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Information on EC 1.17.4.4 - vitamin-K-epoxide reductase (warfarin-sensitive)
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EC Tree
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 enzyme appears in 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, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
EC 1.1.4.1
-
-
formerly
-
phylloquinone epoxide reductase
-
-
-
-
reductase, phylloquinone epoxide
-
-
-
-
vitamin K 2,3-epoxide reductase
vitamin K 2,3-epoxide reductase complex subunit 1
vitamin K epoxide reductase
vitamin K epoxide reductase complex subunit 1
Vitamin K reductase
vitamin K-2,3-epoxide reductase
vitamin K-2,3-epoxide reductase subunit 1
vitamin K-epoxide reductase
vitamin K1 epoxide reductase
-
-
-
-
VKOR
VKOR complex
VKORC1
VKORC1L1
warfarin-sensitive vitamin K1 2,3-epoxide reductase
vitamin K epoxide reductase
-
-
-
-
vitamin K epoxide reductase
-
-
vitamin K epoxide reductase complex subunit 1
-
-
VKOR
-
-
VKORC1
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
phylloquinol + a protein with a disulfide bond = phylloquinone + a protein with reduced L-cysteine residues
(2)
-
-
-
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
ping-pong mechanism
-
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
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
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
(1)
-
-
-
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
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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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.
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CAS REGISTRY NUMBER
COMMENTARY
55963-40-1
-
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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 + reduced thioredoxin
phylloquinone + oxidized thioredoxin
-
-
-
-
?
2-hydroxymethyl-vitamin K 2,3-epoxide + dithiothreitol
2-hydroxymethyl-vitamin K + oxidized dithiothreitol
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
allylbenzene 2',3'-oxide + 1,4-dithiothreitol
allylbenzene + oxidized dithiothreitol
-
-
-
?
styrene 1',2'-oxide + 1,4-dithiothreitol
styrene + oxidized dithiothreitol
-
-
-
?
vitamin K + 1,4-dithiothreitol
vitamin K hydroquinone + oxidized dithiothreitol + H2O
-
-
-
?
vitamin K 2,3-epoxide + oxidized dithiothreitol
vitamin K + 1,4-dithiothreitol
-
-
-
-
ir
vitamin K 2,3-epoxide + reduced dithiothreitol
vitamin K quinone + oxidized dithiothreitol + H2O
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
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
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
-
?
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
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
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
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
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
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
-
i.e. vitamin K 2,3-epoxide
i.e. 3-hydroxy-2,3-dihydro-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. 3-hydroxy-2,3-dihydro-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. 3-hydroxy-2,3-dihydro-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
-
?
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
-
?
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 is supposed to catalyze the reduction of the epoxide to quinone and of the quinone to vitamin K hydroquinone
-
?
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
2-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
-
i.e. vitamin K 2,3-epoxide
i.e. 3-hydroxy-2,3-dihydro-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
-
-
-
?
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. 3-hydroxy-2,3-dihydro-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
-
-
-
?
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. 3-hydroxy-2,3-dihydro-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
-
-
-
?
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-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-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-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 + 1,4-dithiothreitol
phylloquinone + oxidized dithiothreitol
-
-
-
-
?
2,3-epoxyphylloquinone + 1,4-dithiothreitol
phylloquinone + oxidized dithiothreitol
-
-
-
?
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
-
-
?
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
the enzyme catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K1, overview
-
-
?
2-hydroxymethyl-vitamin K 2,3-epoxide + dithiothreitol
2-hydroxymethyl-vitamin K + oxidized dithiothreitol
-
-
-
?
2-hydroxymethyl-vitamin K 2,3-epoxide + dithiothreitol
2-hydroxymethyl-vitamin K + oxidized 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
-
-
-
-
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
-
-
-
-
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
-
-
-
-
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
-
-
-
-
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
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
reduction of vitamin K 2,3-epoxide to vitamin K
-
-
?
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 K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
2-mercaptoethanol, reduced glutathione, cysteine and 1,6-hexanedithiol are inactive as acceptors
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
substrate vitamin K 2,3-epoxide, in the presence of 0.0017 mM R,S-warfarin
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
thioredoxin is the possible physiological electron acceptor
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
reaction in metabolic pathway of vitamin K
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
2-mercaptoethanol, reduced glutathione, cysteine and 1,6-hexanedithiol are inactive as acceptors
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
reaction in metabolic pathway of vitamin K
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
thioredoxin is the possible physiological electron acceptor
-
?
vitamin K 2,3-epoxide + reduced dithiothreitol
vitamin K quinone + oxidized dithiothreitol + H2O
-
-
-
-
r
vitamin K 2,3-epoxide + reduced dithiothreitol
vitamin K quinone + oxidized dithiothreitol + H2O
-
-
-
-
r
vitamin K 2,3-epoxide analogs + dithiothreitol
?
