ArticleFEBS open bio2013
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.
Article in FEBS open bio, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- Structural disruption of VKORC1 by resistance mutations reveals a conserved hydrophobic pattern essential for warfarin binding: insights from molecular dynamics analyses.Molecular diversity · 2026Article
- Effect of Warfarin on Lifespan and Oxidative Stress Tolerance ofInternational journal of molecular sciences · 2025Article
- Warfarin analogs target disulfide bond-forming enzymes and suggest a residue important for quinone and coumarin binding.The Journal of biological chemistry · 2024Article
- Distinct enzymatic strategies forCritical reviews in biochemistry and molecular biology · 2023Article
- Vitamin K-Dependent Protein Activation: Normal Gamma-Glutamyl Carboxylation and Disruption in Disease.International journal of molecular sciences · 2022Review
- Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation.Science (New York, N.Y.) · 2021Article
- Characterization of Warfarin Inhibition Kinetics Requires Stabilization of Intramembrane Vitamin K Epoxide Reductases.Journal of molecular biology · 2020Article
- Competitive tight-binding inhibition of VKORC1 underlies warfarin dosage variation and antidotal efficacy.Blood advances · 2020Article
- Establishment of the Variation of Vitamin K Status According toNutrients · 2019Article
- Evaluation of oral anticoagulants with vitamin K epoxide reductase in its native milieu.Blood · 2018Article
- Missense mutation of VKORC1 leads to medial arterial calcification in rats.Scientific reports · 2018Article
- Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition.Blood · 2018Article
- Warfarin and vitamin K compete for binding to Phe55 in human VKOR.Nature structural & molecular biology · 2017Article
- Structural and functional insights into enzymes of the vitamin K cycle.Journal of thrombosis and haemostasis : JTH · 2016Review
- Effects of VKORC1 Genetic Polymorphisms on Warfarin Maintenance Dose Requirement in a Chinese Han Population.Medical science monitor : international medical journal of experimental and clinical research · 2015Article
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8 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The systematic use of antivitamin K anticoagulants (AVK) as rodenticides caused the selection of rats resistant to AVKs. The resistance is mainly associated to genetic polymorphisms in the Vkorc1 gene encoding the VKORC1 enzyme responsible for the reduction of vitamin K 2,3-epoxide to vitamin K. Five major mutations, which are responsible for AVK resistance, have been described. Possible explanations for the biological cost of these mutations have been suggested. This biological cost might be linked to an increase in the vitamin K requirements. To analyze the possible involvement of VKORC1 in this biological cost, rVKORC1 and its major mutants were expressed in Pichia pastoris as membrane-bound proteins and their catalytic properties were determined for vitamin K and 3-OH-vitamin K production. In this report, we showed that mutations at Leu-120 and Tyr-139 dramatically affect the vitamin K epoxide reductase activity. Moreover, this study allowed the detection of an additional production of 3-hydroxyvitamin K for all the mutants in position 139. This result suggests the involvement of Tyr-139 residue in the second half-step of the catalytic mechanism corresponding to the dehydration of vitamin K epoxide. As a consequence, the biological cost observed in Y139C and Y139S resistant rat strains is at least partially explained by the catalytic properties of the mutated VKORC1 involving a loss of vitamin K from the vitamin K cycle through the formation of 3-hydroxyvitamin K and a very low catalytic efficiency of the VKOR activity.
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