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Information on EC 1.17.4.4 - vitamin-K-epoxide reductase (warfarin-sensitive) and Organism(s) Homo sapiens
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1.17.4.4 vitamin-K-epoxide reductase (warfarin-sensitive)IUBMB Comments
The enzyme catalyses the reduction of vitamin K 2,3-epoxide, which is formed by the activity of EC 4.1.1.90, peptidyl-glutamate 4-carboxylase, back to its phylloquinol active form. The enzyme forms a tight complex with EC 5.3.4.1, protein disulfide-isomerase, which transfers the required electrons from newly-synthesized proteins by catalysing the formation of disulfide bridges. The enzyme acts on the epoxide forms of both phylloquinone (vitamin K1) and menaquinone (vitamin K2). Inhibited strongly by (S)-warfarin and ferulenol.
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Word Map
- 1.17.4.4
- cyp2c9
-
anticoagulant
-
dosing
-
pharmacogenetic
-
bleeding
- cyp4f2
-
thromboembolic
-
k-dependent
-
coagulation
-
acenocoumarol
-
interindividual
-
pharmacogenomics
- fibrillation
- gg
-
caucasian
- prothrombin
- atrial
-
demographic
-
pharmacodynamics
- clot
- valve
-
ethnic
- thrombosis
-
genotype-guided
-
s-warfarin
-
rodenticides
-
gamma-glutamyl
-
non-genetic
- phenprocoumon
-
warfarin-treated
- 4-hydroxycoumarins
- gamma-carboxylase
-
coumadin
-
pharmacogenes
- medicine
-
pivka-ii
-
slco1b1
- calumenin
- amiodarone
-
genotype-based
-
interpatient
- cyp3a5
- hypoprothrombinemia
-
undercarboxylated
- clopidogrel
-
antivitamin
-
gamma-carboxylation
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
+
+
=
+
+
a protein with a disulfide bond
+
=
+
a protein with reduced L-cysteine residues
+
=
+
+
a protein with a disulfide bond
=
+
a protein with reduced L-cysteine residues
Synonyms
vkorc1, vitamin k epoxide reductase, vkorc1l1, vitamin k 2,3-epoxide reductase, vkorc1v2, vitamin k-epoxide reductase, vitamin k oxidoreductase, vitamin k1 epoxide reductase, vkor complex, vkorc1-like 1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
phylloquinone epoxide reductase
-
-
-
-
reductase, phylloquinone epoxide
-
-
-
-
vitamin K 2,3-epoxide reductase complex subunit 1
vitamin K epoxide reductase
vitamin K epoxide reductase complex subunit 1
vitamin K1 epoxide reductase
-
-
-
-
VKOR
VKORC1
VKORC1L1
vitamin K epoxide reductase
-
-
-
-
vitamin K epoxide reductase
-
-
vitamin K epoxide reductase complex subunit 1
-
-
VKOR
-
-
VKORC1
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
analysis of the reaction mechanism by quantum mechanical methods, modeling, the geometries of proposed model intermediates in the mechanisms are energy optimized
-
phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
protein structure and catalytic mechanism, the enzyme activity is rate-limiting for the following gamma-carboxylation step
-
phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
quantum chemical study on mechanism and transition states. Once a key dissulfide is broken, the reaction proceeds largely downhill. The initial protonation of the epoxide oxygen is an important step, with the proton originating from a free mercapto group rather than a water molecule
-
phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
bi bi ping-pong mechanism for VKORC1, kinetic modeling
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-
SYSTEMATIC NAME
IUBMB Comments
phylloquinone:disulfide oxidoreductase
The enzyme catalyses the reduction of vitamin K 2,3-epoxide, which is formed by the activity of EC 4.1.1.90, peptidyl-glutamate 4-carboxylase, back to its phylloquinol active form. The enzyme forms a tight complex with EC 5.3.4.1, protein disulfide-isomerase, which transfers the required electrons from newly-synthesized proteins by catalysing the formation of disulfide bridges. The enzyme acts on the epoxide forms of both phylloquinone (vitamin K1) and menaquinone (vitamin K2). Inhibited strongly by (S)-warfarin and ferulenol.
CAS REGISTRY NUMBER
COMMENTARY
55963-40-1
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol + H2O
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
vitamin K + oxidized dithiothreitol + H2O
-
-
-
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + tris(3-hydroxypropyl)phosphine
?
by replacing dithiothreitol with tris(3-hydroxypropyl)phosphine and replacing imidazole with phosphate as pH buffer, all nonenzymatic side reactions are effectively eliminated and accurate measurement of enzymatic activity in vitro is possible
-
-
?
2,3-epoxyphylloquinone + 1,4-dithiothreitol
phylloquinone + oxidized dithiothreitol
-
-
-
-
?
2,3-epoxyphylloquinone + reduced thioredoxin
phylloquinone + oxidized thioredoxin
-
-
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + dithiothreitol
vitamin K hydroquinone + oxidized dithiothreitol
-
i.e. vitamin K
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
vitamin K + 1,4-dithiothreitol
vitamin K hydroquinone + oxidized dithiothreitol + H2O
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
-
?
vitamin K 2,3-epoxide + oxidized dithiothreitol
vitamin K + 1,4-dithiothreitol
-
-
-
-
ir
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
-
i.e. vitamin K 2,3-epoxide
i.e. vitamin K
-
?
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
-
i.e. vitamin K 2,3-epoxide
i.e. vitamin K, an important cofactor for the posttranslational gamma-carboxylation of several blood coagulation factors
-
?
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
-
i.e. vitamin K 2,3-epoxide, the enzyme initiates the vitamin K catalytic cycle, overview
i.e. vitamin K
-
?
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
-
i.e. vitamin K 2,3-epoxide, two dithiol-dependent steps
i.e. vitamin K
-
?
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol + H2O
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
-
-
-
?, r
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol + H2O
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
-
-
-
-
r
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
-
VKOR reduces vitamin K using membrane-embedded thiols, Cys132 and Cys135, which become oxidized with concomitant VKOR inactivation. VKOR is subsequently reactivated by an unknown redox protein that might act directly on the Cys132-Cys135 residues
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
-
r
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
r
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
crucial role of the Tyr-139 amino acid in this reaction mechanism, Tyr-139 residue appears to determine the second half-step of the catalytic mechanism
-
-
r
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
-
-
-
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
-
-
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
-
-
-
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
two patients suffering from combined deficiency of vitamin K-dependent clotting factors type 2 possess a R98W substitution at the presumed cytoplasmic end of TM alpha-helix 2. Because the residue is far-removed from the proposed active site its mutation is, therefore assumed to disrupt VKORC1 structure or VKOR complex assembly rather than catalysis
-
-
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
VKORC1 contains missense mutations in the two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2, Online Mendelian Inheritance in Man 607473) and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR, Online Mendelian Inheritance in man 122700)
-
-
?
additional information
?
-
-
VKOR is a part of the post-translational protein-modification system that produces gamma-carboxylated proteins. The vitamin K-dependent gamma-carboxylation system consists of the vitamin K-dependent gamma-carboxylase, which requires the reduced hydroquinone form of vitamin K1 as a cofactor and the warfarin-sensitive enzyme vitamin K1 2,3-epoxide reductase, VKOR. VKOR and gamma-carboxylase are close enough together in the membrane to operate as a supramolecular assembly of proteins, in which substrates and products are shuttled efficiently from one component to the next. Calumenin is likely to have a regulatory role in controlling the activity of the system
-
-
?
additional information
?
-
-
the enzyme is involved in coagulation factor activity
-
-
?
additional information
?
-
the enzyme is involved in coagulation factor activity
-
-
?
additional information
?
-
-
the enzyme is involved in reduction of vitamin K, which is required by the gamma-glutamyl carboxylase, GGCX, transforming glutamate to gamma carboxyl glutamic acid in a vitamin K-dependent manner, gamma carboxyl glutamic acid is required for activity of proteins involved in coagulation, overview
-
-
?
additional information
?
