BioPAX pathway converted from "Metabolism of vitamin K" in the Reactome database. Metabolism of vitamin K 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.<P>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). Authored: D'Eustachio, Peter, 2015-11-02 Reviewed: Jassal, Bijay, 2015-11-02 Edited: D'Eustachio, Peter, 2015-11-02 LEFT-TO-RIGHT 2.5.1 UBIA1D prenylates menadione to form MK4 (vitamin K hydroquinone) 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). Authored: D'Eustachio, Peter, 2015-11-02 Reviewed: Jassal, Bijay, 2015-11-02 Edited: D'Eustachio, Peter, 2015-11-02 GGPP geranylgeranyl diphosphare geranylgeranyl diphosphate(3-) geranylgeranyl pyrophosphate Reactome DB_ID: 6806657 endoplasmic reticulum lumen GENE ONTOLOGY GO:0005788 geranylgeranyl diphosphate(3-) [ChEBI:57533] geranylgeranyl diphosphate(3-) geranylgeranyl diphosphate ChEBI CHEBI:57533 Reactome Database ID Release 79 6806657 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806657 Reactome R-ALL-6806657 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6806657.3 Reactome http://www.reactome.org menadione vitamin K3 Reactome DB_ID: 6806891 menadione [ChEBI:28869] menadione ChEBI CHEBI:28869 Reactome Database ID Release 79 6806891 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806891 Reactome R-ALL-6806891 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6806891.2 MK4 vitamin K hydroquinone menatetrenone menaquinone-4 Reactome DB_ID: 6806362 menaquinone-4 [ChEBI:78277] menaquinone-4 ChEBI CHEBI:78277 Reactome Database ID Release 79 6806362 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806362 Reactome R-ALL-6806362 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6806362.4 PPi pyrophosphate diphosphoric acid pyrophosphoric acid diphosphate Reactome DB_ID: 6806656 diphosphate(3-) [ChEBI:33019] diphosphate(3-) ChEBI CHEBI:33019 Reactome Database ID Release 79 6806656 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806656 Reactome R-ALL-6806656 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6806656.4 COMPOUND C00013 additional information MI MI:0361 ACTIVATION UBIAD1 UbiA prenyltransferase domain-containing protein 1 ecNumber2.5.1.-/ecNumber UBIA1_HUMAN Reactome DB_ID: 2980965 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 UniProt:Q9Y5Z9 UBIAD1 UBIAD1 TERE1 FUNCTION Prenyltransferase that mediates the formation of menaquinone-4 (MK-4) and coenzyme Q10. MK-4 is a vitamin K2 isoform present at high concentrations in the brain, kidney and pancreas, and is required for endothelial cell development. Mediates the conversion of phylloquinone (PK) into MK-4, probably by cleaving the side chain of phylloquinone (PK) to release 2-methyl-1,4-naphthoquinone (menadione; K3) and then prenylating it with geranylgeranyl pyrophosphate (GGPP) to form MK-4. Also plays a role in cardiovascular development independently of MK-4 biosynthesis, by acting as a coenzyme Q10 biosynthetic enzyme: coenzyme Q10, also named ubiquinone, plays an important antioxidant role in the cardiovascular system. Mediates biosynthesis of coenzyme Q10 in the Golgi membrane, leading to protect cardiovascular tissues from NOS3/eNOS-dependent oxidative stress.PATHWAY Quinol/quinone metabolism; menaquinone biosynthesis.PATHWAY Cofactor biosynthesis; ubiquinone biosynthesis.SUBUNIT Interacts with HMGCR and SOAT1.TISSUE SPECIFICITY Ubiquitously expressed.MISCELLANEOUS Strongly down-regulated in transitional cell carcinoma of the bladder and in prostate carcinoma (at protein level) (PubMed:11314041, PubMed:12497587).SIMILARITY Belongs to the UbiA prenyltransferase family. Homo sapiens NCBI Taxonomy 9606 UniProt Q9Y5Z9 2 EQUAL 338 EQUAL Reactome Database ID Release 79 2980965 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2980965 Reactome R-HSA-2980965 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2980965.1 GENE ONTOLOGY GO:0004659 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 79 6806376 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806376 Reactome Database ID Release 79 6806674 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806674 Reactome R-HSA-6806674 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6806674.2 20953171 Pubmed 2010 Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme Nakagawa, Kimie Hirota, Yoshihisa Sawada, Natsumi Yuge, Naohito Watanabe, Masato Uchino, Yuri Okuda, Naoko Shimomura, Yuka Suhara, Yoshitomo Okano, Toshio Nature 468:117-21 24085302 Pubmed 2013 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 Hirota, Yoshihisa