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Literature summary for 1.17.4.4 extracted from

  • Matagrin, B.; Hodroge, A.; Montagut-Romans, A.; Andru, J.; Fourel, I.; Besse, S.; Benoit, E.; Lattard, V.
    New insights into the catalytic mechanism of vitamin K epoxide reductase (VKORC1) - The catalytic properties of the major mutations of rVKORC1 explain the biological cost associated to mutations (2013), FEBS Open Bio, 3, 144-150.
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

Cloned (Comment) Organism
gene Vkorc1, expression of wild-type and mutant enzymes in Pichia pastoris as membrane bound protein Homo sapiens

Protein Variants

Protein Variants Comment Organism
L120Q naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, no synthesis of no 2-OH-vitamin K1 or 3-OH-vitamin K1 Homo sapiens
L128Q naturally occuring mutation, no synthesis of no 2-OH-vitamin K1 or 3-OH-vitamin K1 Homo sapiens
Y139C naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, additional synthesis of 3-hydroxyvitamin K1 Homo sapiens
Y139C site-directed mutagenesis, the mutation dramatically affects the vitamin K epoxide reductase activity Homo sapiens
Y139F naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, additional synthesis of 3-hydroxyvitamin K1 Homo sapiens
Y139S naturally occuring mutation, the mutant is resistant to warfarin, but not to difenacoum, additional synthesis of 3-hydroxyvitamin K1 Homo sapiens
Y139S site-directed mutagenesis, the mutation dramatically affects the vitamin K epoxide reductase activity, additional production of 3-hydroxyvitamin K1 in the mutant Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
Difenacoum non-competitive inhibition Homo sapiens
warfarin
-
Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.0072
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, wild-type enzyme Homo sapiens
0.012
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant L128Q Homo sapiens
0.013
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant Y139S Homo sapiens
0.018
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant Y139F Homo sapiens
0.025
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant L120Q Homo sapiens
0.06
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant Y139C Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
microsome
-
Homo sapiens
-
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O Homo sapiens
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
r

Organism

Organism UniProt Comment Textmining
Homo sapiens
-
gene VKORC1
-

Source Tissue

Source Tissue Comment Organism Textmining
liver
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O
-
Homo sapiens 2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
r
2-methyl-3-phytyl-1,4-naphthoquinone + oxidized dithiothreitol + H2O crucial role of the Tyr-139 amino acid in this reaction mechanism, Tyr-139 residue appears to determine the second half-step of the catalytic mechanism Homo sapiens 2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone + 1,4-dithiothreitol
-
r
additional information no synthesis of 3-hydroxyvitamin K1 by the wild-type enzyme, but by mutants Y139C, Y139F, and Y139S Homo sapiens ?
-
?

Synonyms

Synonyms Comment Organism
vitamin K epoxide reductase
-
Homo sapiens
VKORC1
-
Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
assay at Homo sapiens

Turnover Number [1/s]

Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
0.0072
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, wild-type enzyme Homo sapiens
0.012
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant L128Q Homo sapiens
0.013
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant Y139S Homo sapiens
0.018
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant Y139F Homo sapiens
0.025
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant L120Q Homo sapiens
0.06
-
2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-1,4-naphthoquinone pH 7.4, 37°C, mutant Y139C Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.4
-
assay at Homo sapiens

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.00003
-
Difenacoum wild-typpe enzyme, pH 7.4, 37°C Homo sapiens
0.00007
-
Difenacoum mutant L128Q, pH 7.4, 37°C Homo sapiens
0.00009
-
Difenacoum mutant Y139S, pH 7.4, 37°C Homo sapiens
0.0001
-
Difenacoum mutant Y139F, pH 7.4, 37°C Homo sapiens
0.00016
-
Difenacoum mutant Y139C, pH 7.4, 37°C Homo sapiens
0.0005
-
warfarin wild-typpe enzyme, pH 7.4, 37°C Homo sapiens
0.00089
-
Difenacoum mutant L120Q, pH 7.4, 37°C Homo sapiens
0.004
-
warfarin mutant L128Q, pH 7.4, 37°C Homo sapiens