Information on EC 1.17.4.5 - vitamin-K-epoxide reductase (warfarin-insensitive)

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
1.17.4.5
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RECOMMENDED NAME
GeneOntology No.
vitamin-K-epoxide reductase (warfarin-insensitive)
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
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
show the reaction diagram
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
oxidation
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redox reaction
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-
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reduction
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SYSTEMATIC NAME
IUBMB Comments
3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone:oxidized-dithiothreitol oxidoreductase
Vitamin K 2,3-epoxide is reduced to 3-hydroxy- (and 2-hydroxy-) vitamin K by 1,4-dithiothreitol, which is oxidized to a disulfide. Not inhibited by warfarin [cf. EC 1.17.4.4, vitamin-K-epoxide reductase (warfarin-sensitive)].
CAS REGISTRY NUMBER
COMMENTARY hide
97089-80-0
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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Manually annotated by BRENDA team
gene Vkorc1, VKORC1 mutant Y137F
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Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
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 42-60% identical
metabolism
vitamin K cycle, overview
physiological function
vitamin K dependent oxidative protection is independent of VKOR inhibition by warfarin and GGCX inhibition by 2-chloro-vitamin K1, which indicates that vitamin K plays potential physiological roles outside of the realm of carboxylation. The hVKORL1 turnover rate for vitamin K 2,3-epoxide reductase activity is significantly slower than for hVKOR, EC 1.1.4.1. the physiological role for VKORL1 reduction of vitamin K 2,3-epoxide is minimal
additional information
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conserved loop cysteines in VKOR are not required for active site regeneration after each cycle of oxidation. Missense mutations identified in the VKOR coding region, especially hotspot mutation at position 139, lead to a VKOR molecule more resistant to warfarin inhibition, thus requiring higher therapeutic warfarin doses
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
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-
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?
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
show the reaction diagram
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i.e. vitamin K 2,3-epoxide
i.e. 3-hydroxy-2,3-dihydro-vitamin K
?
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
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
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-
-
?
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
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
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2-mercaptoethanol, reduced GSH, 1,2-ethanediol, or reduced lipoic acid are ineffective as cofactors
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
brodifacoum
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bromadiolone
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chlorophacinone
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Difenacoum
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difethialone
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glycerol
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concentrations up to 30% v/v inhibit enzyme activity up to 88%
additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
3-[(3-cholamidopropyl)-dimethyl-ammonio]1-propane sulfonate
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CHAPS, activation
dithiothreitol
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non-physiological cofactor
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00007
brodifacoum
Rattus norvegicus
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mutant Y137F, pH 7.4, 37C
0.00061
bromadiolone
Rattus norvegicus
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mutant Y137F, pH 7.4, 37C
0.0016
chlorophacinone
Rattus norvegicus
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mutant Y137F, pH 7.4, 37C
0.0001
Difenacoum
Rattus norvegicus
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mutant Y137F, pH 7.4, 37C
0.00005
difethialone
Rattus norvegicus
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mutant Y137F, pH 7.4, 37C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.235
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
integral membrane protein
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
25000
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gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
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2 * 12400, SDS-PAGE
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
high ionic strength inactivates during purification
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-70C, microsomal preparation, stable for months
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression of thec-myc-tagged enzyme mutant Y137F in Pichia pastoris membranes
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the VKOR-like gene that encodes hVKORL1 that is found on chromosome 7, sequence comparisons
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
L128R
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the naturally occuring mutant shows significantly increased warfarin resistance, but its enzyme activity is 2fold higher compared to wild-type VKOR
W59L
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the naturally occuring mutant shows significantly increased warfarin resistance, but its enzyme activity is 2fold higher compared to wild-type VKOR
W59R
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the naturally occuring mutant shows significantly increased warfarin resistance, but its enzyme activity is similar to wild-type VKOR
additional information
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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; the W59R mutant has lower activity but higher warfarin resistance than the W59L mutant, warfarin resistance evaluation of the naturally occurring VKOR mutants, overview