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Structural Modeling Insights into Human VKORC1 Phenotypes

Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) catalyses the reduction of vitamin K and its 2,3-epoxide essential to sustain γ-carboxylation of vitamin K-dependent proteins. Two different phenotypes are associated with mutations in human VKORC1. The majority of mutations cause resistance...

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Autores principales: Czogalla, Katrin J., Watzka, Matthias, Oldenburg, Johannes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4555152/
https://www.ncbi.nlm.nih.gov/pubmed/26287237
http://dx.doi.org/10.3390/nu7085313
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author Czogalla, Katrin J.
Watzka, Matthias
Oldenburg, Johannes
author_facet Czogalla, Katrin J.
Watzka, Matthias
Oldenburg, Johannes
author_sort Czogalla, Katrin J.
collection PubMed
description Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) catalyses the reduction of vitamin K and its 2,3-epoxide essential to sustain γ-carboxylation of vitamin K-dependent proteins. Two different phenotypes are associated with mutations in human VKORC1. The majority of mutations cause resistance to 4-hydroxycoumarin- and indandione-based vitamin K antagonists (VKA) used in the prevention and therapy of thromboembolism. Patients with these mutations require greater doses of VKA for stable anticoagulation than patients without mutations. The second phenotype, a very rare autosomal-recessive bleeding disorder caused by combined deficiency of vitamin K dependent clotting factors type 2 (VKCFD2) arises from a homozygous Arg98Trp mutation. The bleeding phenotype can be corrected by vitamin K administration. Here, we summarize published experimental data and in silico modeling results in order to rationalize the mechanisms of VKA resistance and VKCFD2.
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spelling pubmed-45551522015-09-01 Structural Modeling Insights into Human VKORC1 Phenotypes Czogalla, Katrin J. Watzka, Matthias Oldenburg, Johannes Nutrients Review Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) catalyses the reduction of vitamin K and its 2,3-epoxide essential to sustain γ-carboxylation of vitamin K-dependent proteins. Two different phenotypes are associated with mutations in human VKORC1. The majority of mutations cause resistance to 4-hydroxycoumarin- and indandione-based vitamin K antagonists (VKA) used in the prevention and therapy of thromboembolism. Patients with these mutations require greater doses of VKA for stable anticoagulation than patients without mutations. The second phenotype, a very rare autosomal-recessive bleeding disorder caused by combined deficiency of vitamin K dependent clotting factors type 2 (VKCFD2) arises from a homozygous Arg98Trp mutation. The bleeding phenotype can be corrected by vitamin K administration. Here, we summarize published experimental data and in silico modeling results in order to rationalize the mechanisms of VKA resistance and VKCFD2. MDPI 2015-08-14 /pmc/articles/PMC4555152/ /pubmed/26287237 http://dx.doi.org/10.3390/nu7085313 Text en © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Czogalla, Katrin J.
Watzka, Matthias
Oldenburg, Johannes
Structural Modeling Insights into Human VKORC1 Phenotypes
title Structural Modeling Insights into Human VKORC1 Phenotypes
title_full Structural Modeling Insights into Human VKORC1 Phenotypes
title_fullStr Structural Modeling Insights into Human VKORC1 Phenotypes
title_full_unstemmed Structural Modeling Insights into Human VKORC1 Phenotypes
title_short Structural Modeling Insights into Human VKORC1 Phenotypes
title_sort structural modeling insights into human vkorc1 phenotypes
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4555152/
https://www.ncbi.nlm.nih.gov/pubmed/26287237
http://dx.doi.org/10.3390/nu7085313
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