Information on EC 1.17.4.4 - vitamin-K-epoxide reductase (warfarin-sensitive)

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
1.17.4.4
-
RECOMMENDED NAME
GeneOntology No.
vitamin-K-epoxide reductase (warfarin-sensitive)
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
phylloquinone + oxidized dithiothreitol + H2O = 2,3-epoxy-2-methyl-3-phytyl-2,3-dihydro-1,4-naphthoquinone + 1,4-dithiothreitol
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
-
-
-
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redox reaction
-
-
-
-
reduction
-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Ubiquinone and other terpenoid-quinone biosynthesis
-
-
Biosynthesis of secondary metabolites
-
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SYSTEMATIC NAME
IUBMB Comments
phylloquinone:oxidized-dithiothreitol oxidoreductase
Vitamin K 2,3-epoxide is reduced to vitamin K and possibly to vitamin K hydroquinone by 1,4-dithiothreitol, which is oxidized to a disulfide; some other dithiols and 4-butanethiol can also act. Inhibited strongly by warfarin [cf. EC 1.17.4.5, vitamin-K-epoxide reductase (warfarin-insensitive)].
CAS REGISTRY NUMBER
COMMENTARY hide
55963-40-1
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
warfarin-resistant strain
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
Wistar strain
-
-
Manually annotated by BRENDA team
strain Y139F
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
show the reaction diagram
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
show the reaction diagram
2,3-epoxyphylloquinone + 1,4-dithiothreitol
phylloquinone + oxidized dithiothreitol
show the reaction diagram
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
show the reaction diagram
2,3-epoxyphylloquinone + reduced thioredoxin
phylloquinone + oxidized thioredoxin
show the reaction diagram
-
-
-
-
?
2-hydroxymethyl-vitamin K 2,3-epoxide + dithiothreitol
2-hydroxymethyl-vitamin K + oxidized dithiothreitol
show the reaction diagram
2-methyl-3-phytyl-1,4-naphthoquinone + dithiothreitol
vitamin K hydroquinone + oxidized dithiothreitol
show the reaction diagram
-
i.e. vitamin K
-
-
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
show the reaction diagram
-
-
-
-
?
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
show the reaction diagram
allylbenzene 2',3'-oxide + 1,4-dithiothreitol
allylbenzene + oxidized dithiothreitol
show the reaction diagram
-
-
-
?
styrene 1',2'-oxide + 1,4-dithiothreitol
styrene + oxidized dithiothreitol
show the reaction diagram
-
-
-
?
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
show the reaction diagram
vitamin K 2,3-epoxide + oxidized dithiothreitol
vitamin K + 1,4-dithiothreitol
show the reaction diagram
-
-
-
-
ir
vitamin K 2,3-epoxide analogs + dithiothreitol
?
show the reaction diagram
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
show the reaction diagram
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol
show the reaction diagram
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
show the reaction diagram
2,3-epoxyphylloquinone + AH2
phylloquinone + A + ?
show the reaction diagram
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
show the reaction diagram
-
-
-
-
?
