Metabolism of vitamin K (Homo sapiens)

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1, 2, 6, 8, 10...3, 12-142, 4, 105, 7endoplasmic reticulum lumenGamma carboxylation,hypusine formationand arylsulfataseactivationVKORC1 dimerUBIAD1GGPPPPiVKORC1 H+VKORC1L1menadioneMK42,3-epoxymenatetrenone9


Description

Vitamin K is a required co-factor in a single metabolic reaction, the gamma-carboxylation of glutamate residues of proteins catalyzed by GGCX (gamma-carboxyglutamyl carboxylase). Substrates of GGCX include blood clotting factors, osteocalcin (OCN), and growth arrest-specific protein 6 (GAS6) (Brenner et al. 1998). Vitamin K is derived from green leafy vegetables as phylloquinone and is synthesized by gut flora as menaquinone-7. These molecules are taken up by intestinal enterocytes with other lipids, packaged into chylomicrons, and delivered via the lymphatic and blood circulation to tissues of the body, notably hepatocytes and osteoblasts, via processes of lipoprotein trafficking (Shearer & Newman 2014; Shearer et al. 2012) described elsewhere in Reactome.

In these tissues, menadiol (reduced vitamin K3) reacts with geranylgeranyl pyrophosphate to form MK4 (vitamin K hydroquinone), the form of the vitamin required as cofactor for gamma-carboxylation of protein glutamate residues (Hirota et al. 2013). The gamma-carboxylation reactions, annotated elsewhere in Reactome as a part of protein metabolism, convert MK4 to its epoxide form, which is inactive as a cofactor. Two related enzymes, VKORC1 and VKORCL1, can each catalyze the reduction of MK4 epoxide to active MK4. VKORC1 activity is essential for normal operation of the blood clotting cascade and for osteocalcin function (Ferron et al. 2015). A physiological function for VKORCL1 has not yet been definitively established (Hammed et al. 2013; Tie et al. 2014). View original pathway at:Reactome.</div>

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Reactome-Converter 
Pathway is converted from Reactome ID: 6806664
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: D'Eustachio, Peter

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Bibliography

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  1. Norn S, Permin H, Kruse E, Kruse PR.; ''[On the history of vitamin K, dicoumarol and warfarin].''; PubMed Europe PMC Scholia
  2. Nakagawa K, Hirota Y, Sawada N, Yuge N, Watanabe M, Uchino Y, Okuda N, Shimomura Y, Suhara Y, Okano T.; ''Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme.''; PubMed Europe PMC Scholia
  3. Czogalla KJ, Biswas A, Höning K, Hornung V, Liphardt K, Watzka M, Oldenburg J.; ''Warfarin and vitamin K compete for binding to Phe55 in human VKOR.''; PubMed Europe PMC Scholia
  4. Hirota Y, Nakagawa K, Sawada N, Okuda N, Suhara Y, Uchino Y, Kimoto T, Funahashi N, Kamao M, Tsugawa N, Okano T.; ''Functional characterization of the vitamin K2 biosynthetic enzyme UBIAD1.''; PubMed Europe PMC Scholia
  5. Westhofen P, Watzka M, Marinova M, Hass M, Kirfel G, Müller J, Bevans CG, Müller CR, Oldenburg J.; ''Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular antioxidant function.''; PubMed Europe PMC Scholia
  6. Ferron M, Lacombe J, Germain A, Oury F, Karsenty G.; ''GGCX and VKORC1 inhibit osteocalcin endocrine functions.''; PubMed Europe PMC Scholia
  7. Shearer MJ, Fu X, Booth SL.; ''Vitamin K nutrition, metabolism, and requirements: current concepts and future research.''; PubMed Europe PMC Scholia
  8. Hirota Y, Tsugawa N, Nakagawa K, Suhara Y, Tanaka K, Uchino Y, Takeuchi A, Sawada N, Kamao M, Wada A, Okitsu T, Okano T.; ''Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats.''; PubMed Europe PMC Scholia
  9. Tie JK, Jin DY, Stafford DW.; ''Conserved loop cysteines of vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) are involved in its active site regeneration.''; PubMed Europe PMC Scholia
  10. Shearer MJ, Newman P.; ''Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis.''; PubMed Europe PMC Scholia
  11. Rishavy MA, Hallgren KW, Wilson LA, Usubalieva A, Runge KW, Berkner KL.; ''The vitamin K oxidoreductase is a multimer that efficiently reduces vitamin K epoxide to hydroquinone to allow vitamin K-dependent protein carboxylation.''; PubMed Europe PMC Scholia
  12. Hammed A, Matagrin B, Spohn G, Prouillac C, Benoit E, Lattard V.; ''VKORC1L1, an enzyme rescuing the vitamin K 2,3-epoxide reductase activity in some extrahepatic tissues during anticoagulation therapy.''; PubMed Europe PMC Scholia
  13. Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW.; ''Identification of the gene for vitamin K epoxide reductase.''; PubMed Europe PMC Scholia
  14. Shen G, Cui W, Zhang H, Zhou F, Huang W, Liu Q, Yang Y, Li S, Bowman GR, Sadler JE, Gross ML, Li W.; ''Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer.''; PubMed Europe PMC Scholia
  15. Gadisseur AP, van der Meer FJ, Adriaansen HJ, Fihn SD, Rosendaal FR.; ''Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon.''; PubMed Europe PMC Scholia
  16. Brenner B, Sánchez-Vega B, Wu SM, Lanir N, Stafford DW, Solera J.; ''A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors.''; PubMed Europe PMC Scholia
  17. Verhoef TI, Redekop WK, Daly AK, van Schie RM, de Boer A, Maitland-van der Zee AH.; ''Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon.''; PubMed Europe PMC Scholia
  18. Schumacher MM, Elsabrouty R, Seemann J, Jo Y, DeBose-Boyd RA.; ''The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase.''; PubMed Europe PMC Scholia
  19. Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hörtnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Müller CR, Strom TM, Oldenburg J.; ''Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2.''; PubMed Europe PMC Scholia
  20. Naisbitt DJ, Farrell J, Chamberlain PJ, Hopkins JE, Berry NG, Pirmohamed M, Park BK.; ''Characterization of the T-cell response in a patient with phenindione hypersensitivity.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114970view16:49, 25 January 2021ReactomeTeamReactome version 75
113414view11:49, 2 November 2020ReactomeTeamReactome version 74
112616view15:59, 9 October 2020ReactomeTeamReactome version 73
101532view11:40, 1 November 2018ReactomeTeamreactome version 66
101067view21:22, 31 October 2018ReactomeTeamreactome version 65
100597view19:56, 31 October 2018ReactomeTeamreactome version 64
100146view16:41, 31 October 2018ReactomeTeamreactome version 63
99696view15:10, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93932view13:45, 16 August 2017ReactomeTeamreactome version 61
93518view11:25, 9 August 2017ReactomeTeamreactome version 61
87919view12:59, 25 July 2016RyanmillerOntology Term : 'vitamin K metabolic pathway' added !
87915view12:59, 25 July 2016RyanmillerOntology Term : 'classic metabolic pathway' added !
86615view09:22, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2,3-epoxymenatetrenoneMetaboliteCHEBI:90152 (ChEBI)
GGPPMetaboliteCHEBI:57533 (ChEBI)
Gamma carboxylation,