-
-
the enzyme is involved in regulation of response to oral anticoagulants of European-American warfarin patients
-
-
?
additional information
?
-
-
the VKCFD2 disease, a vitamin K-dependent clotting factor deficiency, is caused by enzyme mutations, VKORC1 is the key component of the vitamin K reductase activity targeted by coumarin-derived drugs in prophylaxis and therapy of thrombosis
-
-
?
additional information
?
-
vitamin K epoxide reductase is the enzyme responsible for the recycling of vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the synthesis of several blood coagulation factors
-
-
?
additional information
?
-
-
VKORC1 is the key gene of the vitamin K cycle encoding the molecular target of coumarin-type anticoagulants vitaminK epoxide reductase, VKORC1 recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, which functions as the essential cofactor for gamma-carboxylation of gamma-carboxyl-glutamic acid-domain proteins such as coagulation factors II, VII, IX, and X, proteins C, S, and Z, osteocalcin, matrix Gla protein MGP, and Gas6, gamma-glutamyl carboxylase, GGCX, is the enzyme that accomplishes the carboxylation reaction, VKORC1 represents the rate-limiting step in the reaction
-
-
?
additional information
?
-
-
Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2
-
-
?
additional information
?
-
-
the enzyme, driven by the reducing agent DTT, reduces both vitamin K 2,3-epoxide and vitamin K to the activated hydroquinone form
-
-
?
additional information
?
-
-
advantages and caveats of using the DTT-driven VKOR assay, overview
-
-
?
additional information
?
-
-
no synthesis of 3-hydroxyvitamin K1 by the wild-type enzyme, but by mutants Y139C, Y139F, and Y139S
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol + H2O
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
-
i.e. vitamin K 2,3-epoxide
i.e. vitamin K
-
?
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
-
i.e. vitamin K 2,3-epoxide
i.e. vitamin K, an important cofactor for the posttranslational gamma-carboxylation of several blood coagulation factors
-
?
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
-
i.e. vitamin K 2,3-epoxide, the enzyme initiates the vitamin K catalytic cycle, overview
i.e. vitamin K
-
?
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol + H2O
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
-
-
-
?, r
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol + H2O
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
-
-
-
-
r
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
-
VKOR reduces vitamin K using membrane-embedded thiols, Cys132 and Cys135, which become oxidized with concomitant VKOR inactivation. VKOR is subsequently reactivated by an unknown redox protein that might act directly on the Cys132-Cys135 residues
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
-
r
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
-
-
r
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
two patients suffering from combined deficiency of vitamin K-dependent clotting factors type 2 possess a R98W substitution at the presumed cytoplasmic end of TM alpha-helix 2. Because the residue is far-removed from the proposed active site its mutation is, therefore assumed to disrupt VKORC1 structure or VKOR complex assembly rather than catalysis
-
-
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
VKORC1 contains missense mutations in the two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2, Online Mendelian Inheritance in Man 607473) and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR, Online Mendelian Inheritance in man 122700)
-
-
?
additional information
?
-
-
VKOR is a part of the post-translational protein-modification system that produces gamma-carboxylated proteins. The vitamin K-dependent gamma-carboxylation system consists of the vitamin K-dependent gamma-carboxylase, which requires the reduced hydroquinone form of vitamin K1 as a cofactor and the warfarin-sensitive enzyme vitamin K1 2,3-epoxide reductase, VKOR. VKOR and gamma-carboxylase are close enough together in the membrane to operate as a supramolecular assembly of proteins, in which substrates and products are shuttled efficiently from one component to the next. Calumenin is likely to have a regulatory role in controlling the activity of the system
-
-
?
additional information
?
-
-
the enzyme is involved in coagulation factor activity
-
-
?
additional information
?
-
the enzyme is involved in coagulation factor activity
-
-
?
additional information
?
-
-
the enzyme is involved in reduction of vitamin K, which is required by the gamma-glutamyl carboxylase, GGCX, transforming glutamate to gamma carboxyl glutamic acid in a vitamin K-dependent manner, gamma carboxyl glutamic acid is required for activity of proteins involved in coagulation, overview
-
-
?
additional information
?
-
-
the enzyme is involved in regulation of response to oral anticoagulants of European-American warfarin patients
-
-
?
additional information
?
-
-
the VKCFD2 disease, a vitamin K-dependent clotting factor deficiency, is caused by enzyme mutations, VKORC1 is the key component of the vitamin K reductase activity targeted by coumarin-derived drugs in prophylaxis and therapy of thrombosis
-
-
?
additional information
?
-
vitamin K epoxide reductase is the enzyme responsible for the recycling of vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the synthesis of several blood coagulation factors
-
-
?
additional information
?
-
-
VKORC1 is the key gene of the vitamin K cycle encoding the molecular target of coumarin-type anticoagulants vitaminK epoxide reductase, VKORC1 recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, which functions as the essential cofactor for gamma-carboxylation of gamma-carboxyl-glutamic acid-domain proteins such as coagulation factors II, VII, IX, and X, proteins C, S, and Z, osteocalcin, matrix Gla protein MGP, and Gas6, gamma-glutamyl carboxylase, GGCX, is the enzyme that accomplishes the carboxylation reaction, VKORC1 represents the rate-limiting step in the reaction
-
-
?
additional information
?
-
-
the enzyme, driven by the reducing agent DTT, reduces both vitamin K 2,3-epoxide and vitamin K to the activated hydroquinone form
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
-
Ca2+ might play a role in stabilizing the lipid membranes that surround the VKORC1 protein, but does not affect the DTT-driven enzyme activity
additional information
additional information
-
human VKOR enzymatic activity is not Ca2+-dependent, no effect by EGTA
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
miR-133a
micro-RNA, miR-133a interacts with the 3'-UTR of VKORC1. Transfection of miRNA precursors of miR-133a in HepG2 cells reduces VKORC1 mRNA expression in a dose-dependent manner, quantitative RT-PCR expression analysis, overview. miR-133a levels correlate inversely with VKORC1 mRNA levels in 23 liver samples from healthy subjects. In silico identification of VKORC1 miRNA binding sites, overview
-
phenprocoumon
-
4-hydroxycoumarin-derived anticoagulation drug, blocks the recycling of vitamin K epoxid inhibiting the two dithiol-dependent steps performed by the enzyme
warfarin
mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2
warfarin
the enzyme is the therapeutic target site for warfarin, an anticoagulant that is prescribed widely for the treatment and prevention of thrombosis. Point mutations in VKORC1 may be an important, though rare, cause of warfarin resistance in anticoagulation clinic populations. V66M mutation is responsible for warfarin resistance phenotype
warfarin
-
4-hydroxycoumarin-derived anticoagulation drug, blocks the recycling of vitamin K epoxid inhibiting the two dithiol-dependent steps performed by the enzyme
warfarin
-
acts by blocking vitamin K at the active site of the enzyme and thereby effectively blocking the initial step
warfarin
-
non-competitive inhibitor, displacement of the warfarin binding site away from the vitamin K binding site by at least one turn of the transmembrane helix. The fully extended phenyl group of S-warfarin may interact with the phenyl fragment of Tyr139 of VKOR in a stacking configuration. Binding of S-warfarin to VKOR in the presence of vitamin K could modify, i.e. reduce the rate of flip-flop of lipid membrane, ultimately leading to the decrease of the amount of the vitamin K hydroquinone form
warfarin
-
