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Information on EC 1.17.4.4 - vitamin-K-epoxide reductase (warfarin-sensitive)
for references in articles please use BRENDA:EC1.17.4.4
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EC Tree 1 Oxidoreductases
1.17 Acting on CH or CH2 groups
1.17.4 With a disulfide as acceptor
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.
The enzyme appears in viruses and cellular organisms
- 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
Reaction Schemes
show+
+
=
+
+
a protein with a disulfide bond
+
=
+
a protein with reduced L-cysteine residues
+
=
+
+
a protein with a disulfide bond
=
+
a protein with reduced L-cysteine residues
Synonyms
vkorc1, vitamin k epoxide reductase, vkorc1l1, vitamin k 2,3-epoxide reductase, vkorc1v2, vitamin k-epoxide reductase, vitamin k oxidoreductase, vitamin k1 epoxide reductase, vkor complex, vkorc1-like 1, more
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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
VKOR-like
VKORC1
VKORC1-like 1
VKORC1L1
VKORL
warfarin-sensitive vitamin K1 2,3-epoxide reductase
additional information
vitamin K epoxide reductase
-
-
-
-
vitamin K epoxide reductase
-
-
vitamin K epoxide reductase
-
vitamin K epoxide reductase complex subunit 1
-
-
VKOR
-
-
VKOR
-
VKORC1
-
-
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
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
analysis of the reaction mechanism by quantum mechanical methods, modeling, the geometries of proposed model intermediates in the mechanisms are energy optimized
-
phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
protein structure and catalytic mechanism, the enzyme activity is rate-limiting for the following gamma-carboxylation step
-
phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
quantum chemical study on mechanism and transition states. Once a key dissulfide is broken, the reaction proceeds largely downhill. The initial protonation of the epoxide oxygen is an important step, with the proton originating from a free mercapto group rather than a water molecule
-
phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
bi bi ping-pong mechanism for VKORC1, kinetic modeling
-
phylloquinone + a protein with a disulfide bond + H2O = 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
(1)
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
BRENDA
MetaCyc
vitamin K-epoxide cycle
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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
LITERATURE
COMMENTARY
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
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-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
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + reduced thiol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized thiol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + tris(3-hydroxypropyl)phosphine
?
Substrates: 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
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
2,3-epoxyphylloquinone + reduced human protein disulfide isomerase
phylloquinone + human protein disulfide isomerase + H2O
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + reduced thioredoxin
phylloquinone + oxidized thioredoxin
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: i.e. vitamin K
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
?
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
phylloquinone + reduced human protein disulfide isomerase
phylloquinol + human protein disulfide isomerase
Substrates: -
Products: -
Products: -
?
styrene 1',2'-oxide + 1,4-dithiothreitol
styrene + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K + 1,4-dithiothreitol
vitamin K hydroquinone + oxidized dithiothreitol + H2O
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + oxidized dithiothreitol
vitamin K + 1,4-dithiothreitol
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: i.e. vitamin K 2,3-epoxide, the enzyme initiates the vitamin K catalytic cycle, overview
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K, an important cofactor for the posttranslational gamma-carboxylation of several blood coagulation factors
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide, two dithiol-dependent steps
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. 3-hydroxy-2,3-dihydro-vitamin K
Products: 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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: 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
Products: -
Products: -
?
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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. 3-hydroxy-2,3-dihydro-vitamin K
Products: 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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. 3-hydroxy-2,3-dihydro-vitamin K
Products: 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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. 3-hydroxy-2,3-dihydro-vitamin K
Products: 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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
r
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + 1,4-dithiothreitol
phylloquinone + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + 1,4-dithiothreitol
phylloquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
Substrates: substrate KO
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
Substrates: substrate KO
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
-
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
-
Substrates: 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
Products: -
Products: -
?
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
Substrates: the enzyme catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K1, overview
Products: -
Products: -
?
2,3-epoxyphylloquinone + reduced thioredoxin
phylloquinone + thioredoxin + H2O
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + reduced thioredoxin
phylloquinone + thioredoxin + H2O
-
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + reduced thioredoxin
phylloquinone + thioredoxin + H2O
-
Substrates: -
Products: -
Products: -
?
2-hydroxymethyl-vitamin K 2,3-epoxide + dithiothreitol
2-hydroxymethyl-vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2-hydroxymethyl-vitamin K 2,3-epoxide + dithiothreitol
2-hydroxymethyl-vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
Substrates: -
Products: -
Products: -
?
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
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: 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
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
Substrates: reduction of vitamin K 2,3-epoxide to vitamin K
Products: -
Products: -
?
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
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
r
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
Substrates: -
Products: -
Products: -
?
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
Substrates: vitamin K1 or 2-methyl-3-phytyl-1,4-naphthoquinone
Products: -
Products: -
?
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
Substrates: substrate K
Products: -
Products: -
?
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
Substrates: -
Products: -
Products: -
?
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
Substrates: substrate K
Products: -
Products: -
?
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
Substrates: -
Products: -
Products: -
?
phylloquinone + reduced thioredoxin
phylloquinol + thioredoxin
Substrates: -
Products: -
Products: -
?
phylloquinone + reduced thioredoxin
phylloquinol + thioredoxin
-
Substrates: -
Products: -
Products: -
?
phylloquinone + reduced thioredoxin
phylloquinol + thioredoxin
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: 2-mercaptoethanol, reduced glutathione, cysteine and 1,6-hexanedithiol are inactive as acceptors
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: substrate vitamin K 2,3-epoxide, in the presence of 0.0017 mM R,S-warfarin
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: thioredoxin is the possible physiological electron acceptor
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: reaction in metabolic pathway of vitamin K
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: 2-mercaptoethanol, reduced glutathione, cysteine and 1,6-hexanedithiol are inactive as acceptors
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: reaction in metabolic pathway of vitamin K
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: thioredoxin is the possible physiological electron acceptor
Products: -
Products: -
?
vitamin K 2,3-epoxide + reduced dithiothreitol
vitamin K quinone + oxidized dithiothreitol + H2O
-
Substrates: -
Products: -
Products: -
r
vitamin K 2,3-epoxide + reduced dithiothreitol
vitamin K quinone + oxidized dithiothreitol + H2O
-
Substrates: -
Products: -
Products: -
r
vitamin K 2,3-epoxide analogs + dithiothreitol
?
-
Substrates: such as hydroxymethyl-, chloromethyl-, fluoromethyl-, difluoromethyl-, and formyl-analogs
Products: -
Products: -
?
vitamin K 2,3-epoxide analogs + dithiothreitol
?
-
Substrates: such as hydroxymethyl-, chloromethyl-, fluoromethyl-, difluoromethyl-, and formyl-analogs
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: 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
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
Substrates: 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)
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: 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
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is involved in regulation of response to oral anticoagulants of European-American warfarin patients
Products: -
Products: -
?
additional information
?
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is involved in angiogenesis
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is involved in coagulation factor activity
Products: -
Products: -
?
additional information
?
-
Substrates: the enzyme is involved in coagulation factor activity
Products: -
Products: -
?
additional information
?
-
-
Substrates: Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme, driven by the reducing agent DTT, reduces both vitamin K 2,3-epoxide and vitamin K to the activated hydroquinone form
Products: -
Products: -
?
additional information
?
-
-
Substrates: advantages and caveats of using the DTT-driven VKOR assay, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: no synthesis of 3-hydroxyvitamin K1 by the wild-type enzyme, but by mutants Y139C, Y139F, and Y139S
Products: -
Products: -
?
additional information
?
-
Substrates: VKORC1 produces vitamin K hydroquinone (KH2) in 2 reactions: reduction of vitamin K epoxide (KO) to quinone (K), and then KH2
Products: -
Products: -
?
additional information
?
-
Substrates: replacing the phytyl side-chain with a methylene cyclooctatetraene (COT) moiety at the 3-position of vitamin K1 converts it from a substrate to an inhibitor for VKD carboxylation. ELISA-based vitamin K reductase activity is performed using DGKO reporter cells with vitamin K1 as the substrate. For the conventional HPLC-based KO reductase activity assay, GGCX-knockout FIXgla-PC/HEK-293 cells are cultured with a fixed concentration or with increasing concentrations of the vitamin K derivative in cell culture medium containing 0.005 mM KO. K vitamins are extracted from the cells and the conversion of KO to vitamin K1 was determined by reverse-phase HPLC. Vitamin K reductase activity is evaluated using DGKO reporter cells with vitamin K1 as the substrate. Since reduced vitamin K1 (KH2), an intermediate product in VKD carboxylation, is unstable and difficult to accurately quantify from cells directly, the vitamin K reduction and epoxidation reactions are coupled to quantitate the final stable product vitamin K epoxide (KO). Vitamin K-dependent (VKD) carboxylation in UBIAD1-knockout HEK-293 reporter cells using vitamin K1 (VK), MK-4, menadione, or VK-K-COT as the substrate
Products: -
Products: -
?
additional information
?
-
Substrates: in dithiothreitol (DTT)-driven VKOR activity assays, human VKORC1L1 is able to support vitamin K 2,3-epoxide to vitamin K reduction almost as efficiently as VKORC1
Products: -
Products: -
?
additional information
?
-
-
Substrates: Mycobacterium tuberculosis DsbA protein is oxidized by enzyme VKOR. DsbA binds in a cysteine-dependent manner to a hexapeptide derived from the periplasmic loop of VKOR. VKOR's substrate is a member of the thioredoxin family, as is DsbA. The structural disulfide bond between C140 and C192 of MtDsbA relies on the catalytic activity of the C89XXC92 disulfide bond of MtDsbA, which is in turn reoxidized by MtVKOR
Products: -
Products: -
?
additional information
?
