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Literature summary extracted from

  • Chen, X.; Liu, Y.; Furukawa, N.; Jin, D.Y.; Paul Savage, G.; Stafford, D.W.; Suhara, Y.; Williams, C.M.; Tie, J.K.
    A novel vitamin K derived anticoagulant tolerant to genetic variations of vitamin K epoxide reductase (2021), J. Thromb. Haemost., 19, 689-700.
    View publication on PubMed

Protein Variants

EC Number Protein Variants Comment Organism
1.17.4.4 A26P naturally occuring mutation, located within the first transmembrane domain (TMD1), the mutation causes a 60fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR Homo sapiens
1.17.4.4 F55A naturally occuring mutation, located in the loop region between TMD1 and TMD2, the mutation causes a 417fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR Homo sapiens
1.17.4.4 L128R naturally occuring mutation, located within the last TMD near VKOR's active site, the mutation causes a fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR Homo sapiens
1.17.4.4 W59R naturally occuring mutation, located in the loop region between TMD1 and TMD2, the mutation causes a fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR Homo sapiens
1.17.4.4 Y139F naturally occuring mutation, located within the last TMD near VKOR's active site, the mutation causes a fold increased IC50 value for warfarin inhibition, while the inhibition potency of inhibitor VK-M-COT to the warfarin-resistant VKOR mutation is similar to that of wild-type VKOR Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.17.4.4 2-benzyl-3-methylnaphthalene-1,4-dione
-
 Homo sapiens
1.17.4.4 2-[(4-fluorophenyl)methyl]-3-methylnaphthalene-1,4-dione
-
 Homo sapiens
1.17.4.4 2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione COT-vitamin K or VK-K-COT, replacing the phytyl side-chain with a methylene cyclooctatetraene (COT) moiety at the 3-position of vitamin K1 converts it from a substrate to an inhibitor for VKD carboxylation. This COT-vitamin K derivative displays a similar inhibition potency in warfarin-resistant VKOR mutations whose warfarin resistance varies over 400fold. The compound targets multiple enzymes in the vitamin K redox cycle. The anticoagulation effect of COT-vitamin K can be rescued with high doses of vitamin K. The inhibition potency of the COT-vitamin K derivative is tolerant to genetic variations of VKOR1 Homo sapiens
1.17.4.4 additional information synthesis of a series of vitamin K derivatives with benzyl and related side-chain substitutions at the 3-position of 1,4-naphthoquinone. The effect of vitamin K derivatives as inhibitors of vitamin K reductase or KO reductase activity is evaluated in FIXgla-PC/HEK293 reporter cells with either the endogenous VKOR/VKORL (DGKO) or GGCX knocked out. The anticoagulation effect of VK-M-COT and warfarin is reversible by vitamin K1 Homo sapiens
1.17.4.4 warfarin
-
 Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
1.17.4.4 membrane
-
 Homo sapiens 16020
-
1.17.4.4 microsome
-
 Homo sapiens
-
-

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 Homo sapiens
-
 phylloquinone + a protein with a disulfide bond + H2O
-
 ?
1.17.4.4 phylloquinone + a protein with reduced L-cysteine residues Homo sapiens
-
 phylloquinol + a protein with a disulfide bond
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.17.4.4 Homo sapiens Q9BQB6
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
1.17.4.4 HEK-293 cell
-
 Homo sapiens
-