hVKOR is directly and irreversibly inhibited by warfarin, hVKOR is the target of a common anticoagulant, warfarin. Tyr139 in hVKOR is part of the warfarin binding site
warfarin
-
the oral anticoagulant impairs the synthesis of functional clotting factors through inhibition of VKOR and is widely used for prevention and treatment of thrombosis
warfarin
mutants V29L, V45A, and L128R are resistant to inhibition by warfarin in vivo, oveview; VKORC1 function is measured in vitro using a dithiothreitol-driven vitamin K 2,3-epoxide reductase assay. Warfarin inhibits wild-type VKORC1 function by the DTTVKOR assay. However, VKORC1 variants with warfarin resistance-associated missense mutations often show low VKOR activities and warfarin sensitivity instead of resistance
warfarin
-
overnight treatment with the drug produces similar phenotypes to 7 days of siRNA-mediated VKOR depletion
warfarin
traps human vitamin K epoxide reductase in an intermediate state during electron transfer
warfarin
warfarin inhibits androgen receptor activity (an important driver of prostate cancer development and progression) by inhibiting vitamin K epoxide reductase
additional information
pharmacodynamics of resistance to warfarin, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0072
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, wild-type enzyme
0.012
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant L128Q
0.013
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant Y139S
0.018
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant Y139F
0.025
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant L120Q
0.06
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant Y139C
additional information
additional information
-
detailed thermodynamics, overview
-
additional information
additional information
-
VKORC1 kinetic modeling, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0072
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, wild-type enzyme
0.012
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant L128Q
0.013
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant Y139S
0.018
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant Y139F
0.025
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant L120Q
0.06
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant Y139C
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
VKORC1 kinetic model and derivation of the IC50-Ki transformation, overview
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.27
ATI-5900
Homo sapiens
-
in 250 mM potassium phosphate, 500 mM potassium chloride, 20% (v/v) glycerol and 0.75% (w/v) CHAPS at pH 7.85 and 25°C
0.00067
tecarfarin
Homo sapiens
-
in 250 mM potassium phosphate, 500 mM potassium chloride, 20% (v/v) glycerol and 0.75% (w/v) CHAPS at pH 7.85 and 25°C
0.0000247
warfarin
Homo sapiens
wild-type enzyme, pH and temperature not specified in the publication
0.000062
warfarin
Homo sapiens
mutant enzyme L27V, pH and temperature not specified in the publication
0.000069
warfarin
Homo sapiens
mutant enzyme V66G, pH and temperature not specified in the publication
0.000072
warfarin
Homo sapiens
mutant enzyme H28Q, pH and temperature not specified in the publication
0.000074
warfarin
Homo sapiens
mutant enzyme A26T, pH and temperature not specified in the publication
0.000078
warfarin
Homo sapiens
mutant enzyme D36G, pH and temperature not specified in the publication
0.000085
warfarin
Homo sapiens
mutant enzyme R58G, pH and temperature not specified in the publication
0.000093
warfarin
Homo sapiens
mutant enzyme D36Y, pH and temperature not specified in the publication
0.000096
warfarin
Homo sapiens
mutant enzyme N77Y, pH and temperature not specified in the publication
0.000112
warfarin
Homo sapiens
mutant enzyme V54L, pH and temperature not specified in the publication
0.000127
warfarin
Homo sapiens
mutant enzyme G71A, pH and temperature not specified in the publication
0.000131
warfarin
Homo sapiens
mutant enzyme N77S, pH and temperature not specified in the publication
0.000134
warfarin
Homo sapiens
mutant enzyme V66M, pH and temperature not specified in the publication
0.000136
warfarin
Homo sapiens
mutant V129L, pH and temperature not specified in the publication
0.000136
warfarin
Homo sapiens
mutant enzyme V29L, pH and temperature not specified in the publication
0.00014
warfarin
Homo sapiens
mutant enzyme S53W, pH and temperature not specified in the publication
0.000152
warfarin
Homo sapiens
mutant V145A, pH and temperature not specified in the publication
0.000152
warfarin
Homo sapiens
mutant enzyme V45A, pH and temperature not specified in the publication
0.000167
warfarin
Homo sapiens
mutant enzyme S56F, pH and temperature not specified in the publication
0.000182
warfarin
Homo sapiens
mutant enzyme S52L, pH and temperature not specified in the publication
0.000188
warfarin
Homo sapiens
mutant enzyme W59C, pH and temperature not specified in the publication
0.000209
warfarin
Homo sapiens
mutant enzyme I123N, pH and temperature not specified in the publication
0.000433
warfarin
Homo sapiens
mutant enzyme W59R, pH and temperature not specified in the publication
0.00084
warfarin
Homo sapiens
-
in 250 mM potassium phosphate, 500 mM potassium chloride, 20% (v/v) glycerol and 0.75% (w/v) CHAPS at pH 7.85 and 25°C
0.001224
warfarin
Homo sapiens
mutant enzyme A26P, pH and temperature not specified in the publication
0.001226
warfarin
Homo sapiens
mutant L128R, pH and temperature not specified in the publication
0.001226
warfarin
Homo sapiens
mutant enzyme L128R, pH and temperature not specified in the publication
0.001858
warfarin
Homo sapiens
mutant enzyme W59L, pH and temperature not specified in the publication
additional information
additional information
Homo sapiens
IC50 values for warfarin determined by different assay methods, overview
-
additional information
additional information
Homo sapiens
-
IC50 values for warfarin determined by different assay methods, overview
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
vitamin K epoxide reductase complex subunit 1
Swissprot
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
quantitative expression analysis, no enzyme expression in peripheral blood leukocytes, the enzyme is upregulated in tumour tissue, overview
-
the enzyme is upregulated in fetal heart and in ventricular aneurysm tissue
measurement of allelic mRNA expression. Genotype effect of 2-fold allelic mRNA expression due to single nucleotide polymorphisms -1639G>A and 1173C
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
ER membrane localisation, the enzyme has a typical ER retention signal, KAKRH at the C-terminus of the protein which is indispensable to activity
integral membrane enzyme of the endoplasmic reticulum
topology with large loop between transmembrane one and two facing the lumen of the endoplasmic reticulum (ER). A redox sensitive green fluorescent protein is fused to the N- or C-terminus to show that these regions face the cytosol, and introduction of glycosylation sites along with mixed disulfide formation with thioredoxin-like transmembrane protein (TMX) demonstrate ER localization of the major loop
-
membrane topology, type III membrane protein, overview
-
the enzyme possesses 3 or 4 transmembrane alpha-helices and a large cytoplasmic loop, membrane topology, overview
-
integral membrane protein, topology, overview
-
splice variant 2 of vitamin K epoxide reductase complex subunit 1 adopts a single-transmembrane topology placing the C tail in the endoplasmic reticulum lumen
-
the N-terminus of VKOR resides in the endoplasmic reticulum lumen, whereas its C-terminus is in the cytoplasm, three- and four-transmembrane domain topology models, overview
-
transmembrane protein with 5 transmembrane helices, membrane topology, overview
VKORC1L1 is a four-transmembrane domain protein with both its termini located in the cytoplasm
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
-
the enzyme belongs to the thiol-disulfide oxidoreductases. VKORL1, EC 1.1.4.2, is more highly conserved among vertebrates than its evolutionary relative VKOR, EC 1.1.4.1. The human paralogous proteins are 42% identical with 60% similarity
malfunction
metabolism
physiological function
additional information
malfunction
-
depletion of the protein disulfide formation activity of the enzyme in the endoplasmic reticulum results in cell death. Knockdown of the enzyme results in no detectable increase in expression of the ER Hsp70 chaperone BiP nor evidence of Xbp-1 splicing when measured on the final day of knockdown, indicating that an unfolded protein response is not being induced