-
-
Substrates: Mycobacterium smegmatis DsbA protein is oxidized by enzyme VKOR. VKOR's substrate is a member of the thioredoxin family, as is DsbA
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
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
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + reduced thiol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized thiol
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
2,3-epoxyphylloquinone + reduced human protein disulfide isomerase
phylloquinone + human protein disulfide isomerase + H2O
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
?
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
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
phylloquinone + reduced human protein disulfide isomerase
phylloquinol + human protein disulfide isomerase
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: i.e. vitamin K 2,3-epoxide, the enzyme initiates the vitamin K catalytic cycle, overview
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K, an important cofactor for the posttranslational gamma-carboxylation of several blood coagulation factors
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: 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
Products: -
Products: -
?
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
-
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
Substrates: i.e. vitamin K 2,3-epoxide
Products: i.e. vitamin K
Products: 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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
r
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
Substrates: -
Products: -
Products: -
?
2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
phylloquinone + a protein with a disulfide bond + H2O
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
-
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
-
Substrates: 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
Products: -
Products: -
?
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
Substrates: the enzyme catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K1, overview
Products: -
Products: -
?
2,3-epoxyphylloquinone + reduced thioredoxin
phylloquinone + thioredoxin + H2O
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + reduced thioredoxin
phylloquinone + thioredoxin + H2O
-
Substrates: -
Products: -
Products: -
?
2,3-epoxyphylloquinone + reduced thioredoxin
phylloquinone + thioredoxin + H2O
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
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
Substrates: -
Products: -
Products: -
?
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
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
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
Substrates: reduction of vitamin K 2,3-epoxide to vitamin K
Products: -
Products: -
?
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
-
Substrates: -
Products: -
Products: -
r
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
Substrates: -
Products: -
Products: -
?
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
Substrates: -
Products: -
Products: -
?
phylloquinone + a protein with reduced L-cysteine residues
phylloquinol + a protein with a disulfide bond
Substrates: -
Products: -
Products: -
?
phylloquinone + reduced thioredoxin
phylloquinol + thioredoxin
Substrates: -
Products: -
Products: -
?
phylloquinone + reduced thioredoxin
phylloquinol + thioredoxin
-
Substrates: -
Products: -
Products: -
?
phylloquinone + reduced thioredoxin
phylloquinol + thioredoxin
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: -
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: thioredoxin is the possible physiological electron acceptor
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: reaction in metabolic pathway of vitamin K
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: reaction in metabolic pathway of vitamin K
Products: -
Products: -
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
-
Substrates: thioredoxin is the possible physiological electron acceptor
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: 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
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
Substrates: 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)
Products: -
Products: -
?
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is involved in regulation of response to oral anticoagulants of European-American warfarin patients
Products: -
Products: -
?
additional information
?
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is involved in angiogenesis
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme is involved in coagulation factor activity
Products: -
Products: -
?
additional information
?
-
Substrates: the enzyme is involved in coagulation factor activity
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme, driven by the reducing agent DTT, reduces both vitamin K 2,3-epoxide and vitamin K to the activated hydroquinone form
Products: -
Products: -
?
additional information
?
-
Substrates: VKORC1 produces vitamin K hydroquinone (KH2) in 2 reactions: reduction of vitamin K epoxide (KO) to quinone (K), and then KH2
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
additional information
?
-
-
Substrates: 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
Products: -
Products: -
?
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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
additional information
the use of DTT can be problematic because it is an artificial reductant not found in cells
-
additional information
the use of DTT can be problematic because it is an artificial reductant not found in cells
-
additional information
the use of DTT can be problematic because it is an artificial reductant not found in cells
-
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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
2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
COT-vitamin K or VK-K-COT, replacing the phytyl side-chain with a methylene cyclooctatetraene (COT) moiety at the 3-position of vitamin K1 converts it from a substrate to an inhibitor for VKD carboxylation. This COT-vitamin K derivative displays a similar inhibition potency in warfarin-resistant VKOR mutations whose warfarin resistance varies over 400fold. The compound targets multiple enzymes in the vitamin K redox cycle. The anticoagulation effect of COT-vitamin K can be rescued with high doses of vitamin K. The inhibition potency of the COT-vitamin K derivative is tolerant to genetic variations of VKOR1
6-aminoquinoline-N-hydroxysuccimidyl carbamoyl-L-Tyr-Gly-L-Leu-L-Phe-L-Tyr
-
potent inhibitor, warfarin derivative
-
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
-
in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver
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
-
in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver
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
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; mutants V29L, V45A, and L128R are resistant to inhibition by warfarin in vivo, oveview
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
molecular docking and dynamics of VKORC1-vitamin epoxide K and VKORC1-warfarin complexes, overview. Activity assay data are fitted by nonlinear regression to the noncompetitive inhibition model
warfarin
the anticoagulant warfarin inhibits the vitamin K oxidoreductase (VKORC1). Warfarin inhibition of vitamin K epoxide (KO) to vitamin K reduction and gamma-glutamyl carboxylation that requires full reduction are compared in wild-type VKORC1 or mutants (Y139H, Y139F) that cause warfarin resistance. Carboxylation is much more strongly inhibited (about 400fold) than KO reduction (two to threefold). Warfarin uncouples normal reduction, i.e. inhibiting full KO to vitamin K hydroquinone (KH2) reduction much more than expected from the inhibition of the 2 individual reactions. It is suggested that during warfarin therapy, full KO reduction shifts from a mechanism that requires only VKORC1 to a mechanism that also involves a second reductase. This activity may not be ubiquitously expressed similar to VKORC1, and tissues may therefore respond differently to warfarin in their efficiency of VKD protein carboxylation
warfarin
because of the indirect mechanism of VKA action, a single blocking dose of warfarin does not produce the maximum hypoprothrombinemic response until 2 to 4 days after administration
warfarin
warfarin reversibly inhibits VKOR by competing with vitamin K, inhibition mechanism, overview. Warfarin-resistant VKOR mutations identified in patients significantly decrease warfarin's binding affinity, but have only a minor effect on vitamin K binding. A T-shaped stacking interaction between warfarin and tyrosine residue 139, within the proposed TY139A warfarin-binding motif, is observed. Furthermore, a reversible dynamic warfarin-binding pocket opening and conformational changes are observed when warfarin binds to VKOR. Several residues (Y25, A26, and Y139) are found essential for warfarin binding to VKOR. Molecular dynamics simulations and in vivo assays. No direct interaction between warfarin and the experimentally supported TY139A warfarin-binding motif is observed. Dynamic nature of warfarin binding to the 3-TM human VKOR structure. Dynamic binding pocket opening when warfarin binds to VKOR. The phenyl ring of Y139 is essential for stabilizing warfarin binding, Y25 and A26 interact with Y139 to stabilize warfarin binding in VKOR
warfarin
analysis of warfarin inhibition kinetics requires stabilization of intramembrane vitamin K epoxide reductases, inhibition kinetics, overview. Key to maintain the warfarin sensitivity is to stabilize the native enzyme protein conformation in vitro. Effective inhibition of human VKOR-like requires also the use of LMNG, a mild detergent developed for crystallography to increase membrane protein stability. Human VKOR purified in LMNG is stable only with pre-bound warfarin. Under these optimal conditions, warfarin inhibits with tight-binding kinetics. VKOR pre-reduced by DTT becomes less inhibited by warfarin, suggesting that warfarin preferably inhibits oxidized VKOR and DTT reduction interferes with this inhibition process. hVKORL is much better inhibited by warfarin in GSH than in DTT, with both KO and K as the substrate, but GSH alone cannot fully maintain the native conformation of the hVKORL
warfarin
in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver
warfarin
warfarin inhibits androgen receptor activity (an important driver of prostate cancer development and progression) by inhibiting vitamin K epoxide reductase
warfarin
in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver
warfarin
-
in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver
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
warfarin
no inhibition of the wild-type enzyme from Synechococcus sp. by warfarin. The bacterial VKOR enzyme can mutationally be converted to an epoxide reductase, SsVKOR F67G/T72N/V75F/E115S/M118L/L121I/M122L/I137Y, that is also inhibitable by warfarin like the human enzyme
warfarin
analysis of warfarin inhibition kinetics requires stabilization of intramembrane vitamin K epoxide reductases, inhibition kinetics, overview. Reduced glutathione drastically increases the warfarin sensitivity of a VKOR-like protein from Takifugu rubripes (TrVKORL), presumably through maintaining a disulfide-bonded conformation. Tight-binding inhibition
warfarin
in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver
warfarin
analysis of warfarin inhibition kinetics requires stabilization of intramembrane vitamin K epoxide reductases
warfarin
-
in vitro and in cell culture models, VKORC1L1 is less sensitive to warfarin than VKORC1. VKORC1L1 is not the warfarin-resistant vitamin K quinone reductase present in the liver
additional information
pharmacodynamics of resistance to warfarin, overview
-
additional information