-
such as hydroxymethyl-, chloromethyl-, fluoromethyl-, difluoromethyl-, and formyl-analogs
-
-
?
vitamin K 2,3-epoxide analogs + dithiothreitol
?
-
such as hydroxymethyl-, chloromethyl-, fluoromethyl-, difluoromethyl-, and formyl-analogs
-
-
?
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
-
-
-
-
?
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)
-
-
?
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 K is an essential cofactor for post-translational gamma-carboxylation of vitamin K-dependent coagulation factors. The modification is carried out by a system of integral proteins of the endoplasmic reticulum membrane where the warfarin sensitive vitamin K 2,3-epoxide reductase (VKOR) produces the reduced hydroquinone form of vitamin K needed by the gamma-carboxylase as the active cofactor. VKOR is the rate-limiting step in the system
-
-
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
-
-
-
?
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
-
-
?
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 reduction is linked to dithiol-dependent oxidative folding of proteins in the ER by protein disulfide isomerase, PDI, oxidative folding of reduced RNase triggers the reduction of vitamin K epoxid and the gamma-carboxylation of the synthetic gamma-carboxylase peptide substrate FLEEL, overview
-
-
?
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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
-
-
-
?
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
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
-
?
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
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
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
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
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
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
-
?
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, the enzyme is supposed to catalyze the reduction of the epoxide to quinone and of the quinone to vitamin K hydroquinone
-
?
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
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
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
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
-
-
-
-
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-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-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-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
-
-
?
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
the enzyme catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K1, overview
-
-
?
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
-
-
-
-
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
-
-
-
-
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
-
-
-
-
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
-
-
-
-
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
-
-
-
-
?
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
reduction of vitamin K 2,3-epoxide to vitamin K
-
-
?
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 K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
thioredoxin is the possible physiological electron acceptor
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
reaction in metabolic pathway of vitamin K
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
reaction in metabolic pathway of vitamin K
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
thioredoxin is the possible physiological electron acceptor
-
?
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)
-
-
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
vitamin K is an essential cofactor for post-translational gamma-carboxylation of vitamin K-dependent coagulation factors. The modification is carried out by a system of integral proteins of the endoplasmic reticulum membrane where the warfarin sensitive vitamin K 2,3-epoxide reductase (VKOR) produces the reduced hydroquinone form of vitamin K needed by the gamma-carboxylase as the active cofactor. VKOR is the rate-limiting step in the system
-
-
?
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
-
-
?
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 reduction is linked to dithiol-dependent oxidative folding of proteins in the ER by protein disulfide isomerase, PDI, oxidative folding of reduced RNase triggers the reduction of vitamin K epoxid and the gamma-carboxylation of the synthetic gamma-carboxylase peptide substrate FLEEL, overview
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
reduced thioredoxin
-
likely physiological cofactor, more potent than dithiothreitol
reduced thioredoxin
-
likely physiological cofactor, more potent than dithiothreitol
reduced thioredoxin
-
together with thioredoxin reductase plus protein-disulfide isomerase still more effective than DTT
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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
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2,3,5,6-Tetrachloro-4-pyridinol
-
2.0 mM, 45% inhibition, warfarin-resistant rats
2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone
-
trivial name lapachol, 0.002 mM, 50% inhibition, liver microsomes from normal-strain, inhibition is fully reversible; trivial name lapachol, 50% inhibition of KO reductase activity in whole liver microsomes of warfarin-resistant rats, inhibition is fully reversible
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
-
potassium cholate
-
