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Information on EC 1.17.4.5 - vitamin-K-epoxide reductase (warfarin-insensitive)
for references in articles please use BRENDA:EC1.17.4.5
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EC Tree 1 Oxidoreductases
1.17 Acting on CH or CH2 groups
1.17.4 With a disulfide as acceptor
1.17.4.5 vitamin-K-epoxide reductase (warfarin-insensitive)
IUBMB Comments
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)].
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
- 1.17.4.5
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anticoagulant
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coagulation
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k-dependent
- carboxylase
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non-hepatic
- 4-hydroxycoumarins
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dosing
-
warfarin-resistant
- vkorc1
- 2,3-epoxide
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clotting
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s-warfarin
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pharmacogenetic
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dithiothreitol-dependent
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scottish
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rodenticide
Reaction Schemes
showSynonyms
vkorl1, vitamin ko reductase, vitamin k 2,3 epoxide reductase, non-vkor, vkor-like1, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
EC 1.1.4.2
-
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formerly
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reductase, vitamin K epoxide (warfarin-insensitive)
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-
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vitamin K 2,3 epoxide reductase
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-
-
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vitamin K epoxide reductase
vitamin K epoxide reductase (warfarin-insensitive)
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vitamin KO reductase
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VKOR
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REACTION
REACTION DIAGRAM
COMMENTARY
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
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
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redox reaction
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-
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reduction
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-
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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)].
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CAS REGISTRY NUMBER
COMMENTARY
97089-80-0
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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
-
Substrates: -
Products: -
Products: -
?
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
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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-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
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: -
?
additional information
?
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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: 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: -
?
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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
-
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
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: -
?
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: 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: -
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
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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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
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
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additional information
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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
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additional information
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evaluation of warfarin resistance using TALENs-mediated vitamin K epoxide reductase knockout HEK293 cells, overview
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additional information
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VKORC1 mutant Y137F is resistant against inhibition by warfarin, but not against inhibition by other antocoagulants, overview
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additional information
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
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Neoplasms
Structural and functional insights into human vitamin K epoxide reductase and vitamin K epoxide reductase-like1.
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
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
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
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
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
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). VKOR_SYNJB
Synechococcus sp. (strain JA-2-3B'a(2-13))
283
0
30593
Swiss-Prot
-
VKORL_HUMAN
176
2
19836
Swiss-Prot
other Location (Reliability: 1)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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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
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
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
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
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
additional information
-
the W59R mutant has lower activity but higher warfarin resistance than the W59L mutant, warfarin resistance evaluation of the naturally occurring VKOR mutants, overview
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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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
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Mukharji, I.; Silverman, R.B.
Purification of a vitamin K epoxide reductase that catalyzes conversion of vitamin K 2,3-epoxide to 3-hydroxy-2-methyl-3-phytyl-2,3-dihydronaphthoquinone
Proc. Natl. Acad. Sci. USA
82
2713-2717
1985
Bos taurus
brenda
Hodroge, A.; Longin-Sauvageon, C.; Fourel, I.; Benoit, E.; Lattard, V.
Biochemical characterization of spontaneous mutants of rat VKORC1 involved in the resistance to antivitamin K anticoagulants
Arch. Biochem. Biophys.
515
14-20
2011
Rattus norvegicus
brenda
Van Horn, W.D.
Structural and functional insights into human vitamin K epoxide reductase and vitamin K epoxide reductase-like1
Crit. Rev. Biochem. Mol. Biol.
48
357-372
2013
Homo sapiens (Q8N0U8), Homo sapiens
brenda
Tie, J.K.; Jin, D.Y.; Tie, K.; Stafford, D.W.
Evaluation of warfarin resistance using TALENs-mediated vitamin K epoxide reductase knockout HEK293 cells
J. Thromb. Haemost.
11
1556-1564
2013
Homo sapiens
brenda
Shen, G.; Li, C.; Cao, Q.; Megta, A.; Li, S.; Gao, M.; Liu, H.; Shen, Y.; Chen, Y.; Yu, H.; Li, S.; Li, W.
Structural features determining the vitamin K epoxide reduction activity in the VKOR family of membrane oxidoreductases
FEBS J.
289
4564-4579
2022
Synechococcus sp. (Q2JJF6)
brenda
EXTERNAL LINKS (specific for EC-Number 1.17.4.5)
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