malfunction
-
warfarin interfers with the vitamin K cycle by inhibiting VKOR thus limiting the available activated hydroquinone cofactor and functionally impeding various blood clotting proteins that are dependent on gamma-carboxyglutamate residues
metabolism
-
vitamin K carboxylase converts vitamin K, in the vitamin K cycle, to an alkoxide-epoxide form which then reacts with CO2 and glutamate to generate gamma-carboxyglutamic acid. Subsequently, vitamin K epoxide reductase converts the alkoxide-epoxide to a hydroquinone form. By recycling vitamin K, the two integral-membrane proteins maintain vitamin K levels and sustain the blood coagulation cascade. Heterodimeric form of vitamin K carboxylase and vitamin K epoxide reductase may explain the efficient oxidation and reduction of vitamin K during the vitamin K cycle
metabolism
-
VKOR contributes to an oxidizing endoplasmic reticulum environment under conditions of endoplasmic reticulum oxidoreductin and peroxiredoxin IV deficiency
metabolism
in vivo VKORC1L1 reduces vitamin K epoxide to support vitamin K-dependent carboxylation as efficiently as does VKORC1
metabolism
one of the key enzymes in the vitamin K cycle, which is essential for posttranslational modification of vitamin K-dependent proteins. Essential enzyme for vitamin K-dependent carboxylation
metabolism
vitamin K 2,3-epoxide reductase family enzymes are the gatekeepers between nutritionally acquired K vitamins and the vitamin K cycle responsible for posttranslational modifications that confer biological activity upon vitamin K-dependent proteins with crucial roles in hemostasis, bone development and homeostasis, hormonal carbohydrate regulation and fertility
physiological function
-
human herpesvirus 8 viral interleukin-6 interacts with splice variant 2 of vitamin K epoxide reductase complex subunit 1, VKORC1v2, via the C-terminal residues 31-39 of the enzyme in the endoplasmic reticulum lumen, interaction analysis, VKORC1v2 to intracellular retention of endogenously expressed vIL-6, detailed overview
physiological function
-
the enzyme is involved in the vitamin K cycle maintaining vitamin K levels and sustain the blood coagulation cascade
physiological function
the enzyme is regulated by microRNA miR-133a, which may have potential importance for anticoagulant therapy or aortic calcification. miR-133a levels correlate inversely with VKORC1 mRNA levels in 23 liver samples from healthy subjects
physiological function
-
vitamin K 2,3-epoxide reductase complex subunit 1 is an essential enzyme for proper function of blood coagulation
physiological function
-
vitamin K dependent oxidative protection is independent of VKOR inhibition by warfarin and GGCX inhibition by 2-chloro-vitamin K1, which indicated that vitamin K plays potential physiological roles outside of the realm of carboxylation. The hVKORL1, EC 11.4.2, turnover rate for vitamin K 2,3-epoxide reductase activity is significantly slower than for hVKOR
physiological function
-
vitamin K epoxide reductase contributes to protein disulfide formation and redox homeostasis within the endoplasmic reticulum,depletion of the activity results in cell death, both peroxiredoxin IV and VKOR support cell growth and viability in the face of endoplasmic reticulum oxidoreductin depletion
physiological function
-
vitamin K epoxide reductase is essential for the production of reduced vitamin K that is required for modification of vitamin K-dependent proteins
physiological function
-
the vitamin K oxidoreductase reduces vitamin K to support the carboxylation and consequent activation of vitamin K-dependent proteins
physiological function
VKORC1 is an essential element involved in the correct gamma-carboxylation of vitamin K-dependent proteins such as Gas6, matrix-GLA protein and osteocalcin, as well as hemostatic proteins C, S and Z and coagulation factors II, VII, IX and X. vitamin K 2,3-epoxide reductase complex subunit 1, VKORC1, is a key protein in the vitamin K cycle, it is regulated by microRNA miR-133a, overview. Vitamin K 2,3-epoxide reductase complex subunit 1 is a relevant molecule for cardiovascular diseases, since it plays a role in soft tissue calcification
additional information
-
conserved loop cysteines in VKOR are not required for active site regeneration after each cycle of oxidation
additional information
-
possible heterodimeric form of vitamin K carboxylase and vitamin K epoxide reductase during the vitamin K cycle and co-localization on the lumenal side of endoplasmic reticulum membrane, molecular dynamics simulations and modeling, overview
additional information
-
structure-function relationship, the CXXC redox center active site (hVKOR Cys132 and Cys135) is located in the final transmembrane helix near the endoplasmic reticulum lumen/periplasmic side of the membrane, overview
additional information
VKORC1 function is measured in vitro using a dithiothreitol-driven vitamin K 2,3-epoxide reductase assay. Warfarin inhibits wild-type VKORC1 function by the DTT-VKOR assay. However, VKORC1 variants with warfarin resistance-associated missense mutations often show low VKOR activities and warfarin sensitivity instead of resistance. Development and evaluation of a cell culture-based, indirect VKOR assay accurately reports warfarin sensitivity or resistance for wild-type and variant VKORC1 proteins
additional information
-
VKORC1 function is measured in vitro using a dithiothreitol-driven vitamin K 2,3-epoxide reductase assay. Warfarin inhibits wild-type VKORC1 function by the DTT-VKOR assay. However, VKORC1 variants with warfarin resistance-associated missense mutations often show low VKOR activities and warfarin sensitivity instead of resistance. Development and evaluation of a cell culture-based, indirect VKOR assay accurately reports warfarin sensitivity or resistance for wild-type and variant VKORC1 proteins
additional information
VKORC1 function is measured in vitro using a dithiothreitol-driven vitamin K 2,3-epoxide reductase assay. Warfarin inhibits wild-type VKORC1 function by the DTTVKOR assay. However, VKORC1 variants with warfarin resistance-associated missense mutations often show low VKOR activities and warfarin sensitivity instead of resistance. Development and evaluation of a cell culture-based, indirect VKOR assay accurately reports warfarin sensitivity or resistance for wild-type and variant VKORC1 proteins
additional information
-
VKORC1 function is measured in vitro using a dithiothreitol-driven vitamin K 2,3-epoxide reductase assay. Warfarin inhibits wild-type VKORC1 function by the DTTVKOR assay. However, VKORC1 variants with warfarin resistance-associated missense mutations often show low VKOR activities and warfarin sensitivity instead of resistance. Development and evaluation of a cell culture-based, indirect VKOR assay accurately reports warfarin sensitivity or resistance for wild-type and variant VKORC1 proteins
additional information
-
role for Cys43 and Cys51 in catalysis with a relay mechanism in which a redox protein transfers electrons to these loop residues, which in turn reduce the membrane-embedded Cys132-Cys135 disulfide bond to activate VKOR
additional information
identification of the functional states of human Vitamin K epoxide reductase from molecular dynamics simulations
additional information
phylogenetic characterization of VKOR family proteins. A chronology for the evolution of the five extant VKOR clades is suggested
additional information
-
phylogenetic characterization of VKOR family proteins. A chronology for the evolution of the five extant VKOR clades is suggested
additional information
the conserved loop cysteines of VKORC1L1, but not VKORC1, are involved in active site regeneration through an intra-molecular pathway. The different structures and reaction mechanisms of VKORC1L1 and VKORC1 may imply that these two enzymes have different physiological functions
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). VKOR1_HUMAN
163
3
18235
Swiss-Prot
Secretory Pathway (Reliability: 1)
VKORL_HUMAN
176
2
19836
Swiss-Prot
Mitochondrion (Reliability: 4)
A0A0S2Z5X7_HUMAN
92
1
9875
TrEMBL
Secretory Pathway (Reliability: 1)
A0A0B5EFL6_HUMAN
64
2
7385
TrEMBL
Secretory Pathway (Reliability: 1)
I3L3B4_HUMAN
104
1
11083
TrEMBL
Secretory Pathway (Reliability: 1)
F8W9H0_HUMAN
149
1
15952
TrEMBL
Secretory Pathway (Reliability: 1)
A0A3B3ISV4_HUMAN
223
3
23499
TrEMBL