vitamin K antagonists' (VKAs) inhibitory effects on the activity of vitamin K epoxide reductase (VKOR) and its VKA-resistant mutants in their natural cellular environment, overview. The delayed pharmacodynamic response, due to the indirect mechanism of VKA action, together with variable pharmacokinetics makes it difficult to compare the in vivo potency of different VKAs in humans. The efficacy of inhibition of wild-type VKOR follows the descending order of acenocoumarol, phenprocoumon, warfarin, and fluindione, with the efficacy of acenocoumarol being fivefold to eightfold higher than that of the other VKAs. Differential VKOR inhibition by warfarin enantiomers (S > R) consistent with their in vivo potencies and that 10-hydroxywarfarin and warfarin alcohol metabolites show significant inhibition of VKOR. Apart from VKAs used clinically, second-generation VKAs that belong to the so-called superwarfarin family are powerful, long-acting rodenticides that pose significant health risks from accidental and nonaccidental poisoning
-
additional information
synthesis of a series of vitamin K derivatives with benzyl and related side-chain substitutions at the 3-position of 1,4-naphthoquinone. The effect of vitamin K derivatives as inhibitors of vitamin K reductase or KO reductase activity is evaluated in FIXgla-PC/HEK293 reporter cells with either the endogenous VKOR/VKORL (DGKO) or GGCX knocked out. The anticoagulation effect of VK-M-COT and warfarin is reversible by vitamin K1
-
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
0.000016
warfarin
enzyme hVKOR, microsomal hVKOR not subjected to detergent solubilization, endoplasmic reticulum-enriched microsomes, in presence of glutahione with substrate KO, pH and temperature not specified in the publication
0.000027
warfarin
enzyme TrVKORL, pH and temperature not specified in the publication
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
0.000249 - 0.000658
2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
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
0.000249
2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
Homo sapiens
i.e. VK-K-COT, with F55A mutant enzyme, pH and temperature not specified in the publication
0.000487
2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
Homo sapiens
i.e. VK-K-COT, with A26P mutant enzyme, pH and temperature not specified in the publication
0.000575
2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
Homo sapiens
i.e. VK-K-COT, with L128R mutant enzyme, pH and temperature not specified in the publication
0.000615
2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
Homo sapiens
i.e. VK-K-COT, with W59R mutant enzyme, pH and temperature not specified in the publication
0.000616
2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
Homo sapiens
i.e. VK-K-COT, with wild-type enzyme, pH and temperature not specified in the publication
0.000658
2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
Homo sapiens
i.e. VK-K-COT, with Y139F mutant enzyme, pH and temperature not specified in the publication
0.0000059
warfarin
Homo sapiens
with wild-type enzyme, pH and temperature not specified in the publication
0.0000247
warfarin
Homo sapiens
wild-type enzyme, pH and temperature not specified in the publication
0.00004
warfarin
Homo sapiens
enzyme hVKORL in LMNG medium in presence of glutahione with substrate K, 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
0.000097
warfarin
Takifugu rubripes
enzyme TrVKORL, pH and temperature not specified in the publication
0.0001
warfarin
Homo sapiens
enzyme hVKORL in LMNG medium in presence of glutahione with substrate KO, pH and temperature not specified in the publication
0.000112
warfarin
Homo sapiens
mutant enzyme V54L, pH and temperature not specified in the publication
0.00012
warfarin
Homo sapiens
enzyme hVKORL in presence of glutahione with substrate KO, pH and temperature not specified in the publication
0.000127
warfarin
Homo sapiens
mutant enzyme G71A, pH and temperature not specified in the publication
0.00013
warfarin
Homo sapiens
enzyme hVKOR, microsomal hVKOR not subjected to detergent solubilization, endoplasmic reticulum-enriched microsomes, in presence of glutahione with substrate KO, 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
0.000238
warfarin
Homo sapiens
enzyme hVKORL, pH and temperature not specified in the publication
0.00025
warfarin
Homo sapiens
enzyme hVKORL in presence of glutahione with substrate K, pH and temperature not specified in the publication
0.000255
warfarin
Takifugu rubripes
enzyme TrVKORL in presence of glutathione, GSH, pH and temperature not specified in the publication
0.00036
warfarin
Homo sapiens
with A26P mutant enzyme, pH and temperature not specified in the publication
0.000416
warfarin
Homo sapiens
with L128R mutant enzyme, pH and temperature not specified in the publication
0.000433
warfarin
Homo sapiens
mutant enzyme W59R, pH and temperature not specified in the publication
0.000498
warfarin
Homo sapiens
with W59R mutant enzyme, pH and temperature not specified in the publication
0.000633
warfarin
Homo sapiens
with Y139F mutant enzyme, 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
0.00246
warfarin
Homo sapiens
with F55A mutant enzyme, 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
-
287705, 287707, 287710, 287711, 287715, 287716, 287717, 287719, 287720, 287724, 657388, 657400, 689347, 696976, 700605, 701398, 701400, 724796
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vitamin K (VK) epoxide reductase complex subunit 1 (vkorc1)
UniProt
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vitamin K (VK) epoxide reductase vkorc1 like 1 (vkorc1l1)
UniProt
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
vkorc1 and vkorc1l1 gene expression is altered through larval development and is tissue-specific. Early during their development, Senegalese sole larvae undergo metamorphosis, a highly complex transition process that involves deep morphological, biochemical and physiological transformations
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additional information
high enzyme expression level, adult fish
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moderate enzyme expression level, adult fish
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the enzyme is upregulated in fetal heart and in ventricular aneurysm tissue
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very low enzyme expression level, adult fish
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moderate enzyme expression level, adult fish
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moderate enzyme expression level, adult fish
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measurement of allelic mRNA expression. Genotype effect of 2-fold allelic mRNA expression due to single nucleotide polymorphisms -1639G>A and 1173C
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287705, 287706, 287707, 287708, 287710, 287711, 287712, 287715, 287716, 287717, 287719, 287723, 287720, 287724, 657400, 657388, 671387, 674854, 689347, 701398, 724796, 724119
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low enzyme expression level, adult fish. Highest and almost exclusive ssvkorc1 expression in liver
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low enzyme expression level, adult fish
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low enzyme expression level, adult fish
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high enzyme expression level, adult fish
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low enzyme expression level, adult fish
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moderate enzyme expression level, adult fish
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low enzyme expression level, adult fish
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additional information
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quantitative expression analysis, no enzyme expression in peripheral blood leukocytes, the enzyme is upregulated in tumour tissue, overview
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additional information
expression patterns of Vkorc1 and Vkorc1l1 in adult tissues, overview. Vkorc1l1 levels are the highest in the brain and the lowest in liver, but it is important to note that, even in the brain, Vkorc1l1 is expressed at either an equal or lower level than Vkorc1. No tissue or cell type has to date been identified, in which Vkorc1l1, but not Vkorc1, is expressed, since both Vkorc1 and Vkorc1l1 are broadly and mostly equally expressed in extrahepatic tissues
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additional information
expression patterns of Vkorc1 and Vkorc1l1 in adult tissues, overview. Vkorc1l1 levels are the highest in the brain and the lowest in liver, but it is important to note that, even in the brain, Vkorc1l1 is expressed at either an equal or lower level than Vkorc1. No tissue or cell type has to date been identified, in which Vkorc1l1, but not Vkorc1, is expressed, since both Vkorc1 and Vkorc1l1 are broadly and mostly equally expressed in extrahepatic tissues
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additional information
the expression patterns of vitamin K (VK) epoxide reductase complex subunit 1 (vkorc1) is determined during the larval ontogeny of Senegalese sole (Solea senegalensis), and in early juveniles cultured under different physiological conditions. Full-length transcripts for ssvkorc1 are determined and peptide sequences are found to be evolutionarily conserved. During larval development, expression of ssvkorc1 shows a slight increase during absence or low feed intake. Expression of ssvkorc1l1 continuously decreases until 24 h post-fertilization, and remains constant afterwards. Both ssvkors are ubiquitously expressed in adult tissues, and highest expression is found in liver for ssvkorc1, and ovary and brain for ssvkorc1l1. Expression of ssvkorc1 and ssvkorc1l1 is differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency
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additional information
the expression patterns of vitamin K (VK) epoxide reductase complex subunit 1 (vkorc1) is determined during the larval ontogeny of Senegalese sole (Solea senegalensis), and in early juveniles cultured under different physiological conditions. Full-length transcripts for ssvkorc1 are determined and peptide sequences are found to be evolutionarily conserved. During larval development, expression of ssvkorc1 shows a slight increase during absence or low feed intake. Expression of ssvkorc1l1 continuously decreases until 24 h post-fertilization, and remains constant afterwards. Both ssvkors are ubiquitously expressed in adult tissues, and highest expression is found in liver for ssvkorc1, and ovary and brain for ssvkorc1l1. Expression of ssvkorc1 and ssvkorc1l1 is differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency
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additional information
the expression patterns of vitamin K (VK) epoxide reductase vkorc1 like 1 (vkorc1l1) is determined during the larval ontogeny of Senegalese sole (Solea senegalensis), and in early juveniles cultured under different physiological conditions. Full-length transcripts for ssvkorc1l1 are determined and peptide sequences are found to be evolutionarily conserved. During larval development, expression of ssvkorc1 shows a slight increase during absence or low feed intake. Expression of ssvkorc1l1 continuously decreases until 24 h post-fertilization, and remains constant afterwards. Both ssvkors are ubiquitously expressed in adult tissues, and highest expression is found in liver for ssvkorc1, and ovary and brain for ssvkorc1l1. Expression of ssvkorc1 and ssvkorc1l1 is differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency
brenda
additional information
