Vitamin K metabolism and activation of dependent proteins (Homo sapiens)
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Description
Vitamin K is recycled in the liver in order to maintain sufficient levels for activating vitamin K-dependent proteins (VKDP), including certain coagulation factors. In this process, vitamin K1 (taken up from the diet) is converted to vitamin K hydroquinone (KH2), either by the dithiol-dependent vitamin K-epoxide reductase (VKOR) or by NAD(P)H dehydrogenase quinone 1. KH2 is in turn oxidized to vitamin K epoxide (KO) by the enzyme gamma-glutamyl carboxylase (GGCX). During this conversion, GGCX activates the VKDPs by converting glutamate (Glu) to gamma-carboxyglutamate (Gla). Lastly, KO is converted back into vitamin K quinone by VKOR.
Warfarin, a drug commonly used as a anticoagulant, inhibits VKOR, thus reducing the levels of VKH2 in the bloodstream. A too high dosage of warfarin can lead to heavy bleeding, a life-threatening condition. Threatment of this condition is a high dosis of Vitamine K, which is reduced to VHK2 by FSP1, a warfarin resistant reductase. The influence of FSP1 on this process, as well as its potential to eliminate lipid perozyl radicals, has been recently described in Nature(2022) by Mishima et al.: A non-canonical vitamin K cycle is a potent ferroptosis suppressor.
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Ontology Terms
Bibliography
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- Dmitry A Ravcheev, Ines Thiele; ''Genomic Analysis of the Human Gut Microbiome Suggests Novel Enzymes Involved in Quinone Biosynthesis''; Front Microbiol., 2016 PubMed Europe PMC Scholia
- Villa JKD, Diaz MAN, Pizziolo VR, Martino HSD; ''Effect of vitamin K in bone metabolism and vascular calcification: A review of mechanisms of action and evidences.''; Crit Rev Food Sci Nutr, 2017 PubMed Europe PMC Scholia
- Eikan Mishima, Junya Ito, Zijun Wu, Toshitaka Nakamura, Adam Wahida, Sebastian Doll, Wulf Tonnus, Palina Nepachalovich, Elke Eggenhofer, Maceler Aldrovandi, Bernhard Henkelmann, Ken-Ichi Yamada, Jonas Wanninger, Omkar Zilka, Emiko Sato, Regina Feederle, Daniela Hass, Adriano Maida, André Santos Dias Mourão, Andreas Linkermann, Edward K Geissler, Kiyotaka Nakagawa, Takaaki Abe, Maria Fedorova, Bettina Proneth, Derek A Pratt, Marcus Conrad; ''A non-canonical vitamin K cycle is a potent ferroptosis suppressor''; Nature, 2022 PubMed Europe PMC Scholia
- Han Yan, Yi Chen, Hong Zhu, Wei-Hua Huang, Xin-He Cai, Dan Li, Ya-Juan Lv, Si-Zhao, Hong-Hao Zhou, Fan-Yan Luo, Wei Zhang, Xi Li; ''The Relationship Among Intestinal Bacteria, Vitamin K and Response of Vitamin K Antagonist: A Review of Evidence and Potential Mechanism''; Front Med (Lausanne), 2022 PubMed Europe PMC Scholia
- Gallieni M, Fusaro M; ''Vitamin K and cardiovascular calcification in CKD: is patient supplementation on the horizon?''; Kidney Int, 2014 PubMed Europe PMC Scholia
- Nathan P Ward, Gina M DeNicola; ''Long-sought mediator of vitamin K recycling discovered''; Nature, 2022 PubMed Europe PMC Scholia
History
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External references
DataNodes
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Name | Type | Database reference | Comment |
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Coagulation factor IX | Protein | P00740 (Uniprot-TrEMBL) ![]() | |
Coagulation factor VII | Protein | P08709 (Uniprot-TrEMBL) ![]() | |
Coagulation factor X | Protein | P00742 (Uniprot-TrEMBL) ![]() | |