0.5% (w/v) potassium cholate releases nearly 60% of the VKOR activity originally present in intact microsomes
Vitamin K 2,3-epoxide analogs
-
hydroxymethyl-, chloromethyl-, fluoromethyl-, difluoromethyl-, formyl-analogs and analogs with modified phytyl chain, competitive inhibition
-
Deriphat 160
-
Deriphat 160 is an efficient detergent for the solubilization of VKOR, but the enzyme is inactive in its presence
N-ethylmaleimide
-
inhibition increased if the enzyme is prereduced by DTT, 1,4-butanedithiol or 1,2-ethanediol
phenprocoumon
-
4-hydroxycoumarin-derived anticoagulation drug, blocks the recycling of vitamin K epoxid inhibiting the two dithiol-dependent steps performed by the enzyme
warfarin
-
determination of warfarin metabolic rate in liver microsomes based on P450 content, overview. Conversion to 4-, 6-, 7- and 10-hydroxylated warfarin
warfarin
-
determination of warfarin metabolic rate in liver microsomes based on P450 content, overview. Conversion to 4-, 6-, and 8-hydroxylated warfarin
warfarin
-
determination of warfarin metabolic rate in liver microsomes based on P450 content, overview. Conversion to 4-, 6-, and 8-hydroxylated warfarin
warfarin
-
determination of warfarin metabolic rate in liver microsomes based on P450 content, overview. Conversion to 4-, 6-, 7-, 8- and 10-hydroxylated warfarin
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
warfarin
warfarin inhibits androgen receptor activity (an important driver of prostate cancer development and progression) by inhibiting vitamin K epoxide reductase
warfarin
-
i.e. 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin, inhibition decreased by DTT
warfarin
-
0.01 mM, 18% inhibition, 0.1 mM, 64% inhibition, warfarin-resistant rats
warfarin
-
0.0017 mM, 50% inhibition; mixed non-competitive inhibition vs. vitamin k 2,3-epoxide, competive inhibition vs. DTT
warfarin
the mutant Y139F strain is resistant to warfarin; wild-type rats
warfarin
-
i.e. 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin, VKOR is highly sensitive to inhibition by warfarin
warfarin
-
determination of warfarin metabolic rate in liver microsomes based on P450 content, overview. Conversion to 4-, 6-, 7-, 8- and 10-hydroxylated warfarin
warfarin
the inhibition effect of warfarin on the enzyme activity is neutralized when it was coadministered with puerarin in rats
warfarin
-
determination of warfarin metabolic rate in liver microsomes based on P450 content, overview. Conversion to 4-, 6-, 7-, and 8-hydroxylated warfarin
additional information
pharmacodynamics of resistance to warfarin, overview
-
additional information
-
mechanism of 4-hydroxycoumarin derivative-resistance, overview
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Phospholipids
-
time-dependent inactivation of enzyme activity after phosphlipase A treatment
Protein disulfide isomerase
-
activation, together with thioredoxin/thioredoxin reductase and reduced ribonuclease
-
Protein factor
-
activation, two different protein factors from rat liver cytosol
-
Reduced ribonuclease
-
activation, together with thio-redoxin/thioredoxin reductase, EC 1.6.4.5 plus protein-disulfide isomerase more potent than DTT
-
additional information
-
bacitracin inhibition of reduced RNase triggers VKOR activity, overview
-
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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
0.0195
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
pH 7.4, 25°C
0.025
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant L120Q
0.0577
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
pH 7.4, 25°C
0.06
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C, mutant Y139C
0.1658
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C
0.1761
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C
0.1875
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
-
pH 7.4, 37°C
0.0178
2,3-Epoxyphylloquinone
pH 7.4, 37°C, recombinant mutant Y139F enzyme
0.0195
2,3-Epoxyphylloquinone
pH 7.4, 37°C, liver microsomes from rats homozygous for Y139F
0.0072
2-methyl-3-phytyl-1,4-naphthoquinone
recombinant wild-type enzyme in recombinant Pichia pastoris membranes, pH 7.4, 37°C
0.0084
2-methyl-3-phytyl-1,4-naphthoquinone
native enzyme in membranes, pH 7.4, 37°C
0.0178
2-methyl-3-phytyl-1,4-naphthoquinone
mutant Y137F, pH 7.4, 37°C
0.0195
2-methyl-3-phytyl-1,4-naphthoquinone
wild-type enzyme, pH 7.4, 37°C
additional information
additional information
-
detailed thermodynamics, overview
-
additional information
additional information
-
reduction of vitamin K epoxide to vitamin K, Michaelis-Menten model, recombinant wild-type enzyme
-
additional information
additional information
reduction of vitamin K epoxide to vitamin K, Michaelis-Menten model, recombinant wild-type enzyme
-
additional information
additional information
-
vitamin K 2,3-epoxid reduction kinetics, Michaelis-Menten model, overview
-
additional information
additional information
vitamin K 2,3-epoxid reduction kinetics, Michaelis-Menten model, overview
-
additional information
additional information
-
VKORC1 kinetic modeling, overview
-
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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
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00009
brodifacoum
pH 7.4, 37°C, liver microsomes from rats homozygous for Y139F
0.00091
bromadiolone
pH 7.4, 37°C, liver microsomes from rats homozygous for Y139F
0.00018
chlorophacinone
pH 7.4, 37°C, recombinant mutant L128Q enzyme
0.0016
chlorophacinone
pH 7.4, 37°C, recombinant mutant Y139F enzyme, and liver microsomes from rats homozygous for Y139F