the expression patterns of vitamin K (VK) epoxide reductase vkorc1 like 1 (vkorc1l1) is determined during the larval ontogeny of Senegalese sole (Solea senegalensis), and in early juveniles cultured under different physiological conditions. Full-length transcripts for ssvkorc1l1 are determined and peptide sequences are found to be evolutionarily conserved. During larval development, expression of ssvkorc1 shows a slight increase during absence or low feed intake. Expression of ssvkorc1l1 continuously decreases until 24 h post-fertilization, and remains constant afterwards. Both ssvkors are ubiquitously expressed in adult tissues, and highest expression is found in liver for ssvkorc1, and ovary and brain for ssvkorc1l1. Expression of ssvkorc1 and ssvkorc1l1 is differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
ER membrane localisation, the enzyme has a typical ER retention signal, KAKRH at the C-terminus of the protein which is indispensable to activity
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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
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integral membrane enzyme of the endoplasmic reticulum
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the endoplasmic reticulum distribution of VKORC1 can be explained by the presence, in its C-terminal cytosolic tail, of a di-lysine ER retention signal (KAKRH in human VKORC1)
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membrane topology, type III membrane protein, overview
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the enzyme possesses 3 or 4 transmembrane alpha-helices and a large cytoplasmic loop, membrane topology, overview
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integral membrane protein, topology, overview
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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
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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
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the enzyme contains a VKOR CXXC motif
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VKOR is an integral endoplasmic reticulum membrane protein, transmembrane topology model analysis
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topological view of the the membrane spanning enzyme with these four exoplasmic cysteine residues
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transmembrane protein with 5 transmembrane helices, membrane topology, overview
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VKORC1L1 is a four-transmembrane domain protein with both its termini located in the cytoplasm
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integral membrane protein
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additional information
VKORC1L1 is found in the endoplasmic reticulum, but significant non-endoplasmic reticulum localization is also apparent for this protein
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additional information
immunofluorescence confocal imaging of VKOR in live mammalian cells and PEGylation of VKOR's endogenous cytoplasmic-accessible cysteines in intact microsomes are used to probe the membrane topology of human VKOR. A loop sequence between the first and second transmembrane (TM) domain of VKOR is located in the cytoplasm, supporting a 3-TM topological structure of human VKOR
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Highest Expressing Human Cell Lines
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
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clear difference in VKOR activity and Ki for warfarin among bird species
evolution
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clear difference in VKOR activity and Ki for warfarin among bird species
evolution
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clear difference in VKOR activity and Ki for warfarin among bird species
evolution
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clear difference in VKOR activity and Ki for warfarin among bird species
evolution
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clear difference in VKOR activity and Ki for warfarin among bird species
evolution
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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
evolution
vitamin K epoxide reductases (VKOR) represent a large family of intramembrane thiol oxidoreductases. These enzymes catalyze disulfide-bond formation in bacteria, archaea, and plants to facilitate the oxidative folding of many proteins. In vertebrates, however, the major function of VKOR changes to support blood coagulation through the vitamin K cycle
evolution
full-length transcripts for ssvkorc1 and ssvkorc1l1 are determined and peptide sequences are evolutionarily conserved. Comparisons of conservation of amino acid residues in vitamin K epoxide reductase complex subunit 1 (Vkorc1) and vitamin K epoxide reductase complex subunit 1 like 1 (Vkorc1l1) between fish and tetrapods, overview
evolution
vertebrates, including fishes, rodents and humans, possess two genes encoding VKORs, VKORC1, and a paralog, named VKORC1-like 1 (VKORC1L1). Phylogenic analyses suggest that these two paralogs derive from a single ancestral Vkor gene and that the duplication event that generated two separate genes has occurred in a primitive vertebrate at the origin of the urochordate and vertebrate lineages. The protein sequence alignment of VKORC1 and VKORC1L1 homologues from a range of vertebrate species, including mammals (human and mouse), birds (chickens), reptiles (pitons), amphibians (frogs) and fish (Japanese puffer fish and zebrafish), reveals a remarkable difference in their respective degree of sequence conservation, overview. VKORC1L1 is a vertebrate paralogue of VKORC1. VKORC1 has been more free to diverge than VKORC1L1, following gene duplication. One proposed hypothesis is that VKORC1L1 has retained the original housekeeping functions of the ancestral VKOR, while VKORC1 has diverged to acquire a novel, more specific function in supporting robust vitamin K-dependent carboxylation in the liver
evolution
vertebrates, including fishes, rodents and humans, possess two genes encoding VKORs, VKORC1, and a paralog, named VKORC1-like 1 (VKORC1L1). Phylogenic analyses suggest that these two paralogs derive from a single ancestral Vkor gene and that the duplication event that generated two separate genes has occurred in a primitive vertebrate at the origin of the urochordate and vertebrate lineages. The protein sequence alignment of VKORC1 and VKORC1L1 homologues from a range of vertebrate species, including mammals (human and mouse), birds (chickens), reptiles (pitons), amphibians (frogs) and fish (Japanese puffer fish and zebrafish), reveals a remarkable difference in their respective degree of sequence conservation, overview. VKORC1L1 is a vertebrate paralogue of VKORC1. VKORC1 has been more free to diverge than VKORC1L1, following gene duplication. One proposed hypothesis is that VKORC1L1 has retained the original housekeeping functions of the ancestral VKOR, while VKORC1 has diverged to acquire a novel, more specific function in supporting robust vitamin K-dependent carboxylation in the liver
evolution
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vertebrates, including fishes, rodents and humans, possess two genes encoding VKORs, VKORC1, and a paralog, named VKORC1-like 1 (VKORC1L1). Phylogenic analyses suggest that these two paralogs derive from a single ancestral Vkor gene and that the duplication event that generated two separate genes has occurred in a primitive vertebrate at the origin of the urochordate and vertebrate lineages. The protein sequence alignment of VKORC1 and VKORC1L1 homologues from a range of vertebrate species, including mammals (human and mouse), birds (chickens), reptiles (pitons), amphibians (frogs) and fish (Japanese puffer fish and zebrafish), reveals a remarkable difference in their respective degree of sequence conservation, overview. VKORC1L1 is a vertebrate paralogue of VKORC1. VKORC1 has been more free to diverge than VKORC1L1, following gene duplication. One proposed hypothesis is that VKORC1L1 has retained the original housekeeping functions of the ancestral VKOR, while VKORC1 has diverged to acquire a novel, more specific function in supporting robust vitamin K-dependent carboxylation in the liver
evolution
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vertebrates, including fishes, rodents and humans, possess two genes encoding VKORs, VKORC1, and a paralog, named VKORC1-like 1 (VKORC1L1). Phylogenic analyses suggest that these two paralogs derive from a single ancestral Vkor gene and that the duplication event that generated two separate genes has occurred in a primitive vertebrate at the origin of the urochordate and vertebrate lineages. The protein sequence alignment of VKORC1 and VKORC1L1 homologues from a range of vertebrate species, including mammals (human and mouse), birds (chickens), reptiles (pitons), amphibians (frogs) and fish (Japanese puffer fish and zebrafish), reveals a remarkable difference in their respective degree of sequence conservation, overview. VKORC1L1 is a vertebrate paralogue of VKORC1. VKORC1 has been more free to diverge than VKORC1L1, following gene duplication. One proposed hypothesis is that VKORC1L1 has retained the original housekeeping functions of the ancestral VKOR, while VKORC1 has diverged to acquire a novel, more specific function in supporting robust vitamin K-dependent carboxylation in the liver
evolution
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vertebrates, including fishes, rodents and humans, possess two genes encoding VKORs, VKORC1, and a paralog, named VKORC1-like 1 (VKORC1L1). Phylogenic analyses suggest that these two paralogs derive from a single ancestral Vkor gene and that the duplication event that generated two separate genes has occurred in a primitive vertebrate at the origin of the urochordate and vertebrate lineages. The protein sequence alignment of VKORC1 and VKORC1L1 homologues from a range of vertebrate species, including mammals (human and mouse), birds (chickens), reptiles (pitons), amphibians (frogs) and fish (Japanese puffer fish and zebrafish), reveals a remarkable difference in their respective degree of sequence conservation, overview. VKORC1L1 is a vertebrate paralogue of VKORC1. VKORC1 has been more free to diverge than VKORC1L1, following gene duplication. One proposed hypothesis is that VKORC1L1 has retained the original housekeeping functions of the ancestral VKOR, while VKORC1 has diverged to acquire a novel, more specific function in supporting robust vitamin K-dependent carboxylation in the liver
evolution
vertebrates, including fishes, rodents and humans, possess two genes encoding VKORs, VKORC1, and a paralog, named VKORC1-like 1 (VKORC1L1). Phylogenic analyses suggest that these two paralogs derive from a single ancestral Vkor gene and that the duplication event that generated two separate genes has occurred in a primitive vertebrate at the origin of the urochordate and vertebrate lineages. The protein sequence alignment of VKORC1 and VKORC1L1 homologues from a range of vertebrate species, including mammals (human and mouse), birds (chickens), reptiles (pitons), amphibians (frogs) and fish (Japanese puffer fish and zebrafish), reveals a remarkable difference in their respective degree of sequence conservation, overview. VKORC1L1 is a vertebrate paralogue of VKORC1. VKORC1 has been more free to diverge than VKORC1L1, following gene duplication. One proposed hypothesis is that VKORC1L1 has retained the original housekeeping functions of the ancestral VKOR, while VKORC1 has diverged to acquire a novel, more specific function in supporting robust vitamin K-dependent carboxylation in the liver
evolution