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
-
 Homo sapiens phylloquinone + a protein with a disulfide bond + H2O
-
 ?
1.17.4.4 additional information replacing the phytyl side-chain with a methylene cyclooctatetraene (COT) moiety at the 3-position of vitamin K1 converts it from a substrate to an inhibitor for VKD carboxylation. ELISA-based vitamin K reductase activity is performed using DGKO reporter cells with vitamin K1 as the substrate. For the conventional HPLC-based KO reductase activity assay, GGCX-knockout FIXgla-PC/HEK-293 cells are cultured with a fixed concentration or with increasing concentrations of the vitamin K derivative in cell culture medium containing 0.005 mM KO. K vitamins are extracted from the cells and the conversion of KO to vitamin K1 was determined by reverse-phase HPLC. Vitamin K reductase activity is evaluated using DGKO reporter cells with vitamin K1 as the substrate. Since reduced vitamin K1 (KH2), an intermediate product in VKD carboxylation, is unstable and difficult to accurately quantify from cells directly, the vitamin K reduction and epoxidation reactions are coupled to quantitate the final stable product vitamin K epoxide (KO). Vitamin K-dependent (VKD) carboxylation in UBIAD1-knockout HEK-293 reporter cells using vitamin K1 (VK), MK-4, menadione, or VK-K-COT as the substrate Homo sapiens ?
-
 ?
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 vitamin K1 or 2-methyl-3-phytyl-1,4-naphthoquinone Homo sapiens phylloquinol + a protein with a disulfide bond
-
 ?

Synonyms

EC Number Synonyms Comment Organism
1.17.4.4 KO reductase
-
 Homo sapiens
1.17.4.4 vitamin K epoxide reductase
-
 Homo sapiens
1.17.4.4 Vitamin K reductase
-
 Homo sapiens
1.17.4.4 VKOR
-
 Homo sapiens

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
1.17.4.4 0.0000059
-
 with wild-type enzyme, pH and temperature not specified in the publication Homo sapiens warfarin
1.17.4.4 0.000249
-
 i.e. VK-K-COT, with F55A mutant enzyme, pH and temperature not specified in the publication Homo sapiens 2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
1.17.4.4 0.00036
-
 with A26P mutant enzyme, pH and temperature not specified in the publication Homo sapiens warfarin
1.17.4.4 0.000416
-
 with L128R mutant enzyme, pH and temperature not specified in the publication Homo sapiens warfarin
1.17.4.4 0.000487
-
 i.e. VK-K-COT, with A26P mutant enzyme, pH and temperature not specified in the publication Homo sapiens 2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
1.17.4.4 0.000498
-
 with W59R mutant enzyme, pH and temperature not specified in the publication Homo sapiens warfarin
1.17.4.4 0.000575
-
 i.e. VK-K-COT, with L128R mutant enzyme, pH and temperature not specified in the publication Homo sapiens 2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
1.17.4.4 0.000615
-
 i.e. VK-K-COT, with W59R mutant enzyme, pH and temperature not specified in the publication Homo sapiens 2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
1.17.4.4 0.000616
-
 i.e. VK-K-COT, with wild-type enzyme, pH and temperature not specified in the publication Homo sapiens 2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
1.17.4.4 0.000633
-
 with Y139F mutant enzyme, pH and temperature not specified in the publication Homo sapiens warfarin
1.17.4.4 0.000658
-
 i.e. VK-K-COT, with Y139F mutant enzyme, pH and temperature not specified in the publication Homo sapiens 2-[(cycloocta-1,3,5,7-tetraen-1-yl)methyl]-3-methylnaphthalene-1,4-dione
1.17.4.4 0.00246
-
 with F55A mutant enzyme, pH and temperature not specified in the publication Homo sapiens warfarin

General Information

EC Number General Information Comment Organism
1.17.4.4 malfunction vitamin K antagonists (VKAs), such as warfarin, function by impairing the biosynthesis of vitamin K-dependent (VKD) clotting factors through the inhibition of vitamin K epoxide reductase (VKOR). The challenge of VKAs therapy is their narrow therapeutic index and highly variable dosing requirements, which are partially due to the genetic variations of VKOR Homo sapiens
1.17.4.4 metabolism vitamin K is a family of 2-methyl-1,4-naphthoquinone derivatives, which include the naturally occurring phylloquinone (vitamin K1) and menaquinones (vitamin K2), and the synthetic menadione (vitamin K3). Menaquinones differ from phylloquinone in that the side chain at the 3-position comprises a number of repeating prenyl units rather than the semi-saturated phytyl chain Homo sapiens