0.0045
chlorophacinone
pH 7.4, 37°C, recombinant mutant L120Q enzyme
0.0073
chlorophacinone
pH 7.4, 37°C, recombinant mutant Y139C enzyme
0.0079
chlorophacinone
pH 7.4, 37°C, recombinant mutant Y139S enzyme
0.00026
Difenacoum
pH 7.4, 37°C, liver microsomes from rats homozygous for Y139F
0.00005
difethialone
pH 7.4, 37°C, recombinant enzyme mutants Y139F, and L128Q
0.00009
difethialone
pH 7.4, 37°C, liver microsomes from rats homozygous for Y139F
0.029
warfarin
pH 7.4, 37°C, liver microsomes from rats homozygous for Y139F
0.1
warfarin
above, pH 7.4, 37°C, recombinant enzyme mutants Y139F, L120Q, Y139C, Y139F, and Y139S
additional information
additional information
-
inhibition kinetics
-
additional information
additional information
-
VKORC1 kinetic model and derivation of the IC50-Ki transformation, overview
-
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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
0.0016
chlorophacinone
Rattus norvegicus
wild-type enzyme and mutant Y137F, pH 7.4, 37°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
-
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.000007
-
substrate vitamin K 2,3-epoxide, in the presence of 0.0017 mM R,S-warfarin
0.0000097
-
thioredoxin from bovine thymus as cofactor, enzyme activity in salt washed detergent-solubilized microsomes
0.0000136
-
thioredoxin from Escherichia coli as cofactor, enzyme activity in salt washed detergent-solubilized microsomes
0.0000256
-
cofactor DTT, enzyme activity in salt washed detergent-solubilized microsomes
0.0000498
-
thioredoxin and protein disulfide-isomerase from bovine thymus as cofactors, enzyme activity in salt washed detergent-solubilized microsomes
0.000057
-
thioredoxin and protein disulfide-isomerase from Escherichia coli as cofactors, enzyme activity in salt washed detergent-solubilized microsomes
0.00099
-
substrate dithiothreitol, in the presence of 0.0017 mM R,S-warfarin
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
30
37
41
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TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
vitamin K epoxide reductase complex subunit 1-like 1 (Vkorc1l1)
UniProt
brenda
-
-
-
brenda
vitamin K epoxide reductase complex subunit 1
Swissprot
brenda
VKORC1 subunit 1; Chinese and Causasian men, gene VKORC1
Swissprot
brenda
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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
brenda
-
the enzyme is upregulated in fetal heart and in ventricular aneurysm tissue
brenda
measurement of allelic mRNA expression. Genotype effect of 2-fold allelic mRNA expression due to single nucleotide polymorphisms -1639G>A and 1173C
brenda
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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
brenda
integral membrane enzyme of the endoplasmic reticulum
brenda
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
brenda
-
membrane topology, type III membrane protein, overview
brenda
-
the enzyme possesses 3 or 4 transmembrane alpha-helices and a large cytoplasmic loop, membrane topology, overview
brenda
-
integral membrane protein, topology, overview
brenda
-
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
brenda
-
the enzyme contains a VKOR CXXC motif
brenda
-
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
brenda
-
topological view of the the membrane spanning enzyme with these four exoplasmic cysteine residues
brenda
-
transmembrane protein with 5 transmembrane helices, membrane topology, overview
brenda
VKORC1L1 is a four-transmembrane domain protein with both its termini located in the cytoplasm
brenda
-
-
-
brenda
-
integral membrane protein
-
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
-
clear difference in VKOR activity and Ki for warfarin among bird species
evolution
-
clear difference in VKOR activity and Ki for warfarin among bird species
evolution
-
clear difference in VKOR activity and Ki for warfarin among bird species
evolution
-
clear difference in VKOR activity and Ki for warfarin among bird species
evolution
-
clear difference in VKOR activity and Ki for warfarin among bird species
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
-
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
malfunction
some naturally occuring mutations of the enzyme, e.g. at residues mutations at Leu120, Leu128 and Tyr139, confer resistance against anti-coagulants, sodium warfarin, difenacoum and brodifacoum, to rats
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
-
posttranslocational protein folding in the Gram-positive biofilm-forming actinobacterium Actinomyces oris is mediated by a membrane-bound thiol-disulfide oxidoreductase named MdbA, which catalyzes oxidative folding of nascent polypeptides transported by the Sec translocon. Reoxidation of MdbA involves a bacterial vitamin K epoxide reductase (VKOR)-like protein
metabolism
the enzyme plays important roles in redox regulation. The enzyme is involved in resistance to salt or drought stress. Down- and up-regulation of the enzyme in vivo changes the activities of antioxidant enzymes and results in differential accumulation of reactive oxygen species
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
metabolism
VKORC1 is the key enzyme of the classical vitamin K cycle by which vitamin K-dependent proteins are gamma-carboxylated by the hepatic gamma-glutamyl carboxylase
metabolism
VKORC1L1 is chiefly responsible for antioxidative function by reduction of vitamin K to prevent damage by intracellular reactive oxygen species
