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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Bibliography

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  1. 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
  2. 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
  3. 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
  4. 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
  5. Gallieni M, Fusaro M; ''Vitamin K and cardiovascular calcification in CKD: is patient supplementation on the horizon?''; Kidney Int, 2014 PubMed Europe PMC Scholia
  6. Nathan P Ward, Gina M DeNicola; ''Long-sought mediator of vitamin K recycling discovered''; Nature, 2022 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
135481view05:12, 16 September 2024EgonwUpper-cased the ChEBI identifiers
127081view01:29, 29 July 2023Khanspersadded edits from Artoria2e5
123700view07:36, 11 August 2022DeSlAdded detail on VK3, updated layout
123605view06:09, 6 August 2022EgonwIt was there twice
123604view15:05, 4 August 2022DeSlUpdated with info on Vitamin K3
123597view14:07, 4 August 2022EgonwFixed a datasource
123581view12:32, 4 August 2022DeSlUpdate layout
123580view12:23, 4 August 2022DeSlOntology Term : 'hepatocyte' added !
123579view12:22, 4 August 2022DeSlOntology Term : 'vitamin and vitamin metabolites signaling pathway' added !
123578view12:22, 4 August 2022DeSlOntology Term : 'vitamin K deficiency bleeding' added !
123577view12:21, 4 August 2022DeSlOntology Term : 'vitamin K cycle pathway' added !
123576view12:21, 4 August 2022DeSlOntology Term : 'vitamin K antagonist drug pathway' added !
123575view12:20, 4 August 2022DeSlOntology Term : 'ferroptosis pathway' added !
123574view12:20, 4 August 2022DeSlOntology Term : 'hemostasis pathway' added !
123573view12:18, 4 August 2022DeSlMore layout changes
123572view12:17, 4 August 2022DeSlUpdate layout
123571view12:16, 4 August 2022DeSlUpdate link in description and LOOH visualization
123570view12:13, 4 August 2022DeSlUpdate description, added latest findings on FSP1 and lipid radical reduction against ferroptosis
123569view11:34, 4 August 2022DeSlUpdated comments on Men and Mqn PW nodes
123568view11:23, 4 August 2022DeSlAdded legend for microbioal interaction
123567view11:08, 4 August 2022DeSlAdding synonyms to Vit. K + adding specific metabolites, added NKOR as complex.
122546view22:36, 14 April 2022EweitzModified description
122545view22:36, 14 April 2022EweitzModified title
122121view11:44, 11 March 2022AnnaVanWerschModified description
122120view11:41, 11 March 2022AnnaVanWerschChanged size textbox
122119view11:40, 11 March 2022AnnaVanWerschChanged labels
122032view10:49, 9 March 2022AnnaVanWerschChanged identifiers
122022view10:12, 9 March 2022AnnaVanWerschAdded identifier and changed DataNode type to protein
122016view09:50, 9 March 2022AnnaVanWerschOntology Term : 'lipid metabolic pathway' added !
122010view09:42, 9 March 2022AnnaVanWerschOntology Term : 'classic metabolic pathway' added !
121874view22:50, 7 March 2022DeSllayout changes, condensed pathway
121603view18:48, 21 February 2022AnnaVanWerschChanged box width and alignment
121602view18:17, 21 February 2022AndraOntology Term : 'vitamin K metabolic pathway' added !
121557view11:10, 21 February 2022AnnaVanWerschAdded literature and complexes
121412view10:56, 17 February 2022AnnaVanWerschAdded specific coagulation factors
121408view10:14, 17 February 2022AnnaVanWerschModified title
121381view08:52, 17 February 2022AnnaVanWerschAdded enzyme and metabolites
