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Literature summary for 1.17.4.4 extracted from

  • Li, S.; Liu, S.; Yang, Y.; Li, W.
    Characterization of warfarin inhibition kinetics requires stabilization of intramembrane vitamin K epoxide reductases (2020), J. Mol. Biol., 432, 5197-5208.
    View publication on PubMed
Search for more literature for 1.17.4.4

Cloned(Commentary)

Cloned (Comment) Organism
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 Homo sapiens
gene vkor, recombinant expression of C-terminally GFP-tagged enzyme in Pichia pastoris, the expression level of VKORL is relatively high Takifugu rubripes
gene vkor, recombinant expression of C-terminally GFP-tagged enzyme in Pichia pastoris, the expression level of VKORL is relatively high Xenopus tropicalis

Inhibitors

Inhibitors Comment Organism Structure
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 Homo sapiens
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 Takifugu rubripes
warfarin analysis of warfarin inhibition kinetics requires stabilization of intramembrane vitamin K epoxide reductases Xenopus tropicalis

Localization

Localization Comment Organism GeneOntology No. Textmining
endoplasmic reticulum membrane
-
 Homo sapiens 5789
-
membrane intregral membrane enzyme Xenopus tropicalis 16020
-
membrane intregral membrane enzyme Homo sapiens 16020
-
membrane intregral membrane enzyme Takifugu rubripes 16020
-
microsome
-
 Xenopus tropicalis
-
-
microsome
-
 Homo sapiens
-
-
microsome
-
 Takifugu rubripes
-
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues Xenopus tropicalis
-
 phylloquinone + a protein with a disulfide bond + H2O
-
 ?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues Homo sapiens
-
 phylloquinone + a protein with a disulfide bond + H2O
-
 ?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues Takifugu rubripes
-
 phylloquinone + a protein with a disulfide bond + H2O
-
 ?
phylloquinone + a protein with reduced L-cysteine residues Xenopus tropicalis
-
 phylloquinol + a protein with a disulfide bond
-
 ?
phylloquinone + a protein with reduced L-cysteine residues Homo sapiens
-
 phylloquinol + a protein with a disulfide bond
-
 ?
phylloquinone + a protein with reduced L-cysteine residues Takifugu rubripes
-
 phylloquinol + a protein with a disulfide bond
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q9BQB6
-
-
Takifugu rubripes Q6TEK9
-
-
Xenopus tropicalis B2GUS4
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
-
 Xenopus tropicalis phylloquinone + a protein with a disulfide bond + H2O
-
 ?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
-
 Homo sapiens phylloquinone + a protein with a disulfide bond + H2O
-
 ?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues
-
 Takifugu rubripes phylloquinone + a protein with a disulfide bond + H2O
-
 ?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues substrate KO Homo sapiens phylloquinone + a protein with a disulfide bond + H2O
-
 ?
2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues substrate KO Takifugu rubripes phylloquinone + a protein with a disulfide bond + H2O
-
 ?
phylloquinone + a protein with reduced L-cysteine residues
-
 Xenopus tropicalis phylloquinol + a protein with a disulfide bond
-
 ?
phylloquinone + a protein with reduced L-cysteine residues
-
 Homo sapiens phylloquinol + a protein with a disulfide bond
-
 ?
phylloquinone + a protein with reduced L-cysteine residues
-
 Takifugu rubripes phylloquinol + a protein with a disulfide bond
-
 ?
phylloquinone + a protein with reduced L-cysteine residues substrate K Homo sapiens phylloquinol + a protein with a disulfide bond
-
 ?
phylloquinone + a protein with reduced L-cysteine residues substrate K Takifugu rubripes phylloquinol + a protein with a disulfide bond
-
 ?

Synonyms

Synonyms Comment Organism
hVKORL
-
 Homo sapiens
TrVKORL
-
 Takifugu rubripes
vitamin K epoxide reductase
-
 Xenopus tropicalis
vitamin K epoxide reductase
-
 Homo sapiens
vitamin K epoxide reductase
-
 Takifugu rubripes
VKOR
-
 Xenopus tropicalis
VKOR
-
 Homo sapiens
VKOR-like
-
 Xenopus tropicalis
VKOR-like
-
 Homo sapiens
VKOR-like
-
 Takifugu rubripes
VKORC1
-
 Xenopus tropicalis
VKORC1
-
 Homo sapiens
VKORL
-
 Xenopus tropicalis
VKORL
-
 Takifugu rubripes

Cofactor

Cofactor Comment Organism Structure
additional information the use of DTT can be problematic because it is an artificial reductant not found in cells Xenopus tropicalis
additional information the use of DTT can be problematic because it is an artificial reductant not found in cells Homo sapiens
additional information the use of DTT can be problematic because it is an artificial reductant not found in cells Takifugu rubripes

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
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 Homo sapiens
0.000027
-
 warfarin enzyme TrVKORL, pH and temperature not specified in the publication Takifugu rubripes

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.00004
-
 enzyme hVKORL in LMNG medium in presence of glutahione with substrate K, pH and temperature not specified in the publication Homo sapiens warfarin
0.000097
-
 enzyme TrVKORL, pH and temperature not specified in the publication Takifugu rubripes warfarin
0.0001
-
 enzyme hVKORL in LMNG medium in presence of glutahione with substrate KO, pH and temperature not specified in the publication Homo sapiens warfarin
0.00012
-
 enzyme hVKORL in presence of glutahione with substrate KO, pH and temperature not specified in the publication Homo sapiens warfarin
0.00013
-
 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 Homo sapiens warfarin
0.000238
-
 enzyme hVKORL, pH and temperature not specified in the publication Homo sapiens warfarin
0.00025
-
 enzyme hVKORL in presence of glutahione with substrate K, pH and temperature not specified in the publication Homo sapiens warfarin
0.000255
-
 enzyme TrVKORL in presence of glutathione, GSH, pH and temperature not specified in the publication Takifugu rubripes warfarin

General Information

General Information Comment Organism
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 Xenopus tropicalis
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 Homo sapiens
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 Takifugu rubripes
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 Homo sapiens
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 Homo sapiens