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>
Norn S, Permin H, Kruse E, Kruse PR.; ''[On the history of vitamin K, dicoumarol and warfarin].''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Ferron M, Lacombe J, Germain A, Oury F, Karsenty G.; ''GGCX and VKORC1 inhibit osteocalcin endocrine functions.''; PubMedEurope PMCScholia
Shearer MJ, Fu X, Booth SL.; ''Vitamin K nutrition, metabolism, and requirements: current concepts and future research.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW.; ''Identification of the gene for vitamin K epoxide reductase.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.''; PubMedEurope PMCScholia
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.
The regeneration of reduced vitamin K (vitamin K hydroquinone) from vitamin K epoxide is catalyzed by vitamin K epoxide reductase (VKORC1) (Sadler 2004). Two important features of this reaction remain unclear. First, dithiothreitol functions efficiently as a reductant in vitro (Wallin & 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.
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).
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).
4-Hydroxycoumarins belong to a class of vitamin K antagonist anticoagulant drug molecules derived from coumarin, a bitter-tasting but sweet-smelling natural substance made by plants. It itself doesn't affect coagulation, but is transformed in mouldy feeds or silages by a number of fungi into active dicumarol, a substance that does have anticoagulant properties. Identified in 1940, dicumarol became the prototypical drug of the 4-hydroxycoumarin anticoagulant drug class but has been superceded by warfarin since the 1950's (Norn et al. 2014). Phenindione was introduced in the early 1950s and acts similarly to warfarin, but it has been associated with hypersensitivity reactions so is now rarely used (Naisbitt et al. 2005). Other coumarin-derivatives commonly prescribed in Europe and other regions are the long-acting phenprocoumon (half-life 140 hours) and short-acting acenocoumarol (half-life 11 hours) (Gadisseur et al. 2002). Warfarin, the more potent form of dicumarol and initially used as rat poison, was introduced as an oral anticoagulant in the 1950s and is currently the most widely used oral anticoagulant. Although the working mechanism of the 4-Hydroxycoumarin drugs is similar, there are some important differences in pharmacokinetics between them (Verhoef et al. 2014).
The reduction of vitamin K 2,3-epoxide (MK4 epoxide) by VKORC1 is essential to sustain gamma-carboxylation of vitamin K-dependent proteins such as the clotting factors II, VII, IX and X. The anticoagulant drug warfarin inhibits VKORC1 (Whitlon et al. 1978), thereby reducing clotting ability (Choonara et al. 1985, 1988), which is used as a treatment for thrombotic disorders such as deep vein thrombosis (DVT), pulmonary embolism and to prevent stroke (Ageno et al. 2012). A common side-effect of warfarin anticoagulation is bleeding which can be counteracted by vitamin K supplementation (Ageno et al. 2012). The exact mechanism by which warfarin inhibits VKORC1 remains elusive. Several recent mechanistic studies suggest competitive binding of a key residue in VKORC1 (Czogalla et al. 2017) or blockage of a dynamic electron-transfer process in VKORC1 (Shen et al. 2017). New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation. Unlike warfarin, they are fast-acting and don't require routine coagulation monitoring (Gomez-Outes et al. 2013).
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hypusine formation and arylsulfatase
activationinhibitors:VKORC1
dimerAnnotated Interactions
The reduction of vitamin K 2,3-epoxide (MK4 epoxide) by VKORC1 is essential to sustain gamma-carboxylation of vitamin K-dependent proteins such as the clotting factors II, VII, IX and X. The anticoagulant drug warfarin inhibits VKORC1 (Whitlon et al. 1978), thereby reducing clotting ability (Choonara et al. 1985, 1988), which is used as a treatment for thrombotic disorders such as deep vein thrombosis (DVT), pulmonary embolism and to prevent stroke (Ageno et al. 2012). A common side-effect of warfarin anticoagulation is bleeding which can be counteracted by vitamin K supplementation (Ageno et al. 2012). The exact mechanism by which warfarin inhibits VKORC1 remains elusive. Several recent mechanistic studies suggest competitive binding of a key residue in VKORC1 (Czogalla et al. 2017) or blockage of a dynamic electron-transfer process in VKORC1 (Shen et al. 2017). New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation. Unlike warfarin, they are fast-acting and don't require routine coagulation monitoring (Gomez-Outes et al. 2013).
inhibitors:VKORC1
dimerinhibitors:VKORC1
dimer