121314view17:57, 14 February 2022AnnaVanWerschAdded notes
121305view17:31, 14 February 2022AnnaVanWerschNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
Coagulation factor IXProteinP00740 (Uniprot-TrEMBL)
Coagulation factor VIIProteinP08709 (Uniprot-TrEMBL)
Coagulation factor XProteinP00742 (Uniprot-TrEMBL)
Dietary Vitamin K1MetaboliteCHEBI:18067 (ChEBI)
FSP1ProteinQ9BRQ8 (Uniprot-TrEMBL)
FerroptosisPathwayWP4313 (WikiPathways)
GGCXProteinP38435 (Uniprot-TrEMBL) AKA γ-glutamyl carboxylase
LOOHMetaboliteQ76617139 (Wikidata) lipid hydroperoxides (LOOH)
LOO•Metabolitelipid peroxyl radicals (LOO•)
MenPathway2-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].
MenadiolMetaboliteCHEBI:6746 (ChEBI)
MqnPathwayCompleted through futalosine, involving five types of enzymes (MenA-MenE). 10 genomes of Firmicutes, Proteobacteria, and Bacteroidetes have a complete Men pathway [PMID:26904004].
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteHMDB00221 (HMDB)
NQO1ProteinP15559 (Uniprot-TrEMBL) AKA NAD(P)H dehydrogenase [quinone] 1
ProthrombinProteinP00734 (Uniprot-TrEMBL)
ThrombinProteinENSG00000180210 (Ensembl)
UBIAD1GeneProduct29914 (Entrez Gene)
VKORProtein1.17.4.4 (Enzyme Nomenclature) Vitamin-K-epoxide reductase
VKORC1L1ProteinQ8N0U8 (Uniprot-TrEMBL) "Can reduce inactive vitamin K 2,3-epoxide to active vitamin K (in vitro)" Source: https://www.uniprot.org/uniprotkb/Q8N0U8/entry
VKORC1ProteinQ9BQB6 (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)MetaboliteCHEBI:28384 (ChEBI) Group of metabolites known as Vitamin K, which are structurally similar and found in food.
Vitamin K epoxide (VKO)MetaboliteCHEBI:15759 (ChEBI) AKA Vitamin K1 oxide, VKO
Vitamin K hydroquinone (VKH2)MetaboliteCHEBI:28433 (ChEBI)
  • AKA phyllohydroquinone, phylloquinol, VKH2
  • cofactor for the enzyme γ-glutamyl carboxylase (GGCX)
Vitamin K-dependent protein CProteinP04070 (Uniprot-TrEMBL)
Vitamin K-dependent protein SProteinP07225 (Uniprot-TrEMBL)
Vitamin K-dependent protein ZProteinP22891 (Uniprot-TrEMBL)
Vitamin K1MetaboliteCHEBI:18067 (ChEBI)
  • AKA phylloquinone, VK
  • Natural vitamer
  • Made in plants (with high concentrations in green leafy vegetables).
  • Converted by bacteria in gut microbiome to MK-4.
Vitamin K3MetaboliteCHEBI:28869 (ChEBI)
  • 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 KMetaboliteCHEBI:28384 (ChEBI)
  • AKA phylloquinone, VK
  • Natural vitamer
  • Made in plants (with high concentrations in green leafy vegetables).
  • Converted by bacteria in gut microbiome to MK-4.
WarfarinMetaboliteHMDB0001935 (HMDB)
disulfidesMetaboliteCHEBI:48343 (ChEBI)
dithiolsMetaboliteCHEBI:23853 (ChEBI)
gamma-carboxyglutamateMetaboliteCHEBI:61938 (ChEBI)
geranylgeranyl diphosphateMetaboliteCHEBI:58756 (ChEBI)
glutamateMetaboliteCHEBI:14321 (ChEBI)
vitamin K2 (MK4)MetaboliteCHEBI:78277 (ChEBI) AKA menaquinone-4
vitamin K2 (MK7)MetaboliteCHEBI:44245 (ChEBI) AKA menaquinone-7
vitamin K2MetaboliteCHEBI:16374 (ChEBI)
  • AKA menaquinone, VK2
  • Natural vitamer
  • Different lengths of C-side chains in the isoprenoid group are known: MK5 ~ MK15 (produces by bacteria) [PMID:35510250]

Annotated Interactions

SourceTargetTypeDatabase referenceComment
Vitamin K hydroquinone (VKH2)Vitamin K epoxide (VKO)mim-conversion45142 (Rhea)
Vitamin KVitamin K hydroquinone (VKH2)mim-conversion57746 (Rhea)
mim-conversion45142 (Rhea)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP5186"
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