Information on EC 1.1.4.2 - vitamin-K-epoxide reductase (warfarin-insensitive)

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The expected taxonomic range for this enzyme is: Eutheria

EC NUMBER
COMMENTARY
1.1.4.2
-
RECOMMENDED NAME
GeneOntology No.
vitamin-K-epoxide reductase (warfarin-insensitive)
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
3-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
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone:oxidized-dithiothreitol oxidoreductase
In the reverse reaction, 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 1.1.4.1 vitamin-K-epoxide reductase (warfarin-sensitive)].
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
non-VKOR
Q8N0U8
-
reductase, vitamin K epoxide (warfarin-insensitive)
-
-
-
-
vitamin K 2,3 epoxide reductase
-
-
-
-
vitamin K epoxide reductase
-
-
vitamin K epoxide reductase (warfarin-insensitive)
-
-
-
-
vitamin K epoxide reductase-like1
Q8N0U8
-
vitamin KO reductase
-
-
-
-
VKOR
-
-
VKOR-like1
Q8N0U8
-
VKORC1L1
-
-
VKORL1
Q8N0U8
-
CAS REGISTRY NUMBER
COMMENTARY
97089-80-0
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
gene Vkorc1, VKORC1 mutant Y137F
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
evolution
-, Q8N0U8
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
physiological function
-, Q8N0U8
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
metabolism
-, Q8N0U8
vitamin K cycle, overview
additional information
-
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 ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
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
3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone + oxidized dithiothreitol
show the reaction diagram
-
i.e. vitamin K 2,3-epoxide
i.e. 3-hydroxy-2,3-dihydro-vitamin K
?
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized 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
-
-
-
-
?
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
-
-
-
-
?
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
-, Q8N0U8
-
-
-
?
additional information
?
-
-, Q8N0U8
the enzyme, driven by the reducing agent DTT, reduces both vitamin K 2,3-epoxide and vitamin K to the activated hydroquinone form
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
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-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
-
-
-
-
?
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
-
-
-
-
?
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
-, Q8N0U8
-
-
-
?
additional information
?
-
-, Q8N0U8
the enzyme, driven by the reducing agent DTT, reduces both vitamin K 2,3-epoxide and vitamin K to the activated hydroquinone form
-
-
-
COFACTOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
additional information
-
2-mercaptoethanol, reduced GSH, 1,2-ethanediol, or reduced lipoic acid are ineffective as cofactors
-
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
bromadiolone
-
-
chlorophacinone
-
-
difethialone
-
-
glycerol
-
concentrations up to 30% v/v inhibit enzyme activity up to 88%
additional information
-
not inhibited by warfarin
-
additional information
-
VKORC1 mutant Y137F is resistant against inhibition by warfarin, but not against inhibition by other antocoagulants, overview
-
additional information
-, Q8N0U8
non-VKOR, warfarin-sensitive enzyme, while hVKORL is mainly insensitive to inhibition by warfarin, but about 30% of hVKORL1 is inhibited by 0.005 mM warfarin, VKORL1 is warfarin sensitive, but not affect warfarin dosage requirements
-
additional information
-
evaluation of warfarin resistance using TALENs-mediated vitamin K epoxide reductase knockout HEK293 cells, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
3-[(3-Cholamidopropyl)-dimethyl-ammonio]1-propane sulfonate
-
CHAPS, activation
dithiothreitol
-
non-physiological cofactor
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.00007
-
brodifacoum
-
mutant Y137F, pH 7.4, 37C
0.00061
-
bromadiolone
-
mutant Y137F, pH 7.4, 37C
0.0016
-
chlorophacinone
-
mutant Y137F, pH 7.4, 37C
0.0001
-
Difenacoum
-
mutant Y137F, pH 7.4, 37C
0.00005
-
difethialone
-
mutant Y137F, pH 7.4, 37C
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.235
-
-
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.4
-
-
assay at
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
25
-
-
-
37
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-, Q8N0U8
integral membrane protein
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
Synechococcus sp. (strain JA-2-3B'a(2-13))
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
25000
-
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
dimer
-
2 * 12400, SDS-PAGE
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
high ionic strength inactivates during purification
-
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
-70C, microsomal preparation, stable for months
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
the VKOR-like gene that encodes hVKORL1 that is found on chromosome 7, sequence comparisons
-, Q8N0U8
expression of thec-myc-tagged enzyme mutant Y137F in Pichia pastoris membranes
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
W59L
-
the naturally occuring mutant shows significantly increased warfarin resistance, but its enzyme activity is 2fold higher compared to wild-type VKOR
W59R
-
the naturally occuring mutant shows significantly increased warfarin resistance, but its enzyme activity is similar to wild-type VKOR
L128R
-
the naturally occuring mutant shows significantly increased warfarin resistance, but its enzyme activity is 2fold higher compared to wild-type VKOR
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; the W59R mutant has lower activity but higher warfarin resistance than the W59L mutant, warfarin resistance evaluation of the naturally occurring VKOR mutants, overview