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Literature summary extracted from
- Characterization of warfarin inhibition kinetics requires stabilization of intramembrane vitamin K epoxide reductases (2020), J. Mol. Biol., 432, 5197-5208.
Cloned(Commentary)
| EC Number | Cloned (Comment) | Organism |
|---|---|---|
| 1.17.4.4 | 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 |
| 1.17.4.4 | gene vkor, recombinant expression of C-terminally GFP-tagged enzyme in Pichia pastoris, the expression level of VKORL is relatively high | Takifugu rubripes |
| 1.17.4.4 | gene vkor, recombinant expression of C-terminally GFP-tagged enzyme in Pichia pastoris, the expression level of VKORL is relatively high | Xenopus tropicalis |
Inhibitors
| EC Number | Inhibitors | Comment | Organism | Structure |
|---|---|---|---|---|
| 1.17.4.4 | 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 |  |
| 1.17.4.4 | 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 | |
| 1.17.4.4 | warfarin | analysis of warfarin inhibition kinetics requires stabilization of intramembrane vitamin K epoxide reductases | Xenopus tropicalis | |
Localization
| EC Number | Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|---|
| 1.17.4.4 | endoplasmic reticulum membrane | - |
Homo sapiens | 5789 | - |
| 1.17.4.4 | membrane | intregral membrane enzyme | Xenopus tropicalis | 16020 | - |
| 1.17.4.4 | membrane | intregral membrane enzyme | Homo sapiens | 16020 | - |
| 1.17.4.4 | membrane | intregral membrane enzyme | Takifugu rubripes | 16020 | - |
| 1.17.4.4 | microsome | - |
Xenopus tropicalis | - |
- |
| 1.17.4.4 | microsome | - |
Homo sapiens | - |
- |
| 1.17.4.4 | microsome | - |
Takifugu rubripes | - |
- |
Natural Substrates/ Products (Substrates)
| EC Number | Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 1.17.4.4 | 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues | Xenopus tropicalis | - |
phylloquinone + a protein with a disulfide bond + H2O | - |
? | |
| 1.17.4.4 | 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues | Homo sapiens | - |
phylloquinone + a protein with a disulfide bond + H2O | - |
? | |
| 1.17.4.4 | 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues | Takifugu rubripes | - |
phylloquinone + a protein with a disulfide bond + H2O | - |
? | |
| 1.17.4.4 | phylloquinone + a protein with reduced L-cysteine residues | Xenopus tropicalis | - |
phylloquinol + a protein with a disulfide bond | - |
? | |
| 1.17.4.4 | phylloquinone + a protein with reduced L-cysteine residues | Homo sapiens | - |
phylloquinol + a protein with a disulfide bond | - |
? | |
| 1.17.4.4 | phylloquinone + a protein with reduced L-cysteine residues | Takifugu rubripes | - |
phylloquinol + a protein with a disulfide bond | - |
? | |
Organism
| EC Number | Organism | UniProt | Comment | Textmining |
|---|---|---|---|---|
| 1.17.4.4 | Homo sapiens | Q9BQB6 | - |
- |
| 1.17.4.4 | Takifugu rubripes | Q6TEK9 | - |
- |
| 1.17.4.4 | Xenopus tropicalis | B2GUS4 | - |
- |
Substrates and Products (Substrate)
| EC Number | Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|---|
| 1.17.4.4 | 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues | - |
Xenopus tropicalis | phylloquinone + a protein with a disulfide bond + H2O | - |
? | |
| 1.17.4.4 | 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues | - |
Homo sapiens | phylloquinone + a protein with a disulfide bond + H2O | - |
? | |
| 1.17.4.4 | 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues | - |
Takifugu rubripes | phylloquinone + a protein with a disulfide bond + H2O | - |
? | |
| 1.17.4.4 | 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues | substrate KO | Homo sapiens | phylloquinone + a protein with a disulfide bond + H2O | - |
? | |
| 1.17.4.4 | 2,3-epoxyphylloquinone + a protein with reduced L-cysteine residues | substrate KO | Takifugu rubripes | phylloquinone + a protein with a disulfide bond + H2O | - |