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
show the reaction diagram
vitamin K 2,3-epoxide + dithiothreitol
vitamin K + oxidized dithiothreitol
show the reaction diagram
vitamin K1 2,3-epoxide + dithiothreitol
vitamin K1 + oxidized dithiothreitol
show the reaction diagram
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
dithiothreitol
reduced thioredoxin
thioredoxin
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
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
K2SO4
-
activation at high concentration
KCl
-
activation at high concentration
LiCl
-
activation at high concentration
NaCl
-
activation at high concentration
additional information
-
EGTA does not affect the DTT-driven enzyme activity; human VKOR enzymatic activity is not Ca2+-dependent, no effect by EGTA
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(R)-warfarin
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(S)-warfarin
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1-hydroxyimidazopyridine
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4.0 mM, 9% inhibition, warfarin-resistant rats
2,3,5,6-Tetrachloro-4-pyridinol
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; 2.0 mM, 45% inhibition, warfarin-resistant rats
2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone
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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
ATI-5900
brodifacoum
bromadiolone
calumenin
-
Chloromenaquinone-2
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-
chlorophacinone
cholate
-
high concentration
coumachlor
-
-
Coumarin anticoagulants
-
-
-
coumatetralyl
-
-
Deriphat 160
dicoumarol
-
-
dicumarol
-
-
Difenacoum
difethialone
diphacinone
-
-
dithiothreitol
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high concentration
Imidazopyridines
-
-
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
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N-ethylmaleimide
phenprocoumon
potassium cholate
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0.5% (w/v) potassium cholate releases nearly 60% of the VKOR activity originally present in intact microsomes
tecarfarin
Triton X-100
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VKOR activity is dramatically decreased in Triton X-100
Vitamin K 2,3-epoxide analogs
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hydroxymethyl-, chloromethyl-, fluoromethyl-, difluoromethyl-, formyl-analogs and analogs with modified phytyl chain, competitive inhibition
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warfarin
additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,2-Ethanedithiol
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activation
1,4-Butanedithiol
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activation
dithioerythritol
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equally effective as DTT
dithiothreitol
DTT
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activation in intact and Cys-mutated membranes
glycerol
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activation
lipoic acid
Phospholipids
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time-dependent inactivation of enzyme activity after phosphlipase A treatment
Protein disulfide isomerase
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activation, together with thioredoxin/thioredoxin reductase and reduced ribonuclease
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Protein factor
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activation, two different protein factors from rat liver cytosol
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Reduced ribonuclease
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activation, together with thio-redoxin/thioredoxin reductase, EC 1.6.4.5 plus protein-disulfide isomerase more potent than DTT
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thioredoxin
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activation only in intact membranes
warfarin
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dependent on
additional information
-
bacitracin inhibition of reduced RNase triggers VKOR activity, overview
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00425 - 0.1875
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
0.0178 - 0.0195
2,3-Epoxyphylloquinone
0.0072 - 0.0195
2-methyl-3-phytyl-1,4-naphthoquinone
0.805
allylbenzene 2',3'-oxide
-
-
0.00042 - 0.16
dithiothreitol
0.065
styrene 1',2'-oxide
-
-
0.0013 - 0.0016
vitamin K 2,3-epoxide
0.004 - 0.0052
vitamin K epoxide
0.00241 - 0.00646
vitamin K1 2,3-epoxide
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0072 - 0.06
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00004 - 0.00022
brodifacoum
0.00013 - 0.00091
bromadiolone
0.00008 - 0.0079
chlorophacinone
0.00012 - 0.0019
coumachlor
0.00013 - 0.0031
coumatetralyl
0.00003 - 0.00089
Difenacoum
0.00005 - 0.00016
difethialone
0.00007 - 0.005
diphacinone
0.00028 - 0.1
warfarin
additional information
additional information
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.27
ATI-5900
Homo sapiens
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in 250 mM potassium phosphate, 500 mM potassium chloride, 20% (v/v) glycerol and 0.75% (w/v) CHAPS at pH 7.85 and 25C
0.00007 - 0.00009
brodifacoum
0.00061 - 0.00091
bromadiolone
0.0016
chlorophacinone
Rattus norvegicus
Q6TEK4
wild-type enzyme and mutant Y137F, pH 7.4, 37C
0.0001 - 0.00026
Difenacoum
0.00005 - 0.00009
difethialone
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 25C
0.0000247 - 0.1
warfarin
additional information
additional information
Homo sapiens
Q9BQB6
IC50 values for warfarin determined by different assay methods, overview
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.000007
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substrate vitamin K 2,3-epoxide, in the presence of 0.0017 mM R,S-warfarin
0.000009
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thioredoxin of bovine thymus
0.0000097
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thioredoxin from bovine thymus as cofactor, enzyme activity in salt washed detergent-solubilized microsomes
0.0000136