physiological function
function of VKORC1 is to regenerate vitamin K and vitamin K hydroquinone from vitamin K 2,3-epoxide, a byproduct of the vitamin K-dependent gamma carboxylation reaction
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
-
compounds target blood coagulation by inhibiting the vitamin K epoxide reductase (VKORC1), which catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K
additional information
compounds target blood coagulation by inhibiting the vitamin K epoxide reductase (VKORC1), which catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K
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
Show AA Sequence and Transmembrane Helices (2046 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
18000
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
the enzyme possesses a dicoumarol binding hydrophobic sequence motif TYA, VKOR complex structure, overview
additional information
-
complex of at least two components, one possesing catalytic activity for the conversion of vitamin K 2,3-epoxide, second component contains the binding site for the exogenous (DTT) and endogenous disulphide reductant, this thiol-disulfide redox centre is also the site of warfarin binding
additional information
-
the VKOR enzyme complex contains protein disulfide reductase, PDI, and VKORC1 as tightly associated subunits, complex organization and structure, overview, VKORC! is a highly hydrophobic protein
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
sitting-drop vapor-diffusion method, the structure of the mutant enzyme Cys50Ala at 2.8 A resolution allows a detailed analysis of an intramembrane enzyme that generates disulfide bonds. In the active site, a continuous electron density connects the thiol group of Cys133 with the C1 atom of the quinone ring. The Cys212Ala structure suggests that the transfer of electrons to the active site is an one-electron process
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C101A
-
formation of of a high-molecular-weight complex that is positive for thiol-disulfide oxidoreductase MdbA and vitamin K epoxide reductase
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
A26S
-
mutant shows about 70% relative VKOR activity as compared to the wild type enzyme
A48T
-
mutant shows about 120% relative VKOR activity as compared to the wild type enzyme
E37G
-
mutant shows about 75% relative VKOR activity as compared to the wild type enzyme
L128S
-
mutant shows about 20% relative VKOR activity as compared to the wild type enzyme
R12W
-
mutant shows about 35% relative VKOR activity as compared to the wild type enzyme
R58G
-
mutant shows about 40% relative VKOR activity as compared to the wild type enzyme
R61L
-
mutant shows about 50% relative VKOR activity as compared to the wild type enzyme
Y139C
-
mutant shows about 30% relative VKOR activity as compared to the wild type enzyme
W59G
-
the single nucleotide polymorphism T175G in gene VKORC1 causes 4-hydroxycoumarin derivative-resistance
A143V
-
mutant shows about 140% relative VKOR activity as compared to the wild type enzyme
A26T
E67K
-
the mutant shows a reduced vitamin K epoxide turnover of about 33% compared to the wild type protein, and has no effect on warfarin sensitivity in vitro
I141V
-
mutant shows about 45% relative VKOR activity as compared to the wild type enzyme
I90L
-
mutant shows about 90% relative VKOR activity as compared to the wild type enzyme
L120Q
L128Q
R33P
-
VKOR activity of the Arg33Pro variant is reduced to 42% of wild type activity
Y139C
Y139F
Y139S
Y39N
-
mutant shows about 30% relative VKOR activity as compared to the wild type enzyme
Y139F
-
the mutation mediates resistance towards chlorophacinone and bromadiolone
-
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
A26T
-
mutant shows about 60% relative VKOR activity as compared to the wild type enzyme
A26T
-
the mutation has only a moderate effect on VKOR activity with a reduction to approximately 56% of wild type activity
L120Q
naturally occuring mutant, resitant to warfarin and other anticoagulants
L120Q
naturally occuring mutant, the mutant rat is resistant to some anticoagulants
L128Q
-
mutant shows moderately reduced VKOR activity (about 60% compared to wild type protein) and is resistant to warfarin inhibition to a variable degree
L128Q
naturally occuring mutant, resitant to warfarin and other anticoagulants
L128Q
naturally occuring mutant, the mutant rat is resistant to some anticoagulants
Y139C
-
mutant shows moderately reduced VKOR activity (about 60% compared to wild type protein) and is resistant to warfarin inhibition to a variable degree
Y139C
naturally occuring mutant, resitant to warfarin and other anticoagulants
Y139C
naturally occuring mutant, the mutant rat is resistant to some anticoagulants
Y139F
the natural occuring mutation confers resistance to enzyme inhibitor warfarin, the mutant rats do not show vitamin K deficiency
Y139F
-
highly resistant to warfarin and increased resistance to further anticoagulants
Y139F
-
the mutation mediates resistance towards chlorophacinone and bromadiolone
Y139F
naturally occuring mutant, resitant to warfarin and other anticoagulants
Y139F
naturally occuring mutant, the mutant rat is resistant to some anticoagulants
Y139S
-
mutant shows moderately reduced VKOR activity and is resistant to warfarin inhibition to a variable degree
Y139S
naturally occuring mutant, resitant to warfarin and other anticoagulants
Y139S
naturally occuring mutant, the mutant rat is resistant to some anticoagulants