? | |
| 1.17.4.4 | phylloquinone + a protein with reduced L-cysteine residues | - |
Xenopus tropicalis | phylloquinol + a protein with a disulfide bond | - |
? | |
| 1.17.4.4 | phylloquinone + a protein with reduced L-cysteine residues | - |
Homo sapiens | phylloquinol + a protein with a disulfide bond | - |
? | |
| 1.17.4.4 | phylloquinone + a protein with reduced L-cysteine residues | - |
Takifugu rubripes | phylloquinol + a protein with a disulfide bond | - |
? | |
| 1.17.4.4 | phylloquinone + a protein with reduced L-cysteine residues | substrate K | Homo sapiens | phylloquinol + a protein with a disulfide bond | - |
? | |
| 1.17.4.4 | phylloquinone + a protein with reduced L-cysteine residues | substrate K | Takifugu rubripes | phylloquinol + a protein with a disulfide bond | - |
? | |
Synonyms
| EC Number | Synonyms | Comment | Organism |
|---|---|---|---|
| 1.17.4.4 | hVKORL | - |
Homo sapiens |
| 1.17.4.4 | TrVKORL | - |
Takifugu rubripes |
| 1.17.4.4 | vitamin K epoxide reductase | - |
Xenopus tropicalis |
| 1.17.4.4 | vitamin K epoxide reductase | - |
Homo sapiens |
| 1.17.4.4 | vitamin K epoxide reductase | - |
Takifugu rubripes |
| 1.17.4.4 | VKOR | - |
Xenopus tropicalis |
| 1.17.4.4 | VKOR | - |
Homo sapiens |
| 1.17.4.4 | VKOR-like | - |
Xenopus tropicalis |
| 1.17.4.4 | VKOR-like | - |
Homo sapiens |
| 1.17.4.4 | VKOR-like | - |
Takifugu rubripes |
| 1.17.4.4 | VKORC1 | - |
Xenopus tropicalis |
| 1.17.4.4 | VKORC1 | - |
Homo sapiens |
| 1.17.4.4 | VKORL | - |
Xenopus tropicalis |
| 1.17.4.4 | VKORL | - |
Takifugu rubripes |
Cofactor
| EC Number | Cofactor | Comment | Organism | Structure |
|---|---|---|---|---|
| 1.17.4.4 | additional information | the use of DTT can be problematic because it is an artificial reductant not found in cells | Xenopus tropicalis | |
| 1.17.4.4 | additional information | the use of DTT can be problematic because it is an artificial reductant not found in cells | Homo sapiens | |
| 1.17.4.4 | additional information | the use of DTT can be problematic because it is an artificial reductant not found in cells | Takifugu rubripes |
Ki Value [mM]
| EC Number | Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|---|
| 1.17.4.4 | 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 | |
| 1.17.4.4 | 0.000027 | - |
warfarin | enzyme TrVKORL, pH and temperature not specified in the publication | Takifugu rubripes | |
IC50 Value
| EC Number | IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|---|
| 1.17.4.4 | 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 | |
| 1.17.4.4 | 0.000097 | - |
enzyme TrVKORL, pH and temperature not specified in the publication | Takifugu rubripes | warfarin | |
| 1.17.4.4 | 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 | |
| 1.17.4.4 | 0.00012 | - |
enzyme hVKORL in presence of glutahione with substrate KO, pH and temperature not specified in the publication | Homo sapiens | warfarin | |
| 1.17.4.4 | 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 | |
| 1.17.4.4 | 0.000238 | - |
enzyme hVKORL, pH and temperature not specified in the publication | Homo sapiens | warfarin | |
| 1.17.4.4 | 0.00025 | - |
enzyme hVKORL in presence of glutahione with substrate K, pH and temperature not specified in the publication | Homo sapiens | warfarin | |
| 1.17.4.4 | 0.000255 | - |
enzyme TrVKORL in presence of glutathione, GSH, pH and temperature not specified in the publication | Takifugu rubripes | warfarin | |
General Information
| EC Number | General Information | Comment | Organism |
|---|---|---|---|
| 1.17.4.4 | 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 |
| 1.17.4.4 | 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 |
| 1.17.4.4 | 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 |
| 1.17.4.4 | 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 |
| 1.17.4.4 | 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 |
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