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vertebrates, including fishes, rodents and humans, possess two genes encoding VKORs, VKORC1, and a paralog, named VKORC1-like 1 (VKORC1L1). Phylogenic analyses suggest that these two paralogs derive from a single ancestral Vkor gene and that the duplication event that generated two separate genes has occurred in a primitive vertebrate at the origin of the urochordate and vertebrate lineages. The protein sequence alignment of VKORC1 and VKORC1L1 homologues from a range of vertebrate species, including mammals (human and mouse), birds (chickens), reptiles (pitons), amphibians (frogs) and fish (Japanese puffer fish and zebrafish), reveals a remarkable difference in their respective degree of sequence conservation, overview. VKORC1L1 is a vertebrate paralogue of VKORC1. VKORC1 has been more free to diverge than VKORC1L1, following gene duplication. One proposed hypothesis is that VKORC1L1 has retained the original housekeeping functions of the ancestral VKOR, while VKORC1 has diverged to acquire a novel, more specific function in supporting robust vitamin K-dependent carboxylation in the liver
evolution
vitamin K epoxide reductases (VKOR) represent a large family of intramembrane thiol oxidoreductases. These enzymes catalyze disulfide-bond formation in bacteria, archaea, and plants to facilitate the oxidative folding of many proteins. In vertebrates, however, the major function of VKOR changes to support blood coagulation through the vitamin K cycle
evolution
vitamin K epoxide reductases (VKOR) represent a large family of intramembrane thiol oxidoreductases. These enzymes catalyze disulfide-bond formation in bacteria, archaea, and plants to facilitate the oxidative folding of many proteins. In vertebrates, however, the major function of VKOR changes to support blood coagulation through the vitamin K cycle
evolution
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vertebrates, including fishes, rodents and humans, possess two genes encoding VKORs, VKORC1, and a paralog, named VKORC1-like 1 (VKORC1L1). Phylogenic analyses suggest that these two paralogs derive from a single ancestral Vkor gene and that the duplication event that generated two separate genes has occurred in a primitive vertebrate at the origin of the urochordate and vertebrate lineages. The protein sequence alignment of VKORC1 and VKORC1L1 homologues from a range of vertebrate species, including mammals (human and mouse), birds (chickens), reptiles (pitons), amphibians (frogs) and fish (Japanese puffer fish and zebrafish), reveals a remarkable difference in their respective degree of sequence conservation, overview. VKORC1L1 is a vertebrate paralogue of VKORC1. VKORC1 has been more free to diverge than VKORC1L1, following gene duplication. One proposed hypothesis is that VKORC1L1 has retained the original housekeeping functions of the ancestral VKOR, while VKORC1 has diverged to acquire a novel, more specific function in supporting robust vitamin K-dependent carboxylation in the liver
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malfunction
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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
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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
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
malfunction
vitamin K antagonists (VKAs), such as warfarin, function by impairing the biosynthesis of vitamin K-dependent (VKD) clotting factors through the inhibition of vitamin K epoxide reductase (VKOR). The challenge of VKAs therapy is their narrow therapeutic index and highly variable dosing requirements, which are partially due to the genetic variations of VKOR
malfunction
the enzyme VKOR, when inhibited, blocks the hepatic synthesis of active (gamma-carboxylated) vitamin K-dependent coagulation factors. Not all clinically identified VKA-resistant VKOR mutations result in VKA-resistant VKOR activity, even in a cell-based system
malfunction
the inactivation of VKORC1L1 does not impact HEK-293 cell survival in culture
malfunction
no obvious phenotype potentially associated with increased oxidative stress has been detected in Vkorc1l1-/- mice, which are viable and develop normally in comparison to wild-type mice
malfunction
mutations in the carboxylase and VKORC1 can impair carboxylation and decrease VKD clotting factor activities to cause severe bleeding. An inactive VKORC1 mutant lacking active site thiols shows a dominant negative effect on VKORC1-supported carboxylation, indicating the importance of a VKORC1 dimer to efficient KO to KH2 reduction
malfunction
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when the active cysteine C57 in enzyme MtVKOR, involved in binding to reduced DsbA is mutated to alanine, the amount of fully oxidized MtDsbA decreases. When the second cysteine in the C89XXC92 motif of MtDsbA is mutated to alanine, MtDsbA cysteines are mostly reduced suggesting that the structural disulfide bond between C140 and C192 of MtDsbA relies on the catalytic activity of the C89XXC92 disulfide bond of MtDsbA, which is in turn reoxidized by MtVKOR
malfunction
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the deletion of a vkor homologue in Mycobacterium smegmatis causes a severe growth defect. The deletion of MsDsbA causes a more severe growth defect than does the deletion of MsVKOR
malfunction
in the presence of vitamin K antagonists (VKA) or when VKORC1 and VKORC1L1 are knocked out, the K/KO balance decreases significantly due to the accumulation of vitamin KO. In contrast, when VKORC1 is overexpressed, the balance remains unchanged, demonstrating the limitation of vitamin K epoxide reductase (VKOR) activity. This limitation is shown to be due to insufficient expression of the activation partner of VKORC1, as overexpression of protein disulfide isomerase (PDI) overcomes this limitation. Overexpression of protein disulfide isomerase enhances vitamin K epoxide reductase activity
malfunction
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no obvious phenotype potentially associated with increased oxidative stress has been detected in Vkorc1l1-/- mice, which are viable and develop normally in comparison to wild-type mice
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metabolism
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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
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VKOR contributes to an oxidizing endoplasmic reticulum environment under conditions of endoplasmic reticulum oxidoreductin and peroxiredoxin IV deficiency
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
VKORC1L1 is chiefly responsible for antioxidative function by reduction of vitamin K to prevent damage by intracellular 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
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
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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
in vivo VKORC1L1 reduces vitamin K epoxide to support vitamin K-dependent carboxylation as efficiently as does VKORC1
metabolism
vitamin K is a family of 2-methyl-1,4-naphthoquinone derivatives, which include the naturally occurring phylloquinone (vitamin K1) and menaquinones (vitamin K2), and the synthetic menadione (vitamin K3). Menaquinones differ from phylloquinone in that the side chain at the 3-position comprises a number of repeating prenyl units rather than the semi-saturated phytyl chain
metabolism
expression of ssvkorc1 and ssvkorc1l1 is differentially regulated under physiological conditions related to fasting and re-feeding, but also under vitamin K (VK) dietary supplementation and induced deficiency. Vitamin K metabolism in marine fish is sensitive to nutritional and environmental conditions, overview. In fish species, the key role of VK in biological processes, such as sex hormone synthesis/release and reproductive performance, skeletal development and maintenance, neural development and cognitive capacities, and redox system homeostasis, vasculogenesis and visual phototransduction, has been evidenced, and higher VK nutritional requirements during early developmental stages are suggested. VK nutritional requirements throughout larval development. Genes ssvkorc1 and ssvkorc1l1 distinct gene expression patterns may reflect their functional specialization
metabolism
in vertebrates, the only well-described cellular function of vitamin K is to support gamma-glutamyl carboxylation (gamma-carboxylation), a posttranslational modification present in some secreted proteins and characterized by the addition of a carboxyl group to specific glutamic acid (Glu) residues, which converts them to gamma-carboxyglutamic acid (Gla) residues. Several coagulation factors, produced by the liver, including prothrombin, factor VII, factor IX and factor X, are gamma-carboxylated proteins (Gla proteins), and this modification is essential to their function, explaining the positive effect of vitamin K on the clotting cascade. Developmental regulation of the vitamin K cycle in the liver. Partial redundancy between VKORC1 and VKORC1L1 in osteoblasts during the perinatal period
metabolism
in vertebrates, the only well-described cellular function of vitamin K is to support gamma-glutamyl carboxylation (gamma-carboxylation), a posttranslational modification present in some secreted proteins and characterized by the addition of a carboxyl group to specific glutamic acid (Glu) residues, which converts them to gamma-carboxyglutamic acid (Gla) residues. Several coagulation factors, produced by the liver, including prothrombin, factor VII, factor IX and factor X, are gamma-carboxylated proteins (Gla proteins), and this modification is essential to their function, explaining the positive effect of vitamin K on the clotting cascade. Developmental regulation of the vitamin K cycle in the liver. Partial redundancy between VKORC1 and VKORC1L1 in osteoblasts during the perinatal period. Developmental regulation of the vitamin K cycle in bones (caalvaria), overview
metabolism
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in vertebrates, the only well-described cellular function of vitamin K is to support gamma-glutamyl carboxylation (gamma-carboxylation), a posttranslational modification present in some secreted proteins and characterized by the addition of a carboxyl group to specific glutamic acid (Glu) residues, which converts them to gamma-carboxyglutamic acid (Gla) residues. Several coagulation factors, produced by the liver, including prothrombin, factor VII, factor IX and factor X, are gamma-carboxylated proteins (Gla proteins), and this modification is essential to their function, explaining the positive effect of vitamin K on the clotting cascade. Developmental regulation of the vitamin K cycle in the liver
metabolism
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in vertebrates, the only well-described cellular function of vitamin K is to support gamma-glutamyl carboxylation (gamma-carboxylation), a posttranslational modification present in some secreted proteins and characterized by the addition of a carboxyl group to specific glutamic acid (Glu) residues, which converts them to gamma-carboxyglutamic acid (Gla) residues. Several coagulation factors, produced by the liver, including prothrombin, factor VII, factor IX and factor X, are gamma-carboxylated proteins (Gla proteins), and this modification is essential to their function, explaining the positive effect of vitamin K on the clotting cascade. Developmental regulation of the vitamin K cycle in the liver
metabolism
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in vertebrates, the only well-described cellular function of vitamin K is to support gamma-glutamyl carboxylation (gamma-carboxylation), a posttranslational modification present in some secreted proteins and characterized by the addition of a carboxyl group to specific glutamic acid (Glu) residues, which converts them to gamma-carboxyglutamic acid (Gla) residues. Several coagulation factors, produced by the liver, including prothrombin, factor VII, factor IX and factor X, are gamma-carboxylated proteins (Gla proteins), and this modification is essential to their function, explaining the positive effect of vitamin K on the clotting cascade. Developmental regulation of the vitamin K cycle in the liver