hypusine formation and arylsulfatase

activation
PathwayR-HSA-163841 (Reactome) After translation, many newly formed proteins undergo further covalent modifications that alter their functional properties and that are essentially irreversible under physiological conditions in the body. These modifications include the vitamin K-dependent attachment of carboxyl groups to glutamate residues and the conversion of a lysine residue in eIF5A to hypusine, and the conversion of a histidine residue in EEF to diphthamide.
H+MetaboliteCHEBI:15378 (ChEBI)
MK4MetaboliteCHEBI:78277 (ChEBI)
PPiMetaboliteCHEBI:29888 (ChEBI)
UBIAD1ProteinQ9Y5Z9 (Uniprot-TrEMBL)
VKORC1 ProteinQ9BQB6 (Uniprot-TrEMBL)
VKORC1 dimerComplexR-HSA-6806371 (Reactome)
VKORC1L1ProteinQ8N0U8 (Uniprot-TrEMBL)
menadioneMetaboliteCHEBI:28869 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2,3-epoxymenatetrenoneR-HSA-159790 (Reactome)
2,3-epoxymenatetrenoneR-HSA-6806647 (Reactome)
GGPPR-HSA-6806674 (Reactome)
H+R-HSA-159790 (Reactome)
H+R-HSA-6806647 (Reactome)
MK4ArrowR-HSA-159790 (Reactome)
MK4ArrowR-HSA-6806647 (Reactome)
MK4ArrowR-HSA-6806674 (Reactome)
PPiArrowR-HSA-6806674 (Reactome)
R-HSA-159790 (Reactome) The regeneration of reduced vitamin K (vitamin K hydroquinone) from vitamin K epoxide is catalyzed by vitamin K epoxide reductase (VKORC1) (Sadler 2004). This enzyme is the target of the anticoagulant drug warfarin. Two important features of this reaction remain unclear. First, dithiothreitol functions efficiently as a reductant in vitro (Wallin and Martin 1985), but the in vivo reductant remains unknown. Second, while people homozygous for mutations in VKORC1 protein lack epoxide reductase activity (Rost et al. 2004) and cultured insect cells transfected with the cloned human VKORC1 gene express vitamin K epoxide reductase activity (Li et al. 2004), the possibility that the active form of the enzyme is a complex with other proteins cannot be formally excluded.
R-HSA-6806647 (Reactome) VKORC1L1 (Vitamin K epoxide reductase complex subunit 1-like protein 1) in the endoplasmic reticulum catalyzes the reduction of MK4 epoxide to MK4, the active form of vitamin K. A physiological role for this reaction has not been established (Hammed et al. 2013; Tie et al. 2014; Westhofen et al. 2011).
R-HSA-6806674 (Reactome) UBIAD1 (UbiA prenyltransferase domain-containing protein 1) in the endoplasmic reticulum catalyzes the transfer of a geranylgeranyl group from GGPP (geranylgeranyl pyrophosphate)to menadione to form MK4 (vitamin K hydroquinone, menatetrenone) (Nakagawa et al. 2010; Hirota et al. 2013, 2015; Schumacher et al. 2015).
UBIAD1mim-catalysisR-HSA-6806674 (Reactome)
VKORC1 dimermim-catalysisR-HSA-159790 (Reactome)
VKORC1L1mim-catalysisR-HSA-6806647 (Reactome)
menadioneR-HSA-6806674 (Reactome)

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