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Literature summary for 1.17.4.4 extracted from

  • Wu, S.; Chen, X.; Jin, D.Y.; Stafford, D.W.; Pedersen, L.G.; Tie, J.K.
    Warfarin and vitamin K epoxide reductase a molecular accounting for observed inhibition (2018), Blood, 132, 647-657.
    View publication on PubMed
Search for more literature for 1.17.4.4

Cloned(Commentary)

Cloned (Comment) Organism
stable recombinant expression of C-terminally FLAG-tagged VKOR or its C43/51A mutant in HEK-293 cells, whose endogenous VKOR and VKOR-like enzyme (VKORC1L1) are knocked out by transcription activator-like effector nuclease-mediated genome editing Homo sapiens

Protein Variants

Protein Variants Comment Organism
C43A/C51A site-ddirected mutagenesis Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
warfarin warfarin reversibly inhibits VKOR by competing with vitamin K, inhibition mechanism, overview. Warfarin-resistant VKOR mutations identified in patients significantly decrease warfarin's binding affinity, but have only a minor effect on vitamin K binding. A T-shaped stacking interaction between warfarin and tyrosine residue 139, within the proposed TY139A warfarin-binding motif, is observed. Furthermore, a reversible dynamic warfarin-binding pocket opening and conformational changes are observed when warfarin binds to VKOR. Several residues (Y25, A26, and Y139) are found essential for warfarin binding to VKOR. Molecular dynamics simulations and in vivo assays. No direct interaction between warfarin and the experimentally supported TY139A warfarin-binding motif is observed. Dynamic nature of warfarin binding to the 3-TM human VKOR structure. Dynamic binding pocket opening when warfarin binds to VKOR. The phenyl ring of Y139 is essential for stabilizing warfarin binding, Y25 and A26 interact with Y139 to stabilize warfarin binding in VKOR Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
endoplasmic reticulum membrane VKOR is an integral endoplasmic reticulum membrane protein, transmembrane topology model analysis Homo sapiens 5789
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additional information immunofluorescence confocal imaging of VKOR in live mammalian cells and PEGylation of VKOR's endogenous cytoplasmic-accessible cysteines in intact microsomes are used to probe the membrane topology of human VKOR. A loop sequence between the first and second transmembrane (TM) domain of VKOR is located in the cytoplasm, supporting a 3-TM topological structure of human VKOR Homo sapiens
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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 Homo sapiens
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 phylloquinone + a protein with a disulfide bond + H2O
-
 ?
phylloquinone + a protein with reduced L-cysteine residues Homo sapiens
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 phylloquinol + a protein with a disulfide bond
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q9BQB6
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-

Source Tissue

Source Tissue Comment Organism Textmining
HEK-293 cell
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 Homo sapiens
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Substrates and Products (Substrate)

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

Synonyms

Synonyms Comment Organism
vitamin K epoxide reductase
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 Homo sapiens
VKOR
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 Homo sapiens

General Information

General Information Comment Organism
additional information cysteines 132 and 135 comprise a C132XXC135 active site redox center of VKOR, the C132XXC135 redox motif is VKOR's active site Homo sapiens
physiological function vitamin K epoxide reductase (VKOR), an endoplasmic reticulum membrane protein, is the key enzyme for vitamin K-dependent carboxylation, a posttranslational modification that is essential for the biological functions of coagulation factors. VKOR is the target of the most widely prescribed oral anticoagulant, warfarin Homo sapiens