metabolism
in vertebrates, the only well-described cellular function of vitamin K is to support gamma-glutamyl carboxylation (gamma-carboxylation), a posttranslational modification present in some secreted proteins and characterized by the addition of a carboxyl group to specific glutamic acid (Glu) residues, which converts them to gamma-carboxyglutamic acid (Gla) residues. Several coagulation factors, produced by the liver, including prothrombin, factor VII, factor IX and factor X, are gamma-carboxylated proteins (Gla proteins), and this modification is essential to their function, explaining the positive effect of vitamin K on the clotting cascade. Developmental regulation of the vitamin K cycle in the liver
metabolism
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in vertebrates, the only well-described cellular function of vitamin K is to support gamma-glutamyl carboxylation (gamma-carboxylation), a posttranslational modification present in some secreted proteins and characterized by the addition of a carboxyl group to specific glutamic acid (Glu) residues, which converts them to gamma-carboxyglutamic acid (Gla) residues. Several coagulation factors, produced by the liver, including prothrombin, factor VII, factor IX and factor X, are gamma-carboxylated proteins (Gla proteins), and this modification is essential to their function, explaining the positive effect of vitamin K on the clotting cascade. Developmental regulation of the vitamin K cycle in the liver
metabolism
the enzyme is involved in the vitamin K cycle, the vitamin K cycle consists of three steps. First, vitamin K hydroquinone (KH2) is converted into vitamin K epoxide (KO) by gamma-glutamyl carboxylase (GGCX). This enzymatic activity is known as vitamin K-dependent carboxylation (VKDC). Second, vitamin KO is converted into vitamin K quinone by the vitamin K epoxide reductase complex subunit 1 enzyme (VKORC1) and vitamin K epoxide reductase complex subunit 1-like enzyme (VKORC1L1). This enzymatic activity is called vitamin K epoxide reductase (VKOR) activity. Finally, vitamin K quinone is regenerated in KH2 by vitamin K reductase activity (VR) supported by VKORC1, VKORC1L1, and presumably other enzymes, such as NAD(P)H dehydrogenase quinone 1 (NQO1). It is supposed, that VKORC1 and VKORC1L1 reduced activation by protein disulfide isomerase-like proteins (PDIs) system constitutes a limiting step for vitamin K cycle
metabolism
the major function of VKOR changes to support blood coagulation through the vitamin K cycle. This cycle begins with the gamma-carboxylation of selected glutamic acids in several coagulation factors, a posttranslational modification required for their activity. The gamma-carboxylation is driven by the epoxidation of the vitamin K hydroquinone, which is regenerated by VKOR to complete the vitamin K cycle
metabolism
-
in vertebrates, the only well-described cellular function of vitamin K is to support gamma-glutamyl carboxylation (gamma-carboxylation), a posttranslational modification present in some secreted proteins and characterized by the addition of a carboxyl group to specific glutamic acid (Glu) residues, which converts them to gamma-carboxyglutamic acid (Gla) residues. Several coagulation factors, produced by the liver, including prothrombin, factor VII, factor IX and factor X, are gamma-carboxylated proteins (Gla proteins), and this modification is essential to their function, explaining the positive effect of vitamin K on the clotting cascade. Developmental regulation of the vitamin K cycle in the liver. Partial redundancy between VKORC1 and VKORC1L1 in osteoblasts during the perinatal period. Developmental regulation of the vitamin K cycle in bones (caalvaria), overview
-
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
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
-
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 2,3-epoxide reductase complex subunit 1 is an essential enzyme for proper function of blood coagulation
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 enzyme is involved in the vitamin K cycle maintaining vitamin K levels and sustain the blood coagulation cascade
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
-
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
-
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
physiological function
Vkorc1 is the main isoform responsible for recycling VK epoxide originated from hepatic gamma-carboxylation of hemostasis-related VKDPs. Vkorc1l1 has been shown to support in vivo VKDP carboxylation in liver and bone during the pre- and perinatal periods in the absence of Vkorc1, suggesting a partial redundancy between both Vkors. An increased VK recycling through Vkorc1 might help to sustain VKDPs hepatic gamma-carboxylation. Expression of ssvkorc1 and ssvkorc1l1 is differentially regulated under relevant physiological conditions
physiological function
vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the gamma-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralogue, VKORC1-like 1 (VKORC1L1), structure, function and expression pattern of VKORC1L1, overview. In the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. The partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth. VKORC1L1 is responsible for supporting the basal level of vitamin K reduction in most tissues, while VKORC1 has evolved to be temporally regulated and highly expressed in cell types, such as hepatocytes and osteoblasts, where a very high demand for carboxylation is needed after birth
physiological function
vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the gamma-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralogue, VKORC1-like 1 (VKORC1L1), structure, function and expression pattern of VKORC1L1, overview. In the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. The partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth. VKORC1L1 protects mice from hemorrhages and premature death in the absence of VKORC1. VKORC1L1 is responsible for supporting the basal level of vitamin K reduction in most tissues, while VKORC1 has evolved to be temporally regulated and highly expressed in cell types, such as hepatocytes and osteoblasts, where a very high demand for carboxylation is needed after birth
physiological function
-
vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the cofactor for the gamma-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralogue, VKORC1-like 1 (VKORC1L1), structure, function and expression pattern of VKORC1L1, overview. In the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. The partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth
physiological function
the vitamin K oxidoreductase (VKORC1) generates vitamin K hydroquinone (KH2) and is required for the carboxylation and consequent activation of vitamin K-dependent (VKD) proteins. VKORC1 produces KH2 in 2 reactions: reduction of vitamin K epoxide (KO) to quinone (K), and then KH2. gamma-Glutamyl carboxylation by gamma-glutamyl-carboxylase uses vitamin K cycling between the gamma-glutamyl carboxylase and vitamin K oxidoreductase (VKORC1), which both reside in the endoplasmic reticulum and mediate VKD protein modification during secretion. The carboxylase uses oxygenation of vitamin K hydroquinone (KH2) to vitamin K epoxide (KO) to convert Glus to carboxylated Glus (Glas)
physiological function
-
vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the gamma-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralogue, VKORC1-like 1 (VKORC1L1), structure, function and expression pattern of VKORC1L1, overview. In the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. The partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth
physiological function
-
vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the gamma-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralogue, VKORC1-like 1 (VKORC1L1), structure, function and expression pattern of VKORC1L1, overview. In the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. The partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth
physiological function
vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the gamma-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralogue, VKORC1-like 1 (VKORC1L1), structure, function and expression pattern of VKORC1L1, overview. In the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. The partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth
physiological function
-
vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the cofactor for the gamma-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralogue, VKORC1-like 1 (VKORC1L1), structure, function and expression pattern of VKORC1L1, overview. In the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. The partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth
physiological function
within cells, vitamin K participates in a cyclic process initiated in the endoplasmic reticulum lumen through a reduction from the inactive vitamin K 2,3-epoxide to the active vitamin K quinone by the enzyme vitamin K epoxide reductase (VKOR). After each vitamin K-dependent protein activation, vitamin K is recycled to the initial inactive state. Vitamin K is a natural K-vitamer generated by plants and preferentially transported to the human liver, it is required for the post-synthesis modification of proteins involved in blood coagulation (blood pro- and anti-clotting enzymes, e.g., endothelial anticoagulant protein S) as well as proteins outside the coagulation cascade. It is reported that vitamin K levels appear to be extremely reduced in the lungs of hospitalised COVID-19 patients and particularly in those who need mechanical ventilation in the intensive care unit and/or died. It seems, therefore, that the activation of endothelial protein S in these patients is more severely compromised than the activation of hepatic procoagulant factors and is compatible with enhanced thrombogenicity in COVID-19
physiological function
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the vkor gene is essential for the growth of Mycobacterium tuberculosis. Mycobacterium tuberculosis DsbA is efficiently oxidized by VKOR in Escherichia coli. Periplasmic enzyme DsbA catalyzes the formation of disulfide bonds when its two active-site cysteines are joined in a disulfide bond. DsbA donates its disulfide bond to substrate proteins and in the process becomes reduced. The Mycobacterium tuberculosis VKOR protein is involved in disulfide bond formation, performing the potential role of endogneous DsbB of Escherichia coli. When the vkor gene is cloned from Mycobacterium tuberculosis, it complements an Escherichia coli dsbB deletion strain, restoring the oxidation of Escherichia coli DsbA and disulfide bond formation, MtVKOR can restore the motility of Escherichia coli DELTAdsbB due to its ability to oxidize EcDsbA
physiological function
-
involvement of VKOR in DsbA oxidation in Mycobacterium smegmatis. Periplasmic enzyme DsbA catalyzes the formation of disulfide bonds when its two active-site cysteines are joined in a disulfide bond. DsbA donates its disulfide bond to substrate proteins and in the process becomes reduced. The Mycobacterium smegmatis VKOR protein is involved in disulfide bond formation, performing the potential role of endogneous DsbB of Escherichia coli
physiological function
vitamin K epoxide reductase (VKOR) activity is catalyzed by the VKORC1 enzyme. It is a target of vitamin K antagonists (VKA). Functional interaction between VKORC1 and protein disulfide isomerase (PDI)
physiological function
the vitamin K epoxide reductase (VKORC1) enzyme is of primary importance in many physiological processes, i.e. blood coagulation, energy metabolism, and arterial calcification prevention, due to its role in the vitamin K cycle. VKORC1 catalyzes reduction of vitamin K epoxide to quinone and then to hydroquinone
