Vitamin K metabolism and activation of dependent proteins (WP5186)

Homo sapiens

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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 [https://doi.org/10.1038/s41586-022-05022-3 Nature(2022)] by Mishima et al.: A non-canonical vitamin K cycle is a potent ferroptosis suppressor.

Authors

Anna Van Wersch , Andra Waagmeester , Denise Slenter , Eric Weitz , Egon Willighagen , and Kristina Hanspers

Activity

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Organisms

Homo sapiens

Communities

Annotations

Disease Ontology

vitamin K deficiency bleeding

Pathway Ontology

vitamin K antagonist drug pathway vitamin and vitamin metabolites signaling pathway vitamin K metabolic pathway ferroptosis pathway hemostasis pathway classic metabolic pathway vitamin K cycle pathway lipid metabolic pathway

Cell Type Ontology

hepatocyte

Participants
Query Drugst.One

Label Type Compact URI Comment
vitamin K2 Metabolite chebi:16374 AKA menaquinone, VK2
Natural vitamer
Different lengths of C-side chains in the isoprenoid group are known: MK5 ~ MK15 (produces by bacteria) [PMID:35510250]
geranylgeranyldiphosphate Metabolite chebi:58756
Vitamin K3 Metabolite chebi:28869 menadione, synthetic form of vitamin K; interferes with glutathione function.
'NQO1 competes with enzymes that redox cycle vitamin K and catalyzes two-electron reduction of vitamin K3 to hydroquinone. This skips formation of semiquinone and ROS. Therefore, NQO1 metabolically detoxifies vitamin K3 and protects cells against oxidative stress and other adverse effects.' [PMID:18374191]
This reaction has been described in more detail in a mouse study [PMID:24015818]
Vitamin K1 Metabolite chebi:18067 AKA phylloquinone, VK
Natural vitamer
Made in plants (with high concentrations in green leafy vegetables).
Converted by bacteria in gut microbiome to MK-4.
disulfides Metabolite chebi:48343
Vitamin K epoxide(VKO) Metabolite chebi:15759 AKA Vitamin K1 oxide, VKO
NADPH Metabolite hmdb:HMDB00221
gamma-carboxyglutamate Metabolite chebi:61938
dithiols Metabolite chebi:23853
Warfarin Metabolite hmdb:HMDB0001935
NADP+ Metabolite chebi:18009
Vitamin K(VK) Metabolite chebi:28384 Group of metabolites known as Vitamin K, which are structurally similar and found in food.
glutamate Metabolite chebi:14321
Menadiol Metabolite chebi:6746
Vitamin K hydroquinone(VKH2) Metabolite chebi:28433 AKA phyllohydroquinone, phylloquinol, VKH2
cofactor for the enzyme γ-glutamyl carboxylase (GGCX)
Dietary Vitamin K1 Metabolite chebi:18067
vitamin K2 (MK4) Metabolite chebi:78277 AKA menaquinone-4
vitamin K2 (MK7) Metabolite chebi:44245 AKA menaquinone-7
Vitamin K Metabolite chebi:28384 AKA phylloquinone, VK
Natural vitamer
Made in plants (with high concentrations in green leafy vegetables).
Converted by bacteria in gut microbiome to MK-4.
LOOH Metabolite wikidata:Q76617139 lipid hydroperoxides (LOOH)
UBIAD1 GeneProduct ncbigene:29914
Coagulation factor X Protein uniprot:P00742
Vitamin K-dependent protein C Protein uniprot:P04070
FSP1 Protein uniprot:Q9BRQ8
Coagulation factor VII Protein uniprot:P08709
GGCX Protein uniprot:P38435 AKA γ-glutamyl carboxylase
Vitamin K-dependent protein S Protein uniprot:P07225
Coagulation factor IX Protein uniprot:P00740
Prothrombin Protein uniprot:P00734
VKORC1 Protein uniprot:Q9BQB6 '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
NQO1 Protein uniprot:P15559 AKA NAD(P)H dehydrogenase [quinone] 1
Vitamin K-dependent protein Z Protein uniprot:P22891
Thrombin Protein ensembl:ENSG00000180210
VKORC1L1 Protein uniprot:Q8N0U8 'Can reduce inactive vitamin K 2,3-epoxide to active vitamin K (in vitro)' Source: https://www.uniprot.org/uniprotkb/Q8N0U8/entry
VKOR Protein eccode:1.17.4.4 Vitamin-K-epoxide reductase

References

  1. Vitamin K and cardiovascular calcification in CKD: is patient supplementation on the horizon? Gallieni M, Fusaro M. Kidney Int. 2014 Aug;86(2):232–4. PubMed Europe PMC Scholia
  2. Genomic Analysis of the Human Gut Microbiome Suggests Novel Enzymes Involved in Quinone Biosynthesis. Ravcheev DA, Thiele I. Front Microbiol. 2016 Feb 9;7:128. PubMed Europe PMC Scholia
  3. Effect of vitamin K in bone metabolism and vascular calcification: A review of mechanisms of action and evidences. Villa JKD, Diaz MAN, Pizziolo VR, Martino HSD. Crit Rev Food Sci Nutr. 2017 Dec 12;57(18):3959–70. PubMed Europe PMC Scholia
  4. The Relationship Among Intestinal Bacteria, Vitamin K and Response of Vitamin K Antagonist: A Review of Evidence and Potential Mechanism. Yan H, Chen Y, Zhu H, Huang WH, Cai XH, Li D, et al. Front Med (Lausanne). 2022 Apr 18;9:829304. PubMed Europe PMC Scholia
  5. Long-sought mediator of vitamin K recycling discovered. Ward NP, DeNicola GM. Nature. 2022 Aug;608(7924):673–4. PubMed Europe PMC Scholia
  6. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Mishima E, Ito J, Wu Z, Nakamura T, Wahida A, Doll S, et al. Nature. 2022 Aug;608(7924):778–83. PubMed Europe PMC Scholia