKORC1
DMDMi62511226

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001916681 – 163Vitamin K epoxide reductase complex subunit 1Add BLAST163

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi132 ↔ 135Redox-active

Keywords - PTMi

Disulfide bond, Quinone

Proteomic databases

EPDiQ9BQB6
MaxQBiQ9BQB6
PaxDbiQ9BQB6
PeptideAtlasiQ9BQB6
PRIDEiQ9BQB6
ProteomicsDBi78652
78653 [Q9BQB6-2]
78654 [Q9BQB6-3]

PTM databases

iPTMnetiQ9BQB6
PhosphoSitePlusiQ9BQB6
SwissPalmiQ9BQB6

Expressioni

Tissue specificityi

Expressed at highest levels in fetal and adult liver, followed by fetal heart, kidney, and lung, adult heart, and pancreas.1 Publication

Gene expression databases

BgeeiENSG00000167397
CleanExiHS_VKORC1
ExpressionAtlasiQ9BQB6 baseline and differential
GenevisibleiQ9BQB6 HS

Organism-specific databases

HPAiHPA042720

Interactioni

Protein-protein interaction databases

BioGridi122472, 100 interactors
IntActiQ9BQB6, 46 interactors
MINTiQ9BQB6
STRINGi9606.ENSP00000378426

Chemistry databases

BindingDBiQ9BQB6

Structurei

3D structure databases

ProteinModelPortaliQ9BQB6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domaini

The number of transmembrane domains and the membrane topology are controversial; supporting evidence is available both for models with three transmembrane domains (PubMed:15716279 and PubMed:22923610) and four transmembrane domains (PubMed:20696932 and PubMed:20978134). According to PubMed:15716279 and PubMed:22923610 the N-terminus of the protein is in the endoplasmic reticulum lumen, while the C-terminus is in the cytosol, which is in favor of three transmembrane domains. According to PubMed:20696932, both N-terminus and C-terminus are in the cytosol, indicating the presence of four transmembrane domains. Besides, the 3D-structure of a bacterial ortholog shows four transmembrane domains. Moreover, proteins that reside in the endoplasmic reticulum lumen can catalyze the reduction of the active site cysteines, possibly via Cys-43 and Cys-51 (PubMed:20696932 and PubMed:20978134), but less efficiently than the synthetic compound dithiothreitol (in vitro). Location of Cys-43 and Cys-51 in the endoplasmic reticulum lumen would be in agreement with four transmembrane domains. Again, these data are controversial, and papers do not agree on the effects of mutating Cys-43 and Cys-51, probably because of differences in the assay systems.

Sequence similaritiesi

Belongs to the VKOR family.Curated

Keywords - Domaini

Redox-active center, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410J0HT Eukaryota
ENOG4111UX7 LUCA
GeneTreeiENSGT00390000002103
HOGENOMiHOG000230752
HOVERGENiHBG076672
InParanoidiQ9BQB6
KOiK05357
OMAiQGKVKGH
OrthoDBiEOG091G0QTR
PhylomeDBiQ9BQB6
TreeFamiTF328467

Family and domain databases

Gene3Di1.20.1440.130, 1 hit
InterProiView protein in InterPro
IPR012932 VKOR
IPR038354 VKOR_sf
PfamiView protein in Pfam
PF07884 VKOR, 1 hit
SMARTiView protein in SMART
SM00756 VKc, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9BQB6-1) [UniParc]FASTAAdd to basket
Also known as: MST576

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MGSTWGSPGW VRLALCLTGL VLSLYALHVK AARARDRDYR ALCDVGTAIS
60 70 80 90 100
CSRVFSSRWG RGFGLVEHVL GQDSILNQSN SIFGCIFYTL QLLLGCLRTR
110 120 130 140 150
WASVLMLLSS LVSLAGSVYL AWILFFVLYD FCIVCITTYA INVSLMWLSF
160
RKVQEPQGKA KRH
Length:163
Mass (Da):18,235
Last modified:June 1, 2001 - v1
Checksum:i2F00526A6C561D5A
GO
Isoform 2 (identifier: Q9BQB6-2) [UniParc]FASTAAdd to basket
Also known as: MST134

The sequence of this isoform differs from the canonical sequence as follows:
     95-163: GCLRTRWASV...QEPQGKAKRH → DGVSPCCPGW...PGLDPVLRAL

Show »
Length:156
Mass (Da):16,701
Checksum:iFBB87922208F471C
GO
Isoform 3 (identifier: Q9BQB6-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     59-163: WGRGFGLVEH...QEPQGKAKRH → LPADTLGLCPDAAELPGVSRWFCLPGLDPVLRAL