physiological function
vitamin K epoxide reductase (VKOR), an endoplasmic reticulum membrane protein, is the key enzyme for vitamin K-dependent carboxylation, a posttranslational modification that is essential for the biological functions of coagulation factors. VKOR is the target of the most widely prescribed oral anticoagulant, warfarin
physiological function
the major function of VKOR changes to support blood coagulation through the vitamin K cycle. This cycle begins with the gamma-carboxylation of selected glutamic acids in several coagulation factors, a posttranslational modification required for their activity. The gamma-carboxylation is driven by the epoxidation of the vitamin K hydroquinone, which is regenerated by VKOR to complete the vitamin K cycle
physiological function
-
vitamin K is an essential nutrient involved in the regulation of blood clotting and tissue mineralization. Vitamin K oxidoreductase (VKORC1) converts vitamin K epoxide into reduced vitamin K, which acts as the co-factor for the gamma-carboxylation of several proteins, including coagulation factors produced by the liver. VKORC1 is also the pharmacological target of warfarin, a widely used anticoagulant. Vertebrates possess a VKORC1 paralogue, VKORC1-like 1 (VKORC1L1), structure, function and expression pattern of VKORC1L1, overview. In the absence of VKORC1, VKORC1L1 can support vitamin K-dependent carboxylation in the liver during the pre- and perinatal periods in vivo. The partial redundancy between VKORC1 and VKORC1L1 also exists in bone around birth. VKORC1L1 protects mice from hemorrhages and premature death in the absence of VKORC1. VKORC1L1 is responsible for supporting the basal level of vitamin K reduction in most tissues, while VKORC1 has evolved to be temporally regulated and highly expressed in cell types, such as hepatocytes and osteoblasts, where a very high demand for carboxylation is needed after birth
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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
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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
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conserved loop cysteines in VKOR are not required for active site regeneration after each cycle of oxidation
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
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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
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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
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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
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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
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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
phylogenetic characterization of VKOR family proteins. A chronology for the evolution of the five extant VKOR clades is suggested
additional information
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phylogenetic characterization of VKOR family proteins. A chronology for the evolution of the five extant VKOR clades is suggested
additional information
identification of the functional states of human Vitamin K epoxide reductase from molecular dynamics simulations
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
additional information
comparison of three-dimensional structures of human VKOR C43S mutant with bound vitamin K1 epoxide and Synechococcus VKOR C50A mutant, identification of substrate binding pocket and key regions responsible for epoxide reductase activity, overview
additional information
comparison of three-dimensional structures of human VKOR C43S mutant with bound vitamin K1 epoxide and Synechococcus VKOR C50A mutant, identification of substrate binding pocket and key regions responsible for epoxide reductase activity, overview
additional information
structure comparisons of VKORC1 and VKORC1L1, overview
additional information
structure comparisons of VKORC1 and VKORC1L1, overview
additional information
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structure comparisons of VKORC1 and VKORC1L1, overview
additional information
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structure comparisons of VKORC1 and VKORC1L1, overview
additional information
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structure comparisons of VKORC1 and VKORC1L1, overview
additional information
structure comparisons of VKORC1 and VKORC1L1, overview
additional information
a suggested mechanism postulates that redox proteins transfer electrons to two conserved cysteines in a luminal loop (L-loop) of hVKORC1. These electrons are transferred to a CXXC motif in the enzyme transmembrane domain (TMD). Finally, the reduced CXXC motif of hVKORC1 transfers electrons to vitamin K. Each step of vitamin K reduction is tightly coupled to the motif CXXC oxidation in the hVKORC1 active site. To repeatedly reduce vitamin K, hVKORC1 must be regularly activated by a redox partner delivering reducing equivalents through a thiol-disulfide exchange reaction. The cooperation of hVKORC1 with a redox protein implies an activation process. Mechanism of the thiol-disulfide exchange reactions between protein disulfide isomerase (PDI) and hVKORC1. Thioldisulfide exchange reactions involve reduced (proton-coupled) PDI and oxidised hVKORC1. For the complex modelling, the de novo model of hVKORC1 in the oxidised inactive state is used as a target of PDI. Conformations derived from crystallographic structures and de novo models are used as PDI targets in protein-protein docking trials, molecular docking and simulations, structure-function analysis, overview
additional information
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a detailed comparison of the mechanism of electron transfer between Mycobacterium tuberculosis VKOR and Escherichia coli DsbA has revealed strong parallels
additional information
VKORC1 enzymatic site structure and function analysis, molecular modeling. Residues F55, N80, and F83 are crucial for vitamin K epoxide binding. Residues F55, N80, and F83 appear to act in a concerted manner to keep vitamin K epoxide close to the C135 catalytic residue. Residues F55 and N80 prevent naphthoquinone head rotation away from the active site, assisted by residue F83 that prevents vitamin K from sliding outside the enzymatic pocket, through hydrophobic tail stabilization. Molecular docking and dynamics of VKORC1-vitamin epoxide K and VKORC1-warfarin complexes, molecular simulations, overview. Substrate binding structure analysis
additional information
cysteines 132 and 135 comprise a C132XXC135 active site redox center of VKOR, the C132XXC135 redox motif is VKOR's active site
additional information
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structure comparisons of VKORC1 and VKORC1L1, overview
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Show AA Sequence and Transmembrane Helices (2276 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
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the enzyme possesses a dicoumarol binding hydrophobic sequence motif TYA, VKOR complex structure, overview
additional information
the enzyme harbors a transmembrane four-helix bundle crowned by the intrinsically disordered luminal loop (L-loop, R33-N77) protruding in the endoplasmic reticulum lumen
additional information
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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
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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
additional information
vitamin K (VK) epoxide reductase complex subunit 1 (vkorc1) and vkorc1 like 1 (vkorc1l1)
additional information
vitamin K (VK) epoxide reductase complex subunit 1 (vkorc1) and vkorc1 like 1 (vkorc1l1)
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
analysis and comparison of crystal structures of human VKOR C43S mutant with bound vitamin K1 epoxide and Synechococcus VKOR C50A mutant, identification of substrate binding pocket and key regions responsible for epoxide reductase activity, overview
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
analysis and comparison of crystal structures of human VKOR C43S mutant with bound vitamin K1 epoxide and Synechococcus VKOR C50A mutant, identification of substrate binding pocket and key regions responsible for epoxide reductase activity, overview
analysis and comparison of crystal structures of human VKOR C43S mutant with bound vitamin K1 epoxide and Synechococcus VKOR C50A mutant, identification of substrate binding pocket and key regions responsible for epoxide reductase activity, overview
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C101A
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formation of of a high-molecular-weight complex that is positive for thiol-disulfide oxidoreductase MdbA and vitamin K epoxide reductase
A26P
C1173T
C132A
C135A
C16A
C43A
C43A/C51A
C51A
C85A
C96A
DELTAC43-C51
F55A
naturally occuring mutation, located in the loop region between TMD1 and TMD2, the mutation causes a 417fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR
F55G
site-directed mutagenesis, the nonconservative mutant is predicted to be inactive by molecular modeling analyses
F55Y
site-directed mutagenesis, the conservative mutant is expected to be active by molecular modeling analyses, molecular docking of vitK1E to the F55G mutant
F83G
site-directed mutagenesis, the nonconservative mutant is predicted to be inactive by molecular modeling analyses, a loss of hydrogen bonds to S52 and S81 induced by the F83G mutation leads to a rotation of vitK1E away from the active site, also facing TM2
G6R
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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
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site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
L120Q
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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
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naturally occuring mutation, no synthesis of no 2-OH-vitamin K1 or 3-OH-vitamin K1
L128R
N80G
site-directed mutagenesis, the nonconservative mutant is predicted to be inactive by molecular modeling analyses, molecular docking of vitK1E to the N80G mutant. The N80G mutation induces a loss of hydrogen bonds to S52 and S81, leading vitK1E to rotate away from C135
R33G
-
site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
R35G
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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
W59R
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
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mutant shows about 75% relative VKOR activity as compared to the wild type enzyme
L128S
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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
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mutant shows about 40% relative VKOR activity as compared to the wild type enzyme
R61L
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mutant shows about 50% relative VKOR activity as compared to the wild type enzyme
Y139C
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mutant shows about 30% relative VKOR activity as compared to the wild type enzyme
W59G
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the single nucleotide polymorphism T175G in gene VKORC1 causes 4-hydroxycoumarin derivative-resistance
C65A
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site-directed mutagenesis, when the active cysteine C57 in enzyme MtVKOR, involved in binding to reduced DsbA is mutated to alanine, the amount of fully oxidized MtDsbA decreases
C92A