other Location (Reliability: 2)
A0A0S2Z6I4_HUMAN
163
3
18235
TrEMBL
Secretory Pathway (Reliability: 1)
H0YD56_HUMAN
121
2
13615
TrEMBL
Secretory Pathway (Reliability: 5)
I3L1P9_HUMAN
43
1
4894
TrEMBL
Secretory Pathway (Reliability: 1)
B5B596_HUMAN
68
2
7862
TrEMBL
Secretory Pathway (Reliability: 1)
A8K0F7_HUMAN
176
4
19776
TrEMBL
Mitochondrion (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
18000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
the enzyme possesses a dicoumarol binding hydrophobic sequence motif TYA, VKOR complex structure, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C1173T
C132A
C135A
C16A
C43A
C43A/C51A
C51A
C85A
C96A
DELTAC43-C51
G6R
-
site-directed mutagenesis, the mutant shows altered membrane topology compared to the wild-type enzyme
G9R
-
site-directed mutagenesis, the mutant shows altered membrane topology compared to the wild-type enzyme
I123N
I86P
mutation has only a minor effect on the activity of wild-type enzyme, but it has a dramatic effect on the activity of the VKOR-CM mutant (a mutant with mutations in the charged residues flanking transmembrane domain 1), decreasing its activity to about 10%
K30L
-
site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
L120Q
-
naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, no synthesis of no 2-OH-vitamin K1 or 3-OH-vitamin K1
L128Q
-
naturally occuring mutation, no synthesis of no 2-OH-vitamin K1 or 3-OH-vitamin K1
L128R
R33G
-
site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
R35G
-
site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
R37G
-
site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
R58G
R98W
S7R
-
site-directed mutagenesis, the mutant shows altered membrane topology compared to the wild-type enzyme
V29L
V45A
V66M
Y139C
Y139F
Y139S
additional information
C1173T
-
a single nucleotide polymorphism, SNP, for haplotypes associated with a lower oral anticoagulant dose requirement
C1173T
natural genetic polymorphism of the enzyme in a Chinese and a Caucasian population, genotyping, the exchange for T at position 1173 in asian patients results in a phenotype with higher sensitivity to oral anticoagulants, overview
C132A
mutation eliminates enzymatic activity in conversion of vitamin K to vitamin K hydroquinone
C135A
mutation eliminates enzymatic activity in conversion of vitamin K to vitamin K hydroquinone
C16A
about 85% of wild-type activity in conversion of vitamin K to vitamin K hydroquinone. Mutant enzyme retains 40% of the wild-type activityin conversion of vitamin K to vitamin K hydroquinone
C43A
-
naturally occuring mutant, active in presence of DTT, which helps to bypass C43
C43A
-
site-directed mutagenesis, the mutant shows vitamin K epoxide reduction activity similar to the wild-type enzyme, but only with the membrane-permeant reductant DTT, no mutant activity with thioredoxin as reductant
C43A
about 75% of wild-type activity in conversion of vitamin K to vitamin K hydroquinone. Mutant enzyme retains 25% of the wild-type activityin conversion of vitamin K to vitamin K hydroquinone
C43A/C51A
-
site-directed mutagenesis, the mutation has a minor effect on VKOR activity, the mutant of the altered four-transmembrane domain form of VKOR is more active than the wild-type three-transmembrane domain enzyme
C43A/C51A
about 50% of wild-type activity in conversion of vitamin K to vitamin K hydroquinone. The deletion mutant enzyme retains 85% of the wild-type activity in the conversion of vitamin K 2,3-epoxide to vitamin K
C51A
-
naturally occuring mutant, active in presence of DTT, which helps to bypass C43
C51A
-
site-directed mutagenesis, the mutation has a minor effect on VKOR activity, the mutant of the altered four-transmembrane domain form of VKOR is more active than the wild-type three-transmembrane domain enzyme
C51A
-
site-directed mutagenesis, the mutant shows vitamin K epoxide reduction activity similar to the wild-type enzyme, but only with the membrane-permeant reductant DTT, no mutant activity with thioredoxin as reductant
C51A
mutant enzyme retains essentially wild-type activity in conversion of vitamin K to vitamin K hydroquinone
C85A
about 55% of wild-type activity in conversion of vitamin K to vitamin K hydroquinone. Mutant enzyme retains 105% of the wild-type activityin conversion of vitamin K to vitamin K hydroquinone
C96A
about 50% of wild-type activity in conversion of vitamin K to vitamin K hydroquinone. Mutant enzyme retains 40% of the wild-type activityin conversion of vitamin K to vitamin K hydroquinone
DELTAC43-C51
about 50% of wild-type activity in conversion of vitamin K to vitamin K hydroquinone. The deletion mutant enzyme retains 112% of the wild-type activity in the conversion of vitamin K 2,3-epoxide to vitamin K
L128R
VKOR activity is reduced to 5.2% of the activity of the wild-type enzyme
L128R
site-directed mutagenesis, the mutant is resistant to warfarin and oral anti-coagulants
R58G
VKOR activity is reduced to 20.6% of the activity of the wild-type enzyme
R98W
-
two patients suffering from combined deficiency of vitamin K-dependent clotting factors type 2 possess a R98W substitution at the presumed cytoplasmic end of TM alpha-helix 2 of vitamin-K-epoxide reductase. Because the residue is far-removed from the proposed active site its mutation is, therefore assumed to disrupt VKORC1 structure or VKOR complex assembly rather than catalysis
R98W
VKOR activity is reduced to 8.9% of the activity of the wild-tyoe enzyme
V29L
VKOR activity is reduced to 96.6% of the activity of the wild-type enzyme.Above 0.02 mM warfarin the mutant enzyme retains higher VKOR activity than the wild-type enzyme
V29L
site-directed mutagenesis, the mutant is resistant to warfarin and oral anti-coagulants
V45A
VKOR activity is reduced to 23% of the activity of the wild-type enzyme
V45A
site-directed mutagenesis, the mutant is resistant to warfarin and oral anti-coagulants
V66M
naturally occuring VKORC1 mutant showing warfarin-resistance, patients with this mutation need a very high dosage of anticoagulants in therapy, overview
Y139C
VKOR activity is reduced to 48% of the activity of the wild-type enzyme. Above 0.02 mM warfarin the mutant enzyme retains higher VKOR activity than the wild-type enzyme
Y139C
-
naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, additional synthesis of 3-hydroxyvitamin K1
Y139C
-
site-directed mutagenesis, the mutation dramatically affects the vitamin K epoxide reductase activity
Y139F
-
naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, additional synthesis of 3-hydroxyvitamin K1
Y139F
-
the mutant is warfarin insensitive and shows altered membrane topology compared to the wild-type enzyme
Y139S
-
naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, additional synthesis of 3-hydroxyvitamin K1
Y139S
-
site-directed mutagenesis, the mutation dramatically affects the vitamin K epoxide reductase activity, additional production of 3-hydroxyvitamin K1 in the mutant
additional information
VKORC1 contains missense mutations in the two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2, Online Mendelian Inheritance in Man 607473) and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR, Online Mendelian Inheritance in man 122700)
additional information
-
VKORC1 contains missense mutations in the two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2, Online Mendelian Inheritance in Man 607473) and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR, Online Mendelian Inheritance in man 122700)
additional information
-
deficient enzyme mutants cause VKCFD2 disease phenotype
additional information
-
enzyme overexpression stimulates cell proliferation, while inhibition of enzyme expression by antisense constructs reduces it, overview
additional information
-
expression of the enzyme in HEK-293 cells significantly improves carboxylation in a HEK-293 cell line overexpressing factor X
additional information
-
mutations in VKORC1 cause 2 distinctive phenotypes: a homozygous missense mutation in the VKORC1 gene leads to combined deficiency of vitamin Kdependent coagulation factors type 2, VKCFD2, and heterozygous missense mutations are responsible for hereditary warfarin resistance, expression of the enzyme in HEK-293 cells significantly improves carboxylation in a HEK-293 cell line overexpressing factor X
additional information
in vitro expression of VKORC1 gene constructs, including coding region and promoter, fails to reveal any genotype effect on transcription and mRNA processing