Note: No experimental confirmation available.
Show »
Length:92
Mass (Da):9,875
Checksum:iCB4ADA0C5ED486BD
GO

Sequence cautioni

The sequence AAQ88821 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06578526A → T in CMRES. 1 Publication1
Natural variantiVAR_02182129V → L in CMRES. 2 PublicationsCorresponds to variant dbSNP:rs104894539EnsemblClinVar.1
Natural variantiVAR_06578636D → G in CMRES. 1 Publication1
Natural variantiVAR_06578736D → Y in CMRES. 1 PublicationCorresponds to variant dbSNP:rs61742245EnsemblClinVar.1
Natural variantiVAR_02182245V → A in CMRES. 1 PublicationCorresponds to variant dbSNP:rs104894540EnsemblClinVar.1
Natural variantiVAR_06578852S → W in CMRES. 1 Publication1
Natural variantiVAR_06578956S → F in CMRES. 1 Publication1
Natural variantiVAR_02182358R → G in CMRES. 1 PublicationCorresponds to variant dbSNP:rs104894541EnsemblClinVar.1
Natural variantiVAR_06579059W → C in CMRES. 1 Publication1
Natural variantiVAR_06579159W → L in CMRES. 1 Publication1
Natural variantiVAR_06579266V → G in CMRES. 1 Publication1
Natural variantiVAR_06579366V → M in CMRES. 1 PublicationCorresponds to variant dbSNP:rs72547529Ensembl.1
Natural variantiVAR_06579471G → A in CMRES. 1 Publication1
Natural variantiVAR_06579577N → S in CMRES. 1 Publication1
Natural variantiVAR_06579677N → Y in CMRES. 1 PublicationCorresponds to variant dbSNP:rs755767348Ensembl.1
Natural variantiVAR_02182498R → W in VKCFD2; strongly reduced enzyme activity. 2 PublicationsCorresponds to variant dbSNP:rs72547528EnsemblClinVar.1
Natural variantiVAR_065797123I → N in CMRES. 1 Publication1
Natural variantiVAR_021825128L → R in CMRES. 1 PublicationCorresponds to variant dbSNP:rs104894542EnsemblClinVar.1
Natural variantiVAR_065798139Y → H in CMRES. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04340759 – 163WGRGF…KAKRH → LPADTLGLCPDAAELPGVSR WFCLPGLDPVLRAL in isoform 3. 1 PublicationAdd BLAST105
Alternative sequenceiVSP_01336395 – 163GCLRT…KAKRH → DGVSPCCPGWSQAICLPQPP KVLGGLQALPADTLGLCPDA AELPGVSRWFCLPGLDPVLR AL in isoform 2. 1 PublicationAdd BLAST69

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY423044 mRNA Translation: AAR82914.1
AY521634 mRNA Translation: AAS01052.1
AF176924 mRNA Translation: AAQ13668.1
AY466113 mRNA Translation: AAR28759.1
AY587020 Genomic DNA Translation: AAS83106.1
AK289790 mRNA Translation: BAF82479.1
AK312005 mRNA Translation: BAG34943.1
AC135050 Genomic DNA No translation available.
CH471192 Genomic DNA Translation: EAW52167.1
CH471192 Genomic DNA Translation: EAW52168.1
BC002911 mRNA Translation: AAH02911.1
AY358456 mRNA Translation: AAQ88821.1 Different initiation.
CCDSiCCDS10703.1 [Q9BQB6-1]
CCDS10704.1 [Q9BQB6-3]
RefSeqiNP_001298240.1, NM_001311311.1
NP_076869.1, NM_024006.5 [Q9BQB6-1]
NP_996560.1, NM_206824.2 [Q9BQB6-3]
UniGeneiHs.324844

Genome annotation databases

EnsembliENST00000319788; ENSP00000326135; ENSG00000167397 [Q9BQB6-2]
ENST00000354895; ENSP00000346969; ENSG00000167397 [Q9BQB6-3]
ENST00000394975; ENSP00000378426; ENSG00000167397 [Q9BQB6-1]
GeneIDi79001
KEGGihsa:79001
UCSCiuc002eas.4 human [Q9BQB6-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiVKOR1_HUMAN
AccessioniPrimary (citable) accession number: Q9BQB6
Secondary accession number(s): A6NIQ6
, B2R4Z6, Q6UX90, Q7Z2R4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: June 1, 2001
Last modified: July 18, 2018
This is version 142 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 16
    Human chromosome 16: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

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