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
additional information
-
allelic mutations in the orthologous gene of VKORC1 can cause warfarin resistance
additional information
-
allelic mutations in the orthologous gene can cause warfarin resistance
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
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ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ethanol
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OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate, Sepharose 6B, hydroxylapatite, microsomal epoxide hydrolase copurifies with vitamin KO reductase
-
DE52 cellulose column chromatography, Bio-Gel P-100 gel filtration, and agarose-glutathione column chromatography
-
MonoS, hydroxyapatite, DEAE-Sepharose, Sephacryl S-200, partially purified enzyme
-
native enzyme from liver microsomes by solubilization, pH 11, deoxycholate-Tris base microsome extraction procedure, immunoprecipitation, gel filtration, and protein A and protein G affinity chromatography
-
partially by microsome preparation
partially by microsome preparation by ultracentrifugation
purification of a high-molecular-weight complex that is positive for thiol-disulfide oxidoreductase MdbA and vitamin K epoxide reductase VKOR in the C101A mutant
-
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
-
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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
expressed in HEK-293 cells
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 c-myc-tagged enzyme mutants in Pichia pastoris membranes
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 rVkorc1, expression of C-terminally c-myc-tagged wild-type and mutant enzymes in Pichia patoris strain SMD1168 as membrane-bound proteins
gene VKORC1 Y139F, DNA and amino acid sequence determination, genotyping, semiquantitative expression analysis
gene VKORC1, DNA and amino acid sequence determination, genotyping, semiquantitative expression analysis
gene VKORC1, expression of the c-myc-tagged VKORC1 in HEK-293 cells and in BHK21 cells
-
gene Vkorc1, expression of wild-type and mutant enzymes in Pichia pastoris as membrane bound protein
-
gene VKORC1, genotyping
gene VKORC1, genotyping, phenotypes of enzyme single nucleotide polymorphisms naturally occuring in Caucasian population
-
gene VKORC1, located on chromosome 1, DNA and amino acid sequenc determination and analysis, expression of wild-type and warfarin-resistant mutant enzymes in HEK-293 cells, expression of the latter alomost completely abolishes the enzyme activity
-
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, located on chromosome 7, DNA and amino acid sequenc determination and analysis
-
gene VKORC1, stable overexpression in factor IX BHK cell microsomes increasing 2.2fold the extent of secreted factor IX in vivo carboxylation, overview
-
genetic selection for mutants of Escherichia coli that promote the efficient membrane integration and expression of the mammalian membrane protein vitamin K epoxide reductase (VKORc1), that is ordinarily barely expressed in a wild-type Escherichia coli. When this poorly expressed enzyme is mutagenized or introduced to a library of Escherichia coli mutants, functional expression is achieved. The results suggest that YidC may play a role in quality control of membrane proteins at the level of insertion. Alteration of this function can greatly enhance functional overexpression of other membrane proteins
mutant enzymes C50A and C212A are both expressed in a Escherichia coli BL21(DE3)
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
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
level of vkorc1l1 expression is the highest at 4-cell stage, diminishing at Prim-5 stage and remaining stable afterward
level of vkorc1l1 expression is the highest at 4-cell stage, diminishing at Prim-5 stage and remaining stable afterward. Significantly overexpressed in differentiating cells (T1M) but not in mineralizating (T3M) cells
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
Vkorc1 is detected at 4-cell stage but shows an expression peak at 72-96 h post fertilization, and a lower and stable gene expression value afterward. Significantly overexpressed in differentiating (T1M) but not in mineralizating (T3M) cells
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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
-
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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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TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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Rattus norvegicus, Rattus norvegicus Holtzman
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Purification and properties of a factor from rat liver cytosol which stimulates vitamin K epoxide reductase
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2001
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Rattus norvegicus, Rattus norvegicus Holtzman
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40
1055-1061
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Rattus norvegicus
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Whitlon, D.S.; Sadowski, J.A.; Suttie, J.W.
Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition
Biochemistry
17
1371-1377
1978
Rattus norvegicus, Rattus norvegicus Holtzman
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Wallin, R.; Hutson, S.M.; Cain, D.; Sweatt, a.; Sane, D.C.