additional information
-
in vitro expression of VKORC1 gene constructs, including coding region and promoter, fails to reveal any genotype effect on transcription and mRNA processing
additional information
-
patient with warfarin resistance due to a 383T>G transition in exon 2 of the VKORC1 gene, patient is heterozygous for the mutation
additional information
genetic variation in the vitamin K epoxide reductase gene is associated with variation in plasma phylloquinone concentrations
additional information
-
genetic variation in the vitamin K epoxide reductase gene is associated with variation in plasma phylloquinone concentrations
additional information
-
VKORC1 gene polymorphisms are associated with warfarin dose requirements in Turkish patients
additional information
construction of warfarin-resistant VKORC1 variants following naturally occuring mutations in patients
additional information
-
construction of warfarin-resistant VKORC1 variants following naturally occuring mutations in patients
additional information
-
knockout of endogenous VKOR activity, i.e. VKOR and VKORC1L1 enzymes, in HEK-293 cells by transcription activator-like effector nucleases (TALENs)-mediated genome editing, overview. VKOR knockout cells regained KO reductase activity through VKORC1L1 after culturing for several generations (Figure 3A). In addition, this activity is sensitive to warfarin inhibition as the wild-type cells
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme from Sf9 insect cell microsomes by ultracentrifugation, followed by HPC4 affinity chromatography in presence of DHPC and reconstitution in mixed detergent micelles, method optimization
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
coexpression of human coagulation factor (F)IX and c-myc-tagged VKORC1 mutant variants in HEK-293T cells in presence of varying warfarin concentrations
coexpression of human coagulation factor (F)IX andc-myc-tagged VKORC1 wild-type and mutants in HEK-293T cells in presence of varying warfarin concentrations
expression in neural cell lines SK-N-MC and Neuro-2a, and in a human kidney cell line, HEK-293
expression in Spodoptera frugiperda Sf21 cell microsomes using baculovirus containing wild-type or mutant VKORs transfection method, in vitro transcription and translation of the human enzyme using r-VKORC1/ZEM229 as the template
-
expression of different constructs of N- or C-terminally NST-tagged or HPC4-tagged enzyme in insect cells, the NST tag is an N-linked glycosylation tag without a flexible linker, ER membrane topology of the recombinant enzymes, the tagged enzyme is glycosylated, overview
-
expression of the human enzyme with the human herpesvirus 8 viral interleukin-6 in the yeast two-hybrid system using Saccharomyces cerevisiae strain AH109
-
expressionof N- and C-terminally GFP-tagged enzyme in HEK293 cells, the N-terminus of VKOR resides in the ER lumen, whereas its C-terminus is in the cytoplasm
-
gene rs9923231 or VKORC1, genotyping of rs9923231, quantitative RT-PCR expression analysis
gene rs9923231, quantitative reverse transcriptasePCR expression analysis
gene Vkorc1, expression of wild-type and mutant enzymes in Pichia pastoris as membrane bound protein
-
gene VKORC1, genotyping, phenotypes of enzyme single nucleotide polymorphisms naturally occuring in Caucasian population
-
gene VKORC1, located on chromosome 16, DNA and amino acid sequenc determination and analysis, genetic structure, expression in Spodoptera frugiperda Sf9 cells and in Pichia pastoris
-
gene VKORC1, stable overexpression in factor IX BHK cell microsomes increasing 2.2fold the extent of secreted factor IX in vivo carboxylation, overview
-
overexpression of the enzyme in HEK-293 cell FX co-expressing factor X mutant I16L possessing a prothrombin propeptide
-
overexpression of the enzyme in HEK-293 cell FX co-expressing factor X mutant I16L possessing a prothrombin propeptide, expression analysis of the functional enzyme, overview
-
overexpression of VKOR in Spodoptera frugiperda Sf9 cells using the baculovirus transfection system
-
recombinant enzyme expression in Pichia pastoris strain SMD 1168 Kex1- endoplasmic reticulum membranes from a vector encoding (in 5'- to 3'-order): N-terminal alpha-mating factor from Saccharomyces cerevisiae, flag-tag epitope, His10-tag, Tev protease cleavage site, multiple cloning site, C-terminal Tev cleavage site, EGFP, Strep-tag II. The human VKORC1 DNA sequence is inserted into the multiple cloning site
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
micro-RNA miR-133a interacts with the 3'-UTR of VKORC1. Transfection of miRNA precursors of miR-133a in HepG2 cells reduces VKORC1 mRNA expression. miR-133a levels correlate inversely with VKORC1 mRNA levels in 23 liver samples from healthy subjects
miR-133a miRNA targeting the enzyme in HepG2 cells reduces VKORC1 mRNA expression in a dose-dependent manner, quantitative reverse transcriptasepolymerase chain reaction expression analysis. miR-133a interacts with the 3'-UTR of VKORC1
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
reconstitution of purified recombinant enzyme using 0.4% DOPC/0.4% deoxycholate/2 mM CaCl2/4 mM THP in 25 mM 3-(Nmorpholino)-propanesulfonic acid, 150 mM NaCl, and 20%glycerol at pH 7.5, method optimization
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
the enzyme is the therapeutic target site for warfarin, an anticoagulant that is prescribed widely for the treatment and prevention of thrombosis. Point mutations in VKORC1 may be an important, though rare, cause of warfarin resistance in anticoagulation clinic populations
medicine
-
comparison of the effect of single nucleotide polymorphisms in African Americans and Caucasians. Subjects carrying an 1173T allele have a lower warfarin maintenance compared with subjects with the CC genotype in African americans and Caucasians. Before reaching maintenance dose, only Caucasians with the T allele have significantly increased risk of international normlized ratio > 3 compared with Caucasians with the CC genotype. Polymorphisms may not be useful in predicting over-coagulation among African Americans
medicine
-
patient with warfarin resistance due to a T383G transition in exon 2 of the VKORC1 gene, patient is heterozygous for the mutation
medicine
-
study on the association between the 1173C>T polymorphism in the VKORC1 gene and calcification of the aortic far wall. Persons with at least one T-allele have a statistically significant 19% risk increase of calcification of the aortic far wall compared to CC homozygous persons, adjusted for age and gender
medicine
the single nucleotide polymorphism G1639A is a suitable biomarker for warfarin dosing across ethnic populations. Preferential association of the promoter -1639 G allele with active chromatin
medicine
-
polymorphisms in the VKORC1 gene are important determinants of warfarin dose requirements in Turkish patients
medicine
-
the determination of VKORC1-3 and VKORC1-4 haplotypes may be an important addition to CYP2C9 and VKORC1-2 genotyping to identify patients at risk of being outside the target range during initial anticoagulation with acenocoumarol
medicine
-
VKORC1 genotype affects daily dose requirements and time to therapeutic international normalized ratio in Turkish patients receiving warfarin for anticoagulation
medicine
VKORC1 haplotypes influence the performance characteristics of protein induced by vitamin K absence II for screening of hepatocellular carcinoma
medicine
the enzyme is regulated by microRNA miR-133a, which may have potential importance for anticoagulant therapy or aortic calcification
medicine
vitamin K 2,3-epoxide reductase complex subunit 1 is is the target of oral anticoagulant drugs and a relevant molecule for cardiovascular diseases
medicine
the T-allele of the VKORC1 1173CT polymorphism is associated with a significantly higher risk of aortic calcification in Whites
medicine
VKORC1 gene rs7294 polymorphism is important for the development of essential hypertension
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VOL.
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ORGANISM (UNIPROT)
PUBMED ID
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Homo sapiens (Q9BQB6), Homo sapiens
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427
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Homo sapiens (Q9BQB6), Homo sapiens
Harrington, D.J.; Underwood, S.; Morse, C.; Shearer, M.J.; Tuddenham, E.G.; Mumford, A.D.