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thioredoxin from Escherichia coli as cofactor, enzyme activity in salt washed detergent-solubilized microsomes
0.000017
-
substrate vitamin K 2,3-epoxide
0.0000256
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cofactor DTT, enzyme activity in salt washed detergent-solubilized microsomes
0.0000498
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thioredoxin and protein disulfide-isomerase from bovine thymus as cofactors, enzyme activity in salt washed detergent-solubilized microsomes
0.000057
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thioredoxin and protein disulfide-isomerase from Escherichia coli as cofactors, enzyme activity in salt washed detergent-solubilized microsomes
0.00008
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substrate dithiothreitol
0.000137
-
-
0.00061
-
normal and warfarin-resistant rats
0.00099
-
substrate dithiothreitol, in the presence of 0.0017 mM R,S-warfarin
0.108
-
substrate styrene 1',2'-oxide
0.718
-
substrate allylbenzene 2',3'-oxide
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 7
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-
7.6
-
assay at
8.6
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assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8.5 - 9.8
-
about half-maximal activity at pH 8.5 and 9.8
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
20
-
assay at
21
-
assay at
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 35
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about half-maximal activity at 7C and 35C
18 - 35
-
about 55% of maximal activity at 18C and 35C
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
10.7
-
sequence calculation
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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mainly in vascular endothelium
Manually annotated by BRENDA team
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dermal, low expression rate
Manually annotated by BRENDA team
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fetal
Manually annotated by BRENDA team
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B lymphocyte, measurement of allelic mRNA expression
Manually annotated by BRENDA team
-
adult
Manually annotated by BRENDA team
additional information
-
quantitative expression analysis, no enzyme expression in peripheral blood leukocytes, the enzyme is upregulated in tumour tissue, overview
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0
-
considerably more stable than at 22C; considerably stable
15
-
rapid inactivation
22
-
rapid inactivation
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
Deriphat 160, detergent, solubilizes and inactivates
-
high ionic strength inactivates during purification
-
KCl stabilizes
-
omission of salt improves storage stability
-
physiological salt concentration stimulates
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Seriphat 160 stabilizes during purification
-
sodium cholate, low-concentrated, stabilizes
-
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ethanol
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
oxidation of the active site thiols during KO reduction inactivates VKOR
-
701399
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4C, acetone powder, stable
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate, Sepharose 6B, hydroxylapatite, microsomal epoxide hydrolase copurifies with vitamin KO reductase
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DE52 cellulose column chromatography, Bio-Gel P-100 gel filtration, and agarose-glutathione column chromatography
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MonoS, hydroxyapatite, DEAE-Sepharose, Sephacryl S-200, partially purified enzyme
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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
partially, microsome preparation by ultracentrifugation
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recombinant enzyme from Sf9 insect cell microsomes by ultracentrifugation, followed by HPC4 affinity chromatography in presence of DHPC and reconstitution in mixed detergent micelles, method optimization
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
; gene VKORC1, located on chromosome 7, DNA and amino acid sequenc determination and analysis
-
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
expressed in Sf9 insect cells
-
expression in Pichia pastoris strain SMD 1168 Kex1-; recombinant enzyme expression in Pichia pastoris strain SMD 1168 Kex1- endoplasmic reticulum membranes from a vector encoding (in 5'- to 3'-order): N-terminal alpha-mating factor from Saccharomyces cerevisiae, flag-tag epitope, His10-tag, Tev protease cleavage site, multiple cloning site, C-terminal Tev cleavage site, EGFP, Strep-tag II. The human VKORC1 DNA sequence is inserted into the multiple cloning site
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expression in Sf9 cell
-
expression in Sf9 cells
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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
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expression of c-myc-tagged enzyme mutants in Pichia pastoris membranes; gene rVkorc1, expression of C-terminally c-myc-tagged wild-type and mutant enzymes in Pichia patoris strain SMD1168 as membrane-bound proteins
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
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expression of the human enzyme with the human herpesvirus 8 viral interleukin-6 in the yeast two-hybrid system using Saccharomyces cerevisiae strain AH109
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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
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gene rs9923231 or VKORC1, genotyping of rs9923231, quantitative RT-PCR expression analysis; gene rs9923231, quantitative reverse transcriptasePCR expression analysis
gene Vkor, sequence comparisons
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gene VKORC1, DNA and amino acid sequence determination, genotyping, semiquantitative expression analysis; gene VKORC1 Y139F, 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