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site-directed mutagenesis, when the second cysteine in the C89XXC92 motif of MtDsbA is mutated to alanine, MtDsbA cysteines are mostly reduced
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
-
F67G/T72N/V75F/E115S/M118L/L121I/M122L/I137Y
the bacterial VKOR homologue can be converted to an epoxide reductase that is also inhibitable by warfarin like the human enzyme by substituting the residues corresponding to N80 and Y139 in the human VKOR, these residues provide strong hydrogen bonding interactions to facilitate the epoxide reduction. The rest of substitutions, E115S/M118L/L121I/M122L (corresponding to S117/L120/I123/L124 in HsVKOR), increase the size and change the shape of the substrate-binding pocket, and the membrane anchor domain stabilizes this pocket while allowing certain flexibility for optimal binding of the epoxide substrate. Generating the epoxide reductase activity in SsVKOR requires three essential substitutions, F67G, T72N, and I137Y, with contribution from V75F. These mutated residues correspond to G62, N80, Y139, and F83 in HsVKOR, respectively, comparison of the relative epoxide reductase activities of substitutions at the N- and C-half of SsVKOR TM3 luminal region and activities of HsVKOR mutants. The engineered SsVKOR constructs are inhibitable by warfarin. The IC50 values of warfarin inhibition against the S3 and M1 constructs are 190 nM and 400 nM, respectively, approximately 10 to 20fold higher than that of HsVKOR. Removal of the Trx domain from S3 and M1 os SsVKOR increases warfarin IC50 to 0.00111 mM (S3-TM5/Trx) and 0.00187 mM (M2), respectively. Structural comparison shows enlarged substrate binding pocket of the mutant for epoxide reduction
F75V
site-directed mutagenesis, the mutant shows over 60% reduced carboxylation activity compared to wild-type enzyme
G67F
site-directed mutagenesis, the mutant shows over 90% reduced carboxylation activity compared to wild-type enzyme
I121L
site-directed mutagenesis, the mutant shows over 30% reduced carboxylation activity compared to wild-type enzyme
L118M
site-directed mutagenesis, the mutant shows over 60% reduced carboxylation activity compared to wild-type enzyme
L122M
site-directed mutagenesis, the mutant shows over 50% reduced carboxylation activity compared to wild-type enzyme
N72T
site-directed mutagenesis, the mutant shows over 95% reduced carboxylation activity compared to wild-type enzyme
S115E
site-directed mutagenesis, the mutant shows over 80% reduced carboxylation activity compared to wild-type enzyme
Y137I
site-directed mutagenesis, the mutant shows over 90% reduced carboxylation activity compared to wild-type enzyme
additional information
A26P
naturally occuring mutation, located within the first transmembrane domain (TMD1), the mutation causes a 60fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR
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
L128R
naturally occuring mutation, located within the last TMD near VKOR's active site, the mutation causes a fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR
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
W59R
naturally occuring mutation, located in the loop region between TMD1 and TMD2, the mutation causes a fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR
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
-
site-directed mutagenesis, the mutation dramatically affects the vitamin K epoxide reductase activity
Y139C
-
naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, additional synthesis of 3-hydroxyvitamin K1
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
Y139F
naturally occuring mutation, located within the last TMD near VKOR's active site, the mutation causes a fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR
Y139S
-
site-directed mutagenesis, the mutation dramatically affects the vitamin K epoxide reductase activity, additional production of 3-hydroxyvitamin K1 in the mutant
Y139S
-
naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, additional synthesis of 3-hydroxyvitamin K1
A26T
-
the mutation has only a moderate effect on VKOR activity with a reduction to approximately 56% of wild type activity
A26T
-
mutant shows about 60% relative VKOR activity as compared to the wild type enzyme
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
-
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
-
enzyme overexpression stimulates cell proliferation, while inhibition of enzyme expression by antisense constructs reduces it, overview
additional information
-
deficient enzyme mutants cause VKCFD2 disease phenotype
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
-
VKORC1 gene polymorphisms are associated with warfarin dose requirements in Turkish patients
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
-
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
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
in HEK-293 cells lacking the two VKORs, the reintroduction of VKORC1L1 alone is sufficient to fully restore vitamin K epoxide-dependent gamma-carboxylation. VKORC1L1 can support vitamin K-dependent gamma-carboxylation in the absence of VKORC1 in this particular cell line
additional information
the human HEK-293 cell line is used to generate PCR products for VKORC1 (from start to stop codon) and PDI (from signal peptide to stop codon) fused with a c-myc tag (EQKLISEEDL) via a flexible spacer (GGSGGSGGS) at the C-terminal end
additional information
-
allelic mutations in the orthologous gene of VKORC1 can cause warfarin resistance
additional information
transgenic overexpression of VKORC1L1, under the control of the human APOE promoter (APOE-Vkorc1l1) in the liver of Vkorc1-/- mice, is sufficient to restore gamma-carboxylation and normal coagulation. In fact, Vkorc1-/-; APOE-Vkorc1l1 mice survive into adulthood, are fertile and do not display any apparent phenotype. Hence, VKORC1L1, when expressed at a sufficient level, can sustain vitamin K-dependent carboxylation in the adult liver and prevent bleeding and lethality
additional information
-
transgenic overexpression of VKORC1L1, under the control of the human APOE promoter (APOE-Vkorc1l1) in the liver of Vkorc1-/- mice, is sufficient to restore gamma-carboxylation and normal coagulation. In fact, Vkorc1-/-; APOE-Vkorc1l1 mice survive into adulthood, are fertile and do not display any apparent phenotype. Hence, VKORC1L1, when expressed at a sufficient level, can sustain vitamin K-dependent carboxylation in the adult liver and prevent bleeding and lethality
-
additional information
-
gene vkor, cloned from Mycobacterium tuberculosis, it complements an Escherichia coli dsbB deletion strain, restoring the oxidation of Escherichia coli DsbA and disulfide bond formation. Reconstitution of the Mycobacterium tuberculosis disulfide bond formation pathway in Escherichia coli by the pair of recombinant His-tagged MtVKOR and FLAG-tagged Mycobacterium tuberculosis thioredoxin. Integration of myc-tagged Mycobacterium tuberculosis MtdsbA into a phage L5 attachment site on the chromosome (using the pJEB402 plasmid) of the Mycobacterium smegmatis DELTAvkor mutant strain, which expresses Mtvkor from the pTetG plasmid. The expression of MtVKOR is regulated by the Tet promoter and induced with anhydrotetracycline (ATc), while myc-tagged MtDsbA is under the control of a constitutive promoter. The Mycobacterium smegmatis strain with a deletion of vkor grows slowly in 7H9 medium with 1.6 mM cysteine (or oxidized cysteine). When this strain is complemented instead with the pTetG plasmid expressing MtVKOR, the strain grows similarly to the wild-type, even without the addition of ATc. Thus, the basal MtVKOR expression level from the pTetG plasmid is sufficient to support the growth of the DELTAvkor strain
additional information
-
integration of myc-tagged Mycobacterium tuberculosis MtdsbA into a phage L5 attachment site on the chromosome (using the pJEB402 plasmid) of the Mycobacterium smegmatis DELTAvkor mutant strain, which expresses Mtvkor from the pTetG plasmid. The expression of MtVKOR is regulated by the Tet promoter and induced with anhydrotetracycline (ATc), while myc-tagged MtDsbA is under the control of a constitutive promoter. The Mycobacterium smegmatis strain with a deletion of vkor grows slowly in 7H9 medium with 1.6 mM cysteine (or oxidized cysteine). When this strain is complemented instead with the pTetG plasmid expressing MtVKOR, the strain grows similarly to the wild-type, even without the addition of ATc. Thus, the basal MtVKOR expression level from the pTetG plasmid is sufficient to support the growth of the DELTAvkor strain
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 vkor, recombinant coexpression of c-myc-tagged enzyme VKORC1 with protein disulfide isomerase in HEK-293 cells
gene vkor, recombinant expression of C-terminally GFP-tagged enzyme in Pichia pastoris, the expression level of hVKORL is relatively low. When HEK-293 cells are incubated with warfarin, hVKOR is expressed in much larger amount and with a good FSEC profile
gene vkor, recombinant expression of C-terminally GFP-tagged enzyme in Pichia pastoris, the expression level of VKORL is relatively high
gene vkor, recombinant expression of His-tagged enzyme VKOR in Escherichia coli wild-type and DELTAdsbA mutant strains. The Mycobacterium tuberculosis genes dsbA and vkor form an operon
-
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
-
gene VKORC1L1, sequence compaprisons and phylogenetic analysis
genes VKOR-1 and VKORC1L1, DNA and amino acid sequence determination and analysis, sequence comparisons and phylogenetic analysis and tree, quantitative PCR expression analysis under different physiological conditions
genes VKOR-1, DNA and amino acid sequence determination and analysis, sequence comparisons and phylogenetic analysis and tree, quantitative PCR expression analysis under different physiological conditions
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
-
recombinant expression of FLAG-tagged wild-type and mutant enzymes in Spodoptera frugiperda SF21 cells via the baculovirus system
stable recombinant expression of C-terminally FLAG-tagged VKOR or its C43/51A mutant in HEK-293 cells, whose endogenous VKOR and VKOR-like enzyme (VKORC1L1) are knocked out by transcription activator-like effector nuclease-mediated genome editing
gene vkor, recombinant expression of C-terminally GFP-tagged enzyme in Pichia pastoris, the expression level of VKORL is relatively high
gene vkor, recombinant expression of C-terminally GFP-tagged enzyme in Pichia pastoris, the expression level of VKORL is relatively high
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
during larval development, expression of ssvkorc1 shows a slight increase during absence or low feed intake. Expression of ssvkorc1l1 continuously decreases until 24 h post-fertilization, and remains constant afterwards. Expression of ssvkorc1 and ssvkorc1l1 is differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency
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
drug development
VKORC1 is a therapeutic target for vitamin K antagonists (VKAs)
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
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
-
patient with warfarin resistance due to a T383G transition in exon 2 of the VKORC1 gene, patient is heterozygous for the mutation
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
-
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
-
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 haplotypes influence the performance characteristics of protein induced by vitamin K absence II for screening of hepatocellular carcinoma
medicine
-
VKORC1 genotype affects daily dose requirements and time to therapeutic international normalized ratio in Turkish patients receiving warfarin for anticoagulation
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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Release 2026.1 (March 2026)
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