A molecular mechanism for genetic warfarin resistance in the rat
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Rattus norvegicus
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Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2
Nature
427
537-541
2004
Homo sapiens (Q9BQB6), Homo sapiens
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Li, T.; Chang, C.Y.; Jin, D.Y.; Lin, P.J.; Khvorova, A.; Stafford, D.W.
Identification of the gene for vitamin K epoxide reductase
Nature
427
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2004
Homo sapiens (Q9BQB6), Homo sapiens
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Harrington, D.J.; Underwood, S.; Morse, C.; Shearer, M.J.; Tuddenham, E.G.; Mumford, A.D.
Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1
Thromb. Haemost.
93
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2005
Homo sapiens, Homo sapiens (Q9BQB6)
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Wallin, R.; Sane, D.C.; Hutson, S.M.
Vitamin K 2,3-epoxide reductase and the vitamin K-dependent gamma-carboxylation system
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108
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Rattus norvegicus
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Wilson, C.R.; Sauer, J.M.; Carlson, G.P.; Wallin, R.; Ward, M.P.; Hooser, S.B.
Species comparison of vitamin K1 2,3-epoxide reductase activity in vitro: kinetics and warfarin inhibition
Toxicology
189
191-198
2003
Bos taurus, Canis lupus familiaris, Equus caballus, Ovis aries, Homo sapiens, Mus musculus, Sus scrofa
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Goodstadt, L.; Ponting, C.P.
Vitamin K epoxide reductase: homology, active site and catalytic mechanism
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29
289-292
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Homo sapiens
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Warfarin and the vitamin K-dependent gamma-carboxylation system
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10
299-302
2004
Homo sapiens, Rattus norvegicus
brenda
Oldenburg, J.; Bevans, C.G.; Mueller, C.R.; Watzka, M.
Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle
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8
347-353
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Homo sapiens, Mus musculus, Rattus norvegicus
brenda
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
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98
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2006
Homo sapiens (Q9BQB6)
brenda
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
brenda
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
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2005
Homo sapiens
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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
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62
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Homo sapiens
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Quantum chemical study of the mechanism of action of vitamin K epoxide reductase (VKOR)
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Homo sapiens
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Warfarin resistance in a french strain of rats
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19
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Rattus norvegicus, Rattus norvegicus (Q6TEK4)
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20
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Mus musculus, Mus musculus domesticus
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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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Homo sapiens
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Wajih, N.; Hutson, S.M.; Wallin, R.
Disulfide dependent protein folding is linked to operation of the vitamin K cycle in the endoplasmic reticulum: A protein disulfide isomerase-VKORC1 redox enzyme complex appears to be responsible for vitamin K1 2,3-epoxide reduction
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282
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Rattus norvegicus
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4
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Homo sapiens
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Mol. Cancer Res.
3
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2005
Homo sapiens
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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
brenda
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
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28
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Homo sapiens
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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
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2007
Homo sapiens
brenda
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
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112
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2008
Homo sapiens (Q9BQB6), Homo sapiens
brenda
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Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians
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81
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2007
Homo sapiens
brenda
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
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2008
Homo sapiens
brenda
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
brenda
Lasseur, R.; Grandemange, A.; Longin-Sauvageon, C.; Berny, P.; Benoit, E.
Comparison of the inhibition effect of different anticoagulants on vitamin K epoxide reductase activity from warfarin-susceptible and resistant rat
Pestic. Biochem. Physiol.
88
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2007
Rattus norvegicus
-
brenda
Rost, S.; Pelz, H.J.; Menzel, S.; MacNicoll, A.D.; Leon, V.; Song, K.J.; Jaekel, T.; Oldenburg, J.; Mueller, C.R.
Novel mutations in the VKORC1 gene of wild rats and mice--a response to 50 years of selection pressure by warfarin?
BMC Genet.
10
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2009
Mus musculus, Rattus norvegicus
brenda
Song, Y.; Vera, N.; Kohn, M.H.
Vitamin K epoxide reductase complex subunit 1 (Vkorc1) haplotype diversity in mouse priority strains
BMC Res. Notes
1
125
2008
Mus musculus
brenda
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
brenda
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
brenda
Grandemange, A.; Kohn, M.H.; Lasseur, R.; Longin-Sauvageon, C.; Berny, P.; Benoit, E.
Consequences of the Y139F Vkorc1 mutation on resistance to AVKs: in-vivo investigation in a 7th generation of congenic Y139F strain of rats
Pharmacogenet. Genomics
19
742-750
2009
Rattus norvegicus, Rattus norvegicus Y139F
brenda
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
brenda
Tie, J.K.; Stafford, D.W.
Structure and function of vitamin K epoxide reductase
Vitam. Horm.
78
103-130
2008
Rattus norvegicus
brenda
Berkner, K.L.