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Homo sapiens, Homo sapiens (Q9BQB6)
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Species comparison of vitamin K1 2,3-epoxide reductase activity in vitro: kinetics and warfarin inhibition
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2003
Bos taurus, Canis lupus familiaris, Equus caballus, Ovis aries, Homo sapiens, Mus musculus, Sus scrofa
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Homo sapiens
Wallin, R.; Hutson, S.M.
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Homo sapiens, Rattus norvegicus
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Homo sapiens, Mus musculus, Rattus norvegicus
Larramendy-Gozalo, C.; Yang, J.Q.; Verstuyft, C.; Bodin, L.; Dubert, L.; Zhang, Y.; Xu, C.; Fan, L.; Jaillon, P.; Becquemont, L.
Genetic polymorphism of vitamin K epoxide reductase (VKORC1) 1173C>T in a Chinese and a Caucasian population
Basic Clin. Pharmacol. Toxicol.
98
611-613
2006
Homo sapiens (Q9BQB6)
Hallgren, K.W.; Qian, W.; Yakubenko, A.V.; Runge, K.W.; Berkner, K.L.
r-VKORC1 expression in factor IX BHK cells increases the extent of factor IX carboxylation but is limited by saturation of another carboxylation component or by a shift in the rate-limiting step
Biochemistry
45
5587-5598
2006
Homo sapiens
Sun, Y.M.; Jin, D.Y.; Camire, R.M.; Stafford, D.W.
Vitamin K epoxide reductase significantly improves carboxylation in a cell line overexpressing factor X
Blood
106
3811-3815
2005
Homo sapiens
Rettie, A.E.; Farin, F.M.; Beri, N.G.; Srinouanprachanh, S.L.; Rieder, M.J.; Thijssen, H.H.
A case study of acenocoumarol sensitivity and genotype-phenotype discordancy explained by combinations of polymorphisms in VKORC1 and CYP2C9
Br. J. Clin. Pharmacol.
62
617-620
2006
Homo sapiens
Deerfield, D.I.; Davis, C.H.; Wymore, T.; Stafford, D.W.; Pedersen, L.G.
Quantum chemical study of the mechanism of action of vitamin K epoxide reductase (VKOR)
Int. J. Quantum Chem.
106
2944-2952
2006
Homo sapiens
-
Tie, J.K.; Nicchitta, C.; von Heijne, G.; Stafford, D.W.
Membrane topology mapping of vitamin K epoxide reductase by in vitro translation/cotranslocation
J. Biol. Chem.
280
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2005
Homo sapiens
Hatch, E.; Sconce, E.A.; Daly, A.K.; Kamali, F.
A rapid genotyping method for the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene
J. Thromb. Haemost.
4
1158-1159
2006
Homo sapiens
Wang, Y.; Zhen, Y.; Shi, Y.; Chen, J.; Zhang, C.; Wang, X.; Yang, X.; Zheng, Y.; Liu, Y.; Hui, R.
Vitamin K epoxide reductase: a protein involved in angiogenesis
Mol. Cancer Res.
3
317-323
2005
Homo sapiens
Chu, P.H.; Huang, T.Y.; Williams, J.; Stafford, D.W.
Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2
Proc. Natl. Acad. Sci. USA
103
19308-19313
2006
Homo sapiens
Teichert, M.; Visser, L.E.; van Schaik, R.H.; Hofman, A.; Uitterlinden, A.G.; De Smet, P.A.; Witteman, J.C.; Stricker, B.H.
Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism and aortic calcification: the Rotterdam Study
Arterioscler. Thromb. Vasc. Biol.
28
771-776
2008
Homo sapiens
Jin, D.Y.; Tie, J.K.; Stafford, D.W.
The conversion of vitamin K epoxide to vitamin K quinone and vitamin K quinone to vitamin K hydroquinone uses the same active site cysteines
Biochemistry
46
7279-7283
2007
Homo sapiens
Wang, D.; Chen, H.; Momary, K.M.; Cavallari, L.H.; Johnson, J.A.; Sadee, W.
Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement
Blood
112
1013-1021
2008
Homo sapiens (Q9BQB6), Homo sapiens
Schelleman, H.; Chen, Z.; Kealey, C.; Whitehead, A.S.; Christie, J.; Price, M.; Brensinger, C.M.; Newcomb, C.W.; Thorn, C.F.; Samaha, F.F.; Kimmel, S.E.
Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians
Clin. Pharmacol. Ther.
81
742-747
2007
Homo sapiens
Ainle, F.N.; Mumford, A.; Tallon, E.; McCarthy, D.; Murphy, K.
A vitamin K epoxide reductase complex subunit 1 mutation in an Irish patient with warfarin resistance
Ir. J. Med. Sci.
177
159-161
2008
Homo sapiens
Davis, C.H.; Deerfield, D.; Wymore, T.; Stafford, D.W.; Pedersen, L.G.
A quantum chemical study of the mechanism of action of Vitamin K epoxide reductase (VKOR) II. Transition states
J. Mol. Graph. Model.
26
401-408
2007
Homo sapiens
Oner Ozgon, G.; Langaee, T.Y.; Feng, H.; Buyru, N.; Ulutin, T.; Hatemi, A.C.; Siva, A.; Saip, S.; Johnson, J.A.
VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients
Eur. J. Clin. Pharmacol.
64
889-894
2008
Homo sapiens
Crosier, M.D.; Peter, I.; Booth, S.L.; Bennett, G.; Dawson-Hughes, B.; Ordovas, J.M.
Association of sequence variations in vitamin K epoxide reductase and gamma-glutamyl carboxylase genes with biochemical measures of vitamin K status
J. Nutr. Sci. Vitaminol.
55
112-119
2009
Homo sapiens (Q9BQB6), Homo sapiens
Spreafico, M.; Loadigiani, C.; van Leeuwen, Y.; Pizzotti, D.; Rota, L.L.; Rosendaal, F.R.; Mannucci, P.M.; Peyvandi, F.
Effects of CYP2C9 and VKORC1 on INR variations and dose rewuirements during initial phase of anticoagulant therapy
Pharmacogenomics
9
1237-1250
2008
Homo sapiens
Berkner, K.L.
Vitamin K-dependent carboxylation
Vitam. Horm.
78
131-156
2008
Homo sapiens
Wallin, R.; Wajih, N.; Hutson, S.M.
VKORC1: a warfarin-sensitive enzyme in vitamin K metabolism and biosynthesis of vitamin K-dependent blood coagulation factors
Vitam. Horm.
78
227-246
2008
Homo sapiens, Rattus norvegicus
Garcia, A.A.; Reitsma, P.H.
VKORC1 and the vitamin K cycle
Vitam. Horm.
78
23-33
2008
Homo sapiens
Choppin, A.; Irwin, I.; Lach, L.; McDonald, M.G.; Rettie, A.E.; Shao, L.; Becker, C.; Palme, M.P.; Paliard, X.; Bowersox, S.; Dennis, D.M.; Druzgala, P.
Effect of tecarfarin, a novel vitamin K epoxide reductase inhibitor, on coagulation in beagle dogs
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158
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2009
Canis lupus familiaris, Homo sapiens
Wang, Y.; Luo, F.; Zheng, Y.; Fan, X.; Chen, J.; Zhang, Y.; Hui, R.
VKORC1 haplotypes influence the performance characteristics of PIVKAII for screening of hepatocellular carcinoma
Clin. Chem. Lab. Med.
48
1475-1479
2010
Homo sapiens (Q9BQB6), Homo sapiens
Ozer, N.; Cam, N.; Tangurek, B.; Ozer, S.; Uyarel, H.; Oz, D.; Guney, M.R.; Ciloglu, F.
The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements in an adult Turkish population
Heart Vessels
25
155-162
2010
Homo sapiens
Rishavy, M.A.; Usubalieva, A.; Hallgren, K.W.; Berkner, K.L.