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gene Vkorc1, expression of wild-type and mutant enzymes in Pichia pastoris as membrane bound protein
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gene VKORC1, genotyping
gene VKORC1, genotyping, phenotypes of enzyme single nucleotide polymorphisms naturally occuring in Caucasian population
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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
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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
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gene VKORC1, rapid genotyping for C1173T polymorphism, method evaluation
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gene VKORC1, stable overexpression in factor IX BHK cell microsomes increasing 2.2fold the extent of secreted factor IX in vivo carboxylation, overview
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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
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overexpression of VKOR in Spodoptera frugiperda Sf9 cells using the baculovirus transfection system
-
overexpression of wild-type and mutant enzymes in HEK293 cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
micro-RNA miR-133a interacts with the 3'-UTR of VKORC1. Transfection of miRNA precursors of miR-133a in HepG2 cells reduces VKORC1 mRNA expression. miR-133a levels correlate inversely with VKORC1 mRNA levels in 23 liver samples from healthy subjects; miR-133a miRNA targeting the enzyme in HepG2 cells reduces VKORC1 mRNA expression in a dose-dependent manner, quantitative reverse transcriptasepolymerase chain reaction expression analysis. miR-133a interacts with the 3'-UTR of VKORC1
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C1173T
C132A
-
no catalytic activity, part of CXXC motif
C135A
-
no catalytic activity, part of CXXC motif
C16A
-
40% of wild-type activity
C43A/C51A
C6009T
-
naturally occuring single nucleotide polymorphism
C6484T
-
naturally occuring single nucleotide polymorphism
C85A
-
100% of wild-type activity
C96A
-
45% of wild-type activity
D36V
-
naturally occuring mutation, warfarin resistant mutant
DELTAC43-C51
-
85% of wild-type activity
G2653C
-
naturally occuring single nucleotide polymorphism
G3673A
-
naturally occuring single nucleotide polymorphism
G6853C
-
naturally occuring single nucleotide polymorphism
G6R
-
site-directed mutagenesis, the mutant shows altered membrane topology compared to the wild-type enzyme
G9041A
-
naturally occuring single nucleotide polymorphism
G9R
-
site-directed mutagenesis, the mutant shows altered membrane topology compared to the wild-type enzyme
I123N
-
naturally occuring mutant
K30L
-
site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
L120Q
-
naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, no synthesis of no 2-OH-vitamin K1 or 3-OH-vitamin K1
L128Q
-
naturally occuring mutation, no synthesis of no 2-OH-vitamin K1 or 3-OH-vitamin K1
R33G
-
site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
R35G
-
site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
R37G
-
site-directed mutagenesis, the mutation close to the transmembrane domain 1 leads to altered membrane topology compared to the wild-type enzyme
R58G,
-
naturally occuring mutation, warfarin resistant mutant
S57A
-
the mutation eliminates VKOR activity
S7R
-
site-directed mutagenesis, the mutant shows altered membrane topology compared to the wild-type enzyme
T5808G
-
naturally occuring single nucleotide polymorphism
W57A
-
the mutation eliminates VKOR activity
W59R/W59C/W59L
-
naturally occuring mutant
Y139S
-
naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, additional synthesis of 3-hydroxyvitamin K1; site-directed mutagenesis, the mutation dramatically affects the vitamin K epoxide reductase activity, additional production of 3-hydroxyvitamin K1 in the mutant
A26S
-
mutant shows about 70% relative VKOR activity as compared to the wild type enzyme
A48T
-
mutant shows about 120% relative VKOR activity as compared to the wild type enzyme
E37G
-
mutant shows about 75% relative VKOR activity as compared to the wild type enzyme
L128S
-
mutant shows about 20% relative VKOR activity as compared to the wild type enzyme
R12W
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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
A143V
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mutant shows about 140% relative VKOR activity as compared to the wild type enzyme
A26T
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mutant shows about 60% relative VKOR activity as compared to the wild type enzyme; the mutation has only a moderate effect on VKOR activity with a reduction to approximately 56% of wild type activity
E67K
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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
F63C
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the mutation reduces the VKOR activity to about 30% of normal
I141V
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mutant shows about 45% relative VKOR activity as compared to the wild type enzyme
I90L
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mutant shows about 90% relative VKOR activity as compared to the wild type enzyme
L120Q
naturally occuring mutant, resitant to warfarin and other anticoagulants; naturally occuring mutant, the mutant rat is resistant to some anticoagulants
L120Q/L128Q/Y139C/Y139F/Y139S
site-directed mutagenesis
R33P
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VKOR activity of the Arg33Pro variant is reduced to 42% of wild type activity
W59R
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mutant shows 16% residual VKOR activity
Y39N
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mutant shows about 30% relative VKOR activity as compared to the wild type enzyme
Y139F
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the mutation mediates resistance towards chlorophacinone and bromadiolone
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additional information
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 hide
LITERATURE
medicine