Vitamin K-dependent carboxylation
Vitam. Horm.
78
131-156
2008
Homo sapiens
brenda
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
brenda
Garcia, A.A.; Reitsma, P.H.
VKORC1 and the vitamin K cycle
Vitam. Horm.
78
23-33
2008
Homo sapiens
brenda
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
Br. J. Pharmacol.
158
1536-1547
2009
Canis lupus familiaris, Homo sapiens
brenda
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
brenda
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
brenda
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
brenda
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
brenda
Hodroge, A.; Longin-Sauvageon, C.; Fourel, I.; Benoit, E.; Lattard, V.
Biochemical characterization of spontaneous mutants of rat VKORC1 involved in the resistance to antivitamin K anticoagulants
Arch. Biochem. Biophys.
515
14-20
2011
Rattus norvegicus, Rattus norvegicus (Q6TEK4)
brenda
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
brenda
Watanabe, K.P.; Saengtienchai, A.; Tanaka, K.D.; Ikenaka, Y.; Ishizuka, M.
Comparison of warfarin sensitivity between rat and bird species
Comp. Biochem. Physiol. C
152
114-119
2010
Anas platyrhynchos, Gallus gallus, Struthio camelus, Rattus norvegicus, Bubo scandiacus, Bubo virginianus
brenda
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
brenda
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
brenda
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
brenda
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
brenda
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
brenda
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
1577-1588
2012
Homo sapiens
brenda
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
brenda
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
brenda
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)
brenda
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)
brenda
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
brenda
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
brenda
Ge, B.; Zhang, Z.; Lam, T.T.; Zuo, Z.
Puerarin offsets the anticoagulation effect of warfarin in rats by inducing rCyps, upregulating vitamin K epoxide reductase and inhibiting thrombomodulin
Biopharm. Drug Dispos.
38
33-49
2017
Rattus norvegicus (Q6TEK4)
brenda
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
brenda
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
brenda
Fernandez, I.; Vijayakumar, P.; Marques, C.; Cancela, M.L.; Gavaia, P.J.; Laize, V.
Zebrafish vitamin K epoxide reductases expression in vivo, along extracellular matrix mineralization and under phylloquinone and warfarin in vitro exposure
Fish Physiol. Biochem.
41
745-759
2015
Danio rerio (E7F6X2), Danio rerio (Q502B2)
brenda
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
brenda
Luong, T.T.; Reardon-Robinson, M.E.; Siegel, S.D.; Ton-That, H.
Reoxidation of the thiol-disulfide oxidoreductase MdbA by a bacterial vitamin K epoxide reductase in the biofilm-forming actinobacterium actinomyces oris
J. Bacteriol.
199
e00817-16
2017
Actinomyces oris, Mycobacterium tuberculosis
brenda
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)
brenda
Liu, S.; Cheng, W.; Fowle Grider, R.; Shen, G.; Li, W.
Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer
Nat. Commun.
5
3110
2014
Synechococcus sp. JA-2-3B'a(2-13) (Q2JJF6)
brenda
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
brenda
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
brenda
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
brenda
Yu, Z.B.; Yang, X.J.; Du, J.J.; Wan, C.M.; Xu, J.N.; Wang, W.J.; Feng, Y.G.; Wang, X.Y.
A homologue of vitamin K epoxide reductase in Solanum lycopersicum is involved in resistance to osmotic stress
Physiol. Plant.
156
311-322
2016
Solanum lycopersicum (K4BAJ5), Solanum lycopersicum
brenda
Hatahet, F.; Blazyk, J.L.; Martineau, E.; Mandela, E.; Zhao, Y.; Campbell, R.E.; Beckwith, J.; Boyd, D.
Altered Escherichia coli membrane protein assembly machinery allows proper membrane assembly of eukaryotic protein vitamin K epoxide reductase
Proc. Natl. Acad. Sci. USA
112
15184-15189
2015
Rattus norvegicus (Q6TEK4)
brenda
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)
-
brenda
Sinhadri, B.C.S.; Jin, D.Y.; Stafford, D.W.; Tie, J.K.
Vitamin K epoxide reductase and its paralogous enzyme have different structures and functions
Sci. Rep.
7
17632
2017
Homo sapiens (Q9BQB6)
brenda
Caspers, M.; Czogalla, K.J.; Liphardt, K.; Mueller, J.; Westhofen, P.; Watzka, M.; Oldenburg, J.
Two enzymes catalyze vitamin K 2,3-epoxide reductase activity in mouse VKORC1 is highly expressed in exocrine tissues while VKORC1L1 is highly expressed in brain
Thromb. Res.
135
977-983
2015
Mus musculus (Q6TEK5), Mus musculus (Q9CRC0), Mus musculus
brenda
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