Novel insight into the mechanism of the vitamin K oxidoreductase (VKOR): electron relay through Cys43 and Cys51 reduces VKOR to allow vitamin K reduction and facilitation of vitamin K-dependent protein carboxylation
J. Biol. Chem.
286
7267-7278
2011
Homo sapiens
Wu, S.; Liu, S.; Davis, C.H.; Stafford, D.W.; Kulman, J.D.; Pedersen, L.G.
A hetero-dimer model for concerted action of vitamin K carboxylase and vitamin K reductase in vitamin K cycle
J. Theor. Biol.
279
143-149
2011
Homo sapiens
Bevans, C.G.; Krettler, C.; Reinhart, C.; Tran, H.; Kossmann, K.; Watzka, M.; Oldenburg, J.
Determination of the warfarin inhibition constant Ki for vitamin K 2,3-epoxide reductase complex subunit-1 (VKORC1) using an in vitro DTT-driven assay
Biochim. Biophys. Acta
1830
4202-4210
2013
Homo sapiens
Van Horn, W.D.
Structural and functional insights into human vitamin K epoxide reductase and vitamin K epoxide reductase-like1
Crit. Rev. Biochem. Mol. Biol.
48
357-372
2013
Homo sapiens, Mycobacterium tuberculosis
Matagrin, B.; Hodroge, A.; Montagut-Romans, A.; Andru, J.; Fourel, I.; Besse, S.; Benoit, E.; Lattard, V.
New insights into the catalytic mechanism of vitamin K epoxide reductase (VKORC1) - The catalytic properties of the major mutations of rVKORC1 explain the biological cost associated to mutations
FEBS Open Bio
3
144-150
2013
Homo sapiens
Tie, J.K.; Jin, D.Y.; Stafford, D.W.
Human vitamin K epoxide reductase and its bacterial homologue have different membrane topologies and reaction mechanisms
J. Biol. Chem.
287
33945-33955
2012
Homo sapiens
Tie, J.K.; Jin, D.Y.; Tie, K.; Stafford, D.W.
Evaluation of warfarin resistance using TALENs-mediated vitamin K epoxide reductase knockout HEK293 cells
J. Thromb. Haemost.
11
1556-1564
2013
Homo sapiens
Fregin, A.; Czogalla, K.J.; Gansler, J.; Rost, S.; Taverna, M.; Watzka, M.; Bevans, C.G.; Mueller, C.R.; Oldenburg, J.
A new cell culture-based assay quantifies vitamin K 2,3-epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol-driven VKOR assay
J. Thromb. Haemost.
11
872-880
2013
Homo sapiens (Q9BQB6), Homo sapiens
Chen, D.; Cousins, E.; Sandford, G.; Nicholas, J.
Human herpesvirus 8 viral interleukin-6 interacts with splice variant 2 of vitamin K epoxide reductase complex subunit 1
J. Virol.
86
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2012
Homo sapiens
Rutkevich, L.A.; Williams, D.B.
Vitamin K epoxide reductase contributes to protein disulfide formation and redox homeostasis within the endoplasmic reticulum
Mol. Biol. Cell
23
2017-2027
2012
Homo sapiens
Perez-Andreu, V.; Teruel, R.; Corral, J.; Roldan, V.; Garcia-Barbera, N.; Salloum-Asfar, S.; Gomez-Lechon, M.J.; Bourgeois, S.; Deloukas, P.; Wadelius, M.; Vicente, V.; Gonzalez-Conejero, R.; Martinez, C.
miR-133a regulates vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), a key protein in the vitamin K cycle
Mol. Med.
18
1466-1472
2012
Homo sapiens (Q6BQB6), Homo sapiens (Q9BQB6), Homo sapiens
Krettler, C.; Bevans, C.G.; Reinhart, C.; Watzka, M.; Oldenburg, J.
Tris(3-hydroxypropyl)phosphine is superior to dithiothreitol for in vitro assessment of vitamin K 2,3-epoxide reductase activity
Anal. Biochem.
474
89-94
2015
Homo sapiens (Q9BQB6)
Holden, R.M.; Booth, S.L.; Tuttle, A.; James, P.D.; Morton, A.R.; Hopman, W.M.; Nolan, R.L.; Garland, J.S.
Sequence variation in vitamin K epoxide reductase gene is associated with survival and progressive coronary calcification in chronic kidney disease
Arterioscler. Thromb. Vasc. Biol.
34
1591-1596
2014
Homo sapiens (Q9BQB6)
Cao, Z.; van Lith, M.; Mitchell, L.J.; Pringle, M.A.; Inaba, K.; Bulleid, N.J.
The membrane topology of vitamin K epoxide reductase is conserved between human isoforms and the bacterial enzyme
Biochem. J.
473
851-858
2016
Homo sapiens (Q9BQB6), Homo sapiens
Jaenecke, F.; Friedrich-Epler, B.; Parthier, C.; Stubbs, M.T.
Membrane composition influences the activity of in vitro refolded human vitamin K epoxide reductase
Biochemistry
54
6454-6461
2015
Homo sapiens (Q9BQB6), Homo sapiens
Czogalla, K.J.; Biswas, A.; Wendeln, A.C.; Westhofen, P.; Mller, C.R.; Watzka, M.; Oldenburg, J.
Human VKORC1 mutations cause variable degrees of 4-hydroxycoumarin resistance and affect putative warfarin binding interfaces
Blood
122
2743-2750
2013
Homo sapiens (Q9BQB6), Homo sapiens
Itoh, S.; Onishi, S.
Developmental changes of vitamin K epoxidase and reductase activities involved in the vitamin K cycle in human liver
Early Hum. Dev.
57
15-23
2000
Homo sapiens
Turgut Cosan, D.; Yazici, H.U.; Colak, E.; Soyocak, A.; Degirmenci, I.; Kurt, H.; Birdane, A.; Colak, E.; Gunes, H.V.
Susceptiveness of vitamin K epoxide reductase complex subunit 1 gene polymorphism in essential hypertension
Genet. Test. Mol. Biomarkers
21
292-297
2017
Homo sapiens (Q9BQB6), Homo sapiens
Tie, J.K.; Jin, D.Y.; Stafford, D.W.
Conserved loop cysteines of vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) are involved in its active site regeneration
J. Biol. Chem.
289
9396-9407
2014
Homo sapiens (Q8N0U8)
Shen, G.; Cui, W.; Zhang, H.; Zhou, F.; Huang, W.; Liu, Q.; Yang, Y.; Li, S.; Bowman, G.R.; Sadler, J.E.; Gross, M.L.; Li, W.
Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer
Nat. Struct. Mol. Biol.
24
69-76
2017
Homo sapiens (Q9BQB6), Homo sapiens
Bevans, C.G.; Krettler, C.; Reinhart, C.; Watzka, M.; Oldenburg, J.
Phylogeny of the vitamin K 2,3-epoxide reductase (VKOR) family and evolutionary relationship to the disulfide bond formation protein B (DsbB) family
Nutrients
7
6224-6249
2015
Homo sapiens (Q9BQB6), Homo sapiens
Tew, B.Y.; Hong, T.B.; Otto-Duessel, M.; Elix, C.; Castro, E.; He, M.; Wu, X.; Pal, S.K.; Kalkum, M.; Jones, J.O.
Vitamin K epoxide reductase regulation of androgen receptor activity
Oncotarget
8
13818-13831
2017
Homo sapiens (Q9BQB6), Mus musculus (Q9CRC0), Mus musculus
Chatron, N.; Chalmond, B.; Trouve, A.; Benoit, E.; Caruel, H.; Lattard, V.; Tchertanov, L.
Identification of the functional states of human Vitamin K epoxide reductase from molecular dynamics simulations
RSC Adv.
7
52071-52090
2017
Homo sapiens (Q9BQB6)
-
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