Dietary Vitamin K1 | Metabolite | chebi:18067 (ChEBI) ![]() | |
FSP1 | Protein | Q9BRQ8 (Uniprot-TrEMBL) ![]() | |
Ferroptosis | Pathway | WP4313 (WikiPathways) ![]() | |
GGCX | Protein | P38435 (Uniprot-TrEMBL) ![]() | AKA γ-glutamyl carboxylase |
LOOH | Metabolite | Q76617139 (Wikidata) ![]() | lipid hydroperoxides (LOOH) |
LOO• | Metabolite | lipid peroxyl radicals (LOO•) | |
Men | Pathway | 2-demethylmenaquinone serves as a precursor for menaquinone synthesis, involving nine types of enzymes (MenA-MenI). 24 genomes of Firmicutes and Proteobacteria have a complete Men pathway [PMID:26904004]. | |
Menadiol | Metabolite | chebi:6746 (ChEBI) ![]() | |
Mqn | Pathway | Completed through futalosine, involving five types of enzymes (MenA-MenE). 10 genomes of Firmicutes, Proteobacteria, and Bacteroidetes have a complete Men pathway [PMID:26904004]. | |
NADP+ | Metabolite | CHEBI:18009 (ChEBI) ![]() | |
NADPH | Metabolite | HMDB00221 (HMDB) ![]() | |
NQO1 | Protein | P15559 (Uniprot-TrEMBL) ![]() | AKA NAD(P)H dehydrogenase [quinone] 1 |
Prothrombin | Protein | P00734 (Uniprot-TrEMBL) ![]() | |
Thrombin | Protein | ENSG00000180210 (Ensembl) ![]() | |
UBIAD1 | GeneProduct | 29914 (Entrez Gene) ![]() | |
VKOR | Protein | 1.17.4.4 (Enzyme Nomenclature) ![]() | Vitamin-K-epoxide reductase |
VKORC1L1 | Protein | Q8N0U8 (Uniprot-TrEMBL) ![]() | "Can reduce inactive vitamin K 2,3-epoxide to active vitamin K (in vitro)" Source: https://www.uniprot.org/uniprotkb/Q8N0U8/entry |
VKORC1 | Protein | Q9BQB6 (Uniprot-TrEMBL) ![]() | "Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K" Source: https://www.uniprot.org/uniprotkb/Q9BQB6/entry |
Vitamin K (VK) | Metabolite | CHEBI:28384 (ChEBI) ![]() | Group of metabolites known as Vitamin K, which are structurally similar and found in food. |
Vitamin K epoxide (VKO) | Metabolite | CHEBI:15759 (ChEBI) ![]() | AKA Vitamin K1 oxide, VKO |
Vitamin K hydroquinone (VKH2) | Metabolite | CHEBI:28433 (ChEBI) ![]() |
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Vitamin K-dependent protein C | Protein | P04070 (Uniprot-TrEMBL) ![]() | |
Vitamin K-dependent protein S | Protein | P07225 (Uniprot-TrEMBL) ![]() | |
Vitamin K-dependent protein Z | Protein | P22891 (Uniprot-TrEMBL) ![]() | |
Vitamin K1 | Metabolite | CHEBI:18067 (ChEBI) ![]() |
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Vitamin K3 | Metabolite | CHEBI:28869 (ChEBI) ![]() |
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Vitamin K | Metabolite | CHEBI:28384 (ChEBI) ![]() |
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Warfarin | Metabolite | HMDB0001935 (HMDB) ![]() | |
disulfides | Metabolite | CHEBI:48343 (ChEBI) ![]() | |
dithiols | Metabolite | CHEBI:23853 (ChEBI) ![]() | |
gamma-carboxyglutamate | Metabolite | CHEBI:61938 (ChEBI) ![]() | |
geranylgeranyl diphosphate | Metabolite | chebi:58756 (ChEBI) ![]() | |
glutamate | Metabolite | CHEBI:14321 (ChEBI) ![]() | |
vitamin K2 (MK4) | Metabolite | CHEBI:78277 (ChEBI) ![]() | AKA menaquinone-4 |
vitamin K2 (MK7) | Metabolite | CHEBI:44245 (ChEBI) ![]() | AKA menaquinone-7 |
vitamin K2 | Metabolite | CHEBI:16374 (ChEBI) ![]() |
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Annotated Interactions
Source | Target | Type | Database reference | Comment |
---|---|---|---|---|
Vitamin K hydroquinone (VKH2) | Vitamin K epoxide (VKO) | mim-conversion | 45142 (Rhea) ![]() | |
Vitamin K | Vitamin K hydroquinone (VKH2) | mim-conversion | 57746 (Rhea) ![]() | |
mim-conversion | 45142 (Rhea) ![]() |