Tsugawa, Naoko Nakagawa, Kimie Suhara, Yoshitomo Tanaka, Kiyoshi Uchino, Yuri Takeuchi, Atsuko Sawada, Natsumi Kamao, Maya Wada, Akimori Okitsu, Takashi Okano, Toshio J. Biol. Chem. 288:33071-80 25874989 Pubmed 2015 Functional characterization of the vitamin K2 biosynthetic enzyme UBIAD1 Hirota, Yoshihisa Nakagawa, Kimie Sawada, Natsumi Okuda, Naoko Suhara, Yoshitomo Uchino, Yuri Kimoto, Takashi Funahashi, Nobuaki Kamao, Maya Tsugawa, Naoko Okano, Toshio PLoS ONE 10:e0125737 25742604 Pubmed 2015 The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase Schumacher, Marc M Elsabrouty, Rania Seemann, Joachim Jo, Youngah DeBose-Boyd, RA Elife 4: LEFT-TO-RIGHT VKORC1 inhibitors binds VKORC1 dimer 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).<br><br>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). Authored: Jassal, Bijay, 2017-10-25 Reviewed: Gómez-Outes, Antonio, 2018-03-21 Edited: Jassal, Bijay, 2017-10-25 VKORC1 dimer Reactome DB_ID: 6806371 VKORC1 vitamin K epoxide reductase 1 Reactome DB_ID: 159746 UniProt:Q9BQB6 VKORC1 VKORC1 VKOR MSTP134 MSTP576 UNQ308/PRO351 FUNCTION Involved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development.ACTIVITY REGULATION Inhibited by warfarin (coumadin).TISSUE SPECIFICITY Expressed at highest levels in fetal and adult liver, followed by fetal heart, kidney, and lung, adult heart, and pancreas.DOMAIN The number of transmembrane domains and the membrane topology are controversial; supporting evidence is available both for models with three transmembrane domains (PubMed:15716279 and PubMed:22923610) and four transmembrane domains (PubMed:20696932 and PubMed:20978134). According to PubMed:15716279 and PubMed:22923610 the N-terminus of the protein is in the endoplasmic reticulum lumen, while the C-terminus is in the cytosol, which is in favor of three transmembrane domains. According to PubMed:20696932, both N-terminus and C-terminus are in the cytosol, indicating the presence of four transmembrane domains. Besides, the 3D-structure of a bacterial ortholog shows four transmembrane domains. Moreover, proteins that reside in the endoplasmic reticulum lumen can catalyze the reduction of the active site cysteines, possibly via Cys-43 and Cys-51 (PubMed:20696932 and PubMed:20978134), but less efficiently than the synthetic compound dithiothreitol (in vitro). Location of Cys-43 and Cys-51 in the endoplasmic reticulum lumen would be in agreement with four transmembrane domains. Again, these data are controversial, and papers do not agree on the effects of mutating Cys-43 and Cys-51, probably because of differences in the assay systems.MISCELLANEOUS The location of two cysteine active-site residues within a proposed transmembrane is consistent both with the known hydrophobic environment of the thiol redox site of the enzyme and with the lipophilicity of vitamin K and warfarin (coumadin).SIMILARITY Belongs to the VKOR family. UniProt Q9BQB6 1 EQUAL 163 EQUAL Reactome Database ID Release 79 159746 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=159746 Reactome R-HSA-159746 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-159746.1 2 Reactome Database ID Release 79 6806371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806371 Reactome R-HSA-6806371 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6806371.1 Converted from EntitySet in Reactome VKORC1 inhibitors VKORC1 antagonists Reactome DB_ID: 9035082 dicumarol dicoumarol Reactome DB_ID: 9035047 cytosol GENE ONTOLOGY GO:0005829 dicumarol [Guide to Pharmacology:6808] dicumarol bishydroxycoumarin Melitoxin&reg; Guide to Pharmacology 6808 Reactome Database ID Release 79 9035047 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9035047 Reactome R-ALL-9035047 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9035047.2 ChEBI 4513 phenindione Reactome DB_ID: 9035044 phenindione [Guide to Pharmacology:6838] phenindione Dindevan&reg; phenylindanedione Guide to Pharmacology 6838 Reactome Database ID Release 79 9035044 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9035044 Reactome R-ALL-9035044 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9035044.2 ChEBI 8066 phenprocoumon Reactome DB_ID: 9035040 phenprocoumon [Guide to Pharmacology:6839] phenprocoumon Liquamar&reg; phenprocoumarol Guide to Pharmacology 6839 Reactome Database ID Release 79 9035040 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9035040 Reactome R-ALL-9035040 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9035040.2 ChEBI 50438 warfarin Reactome DB_ID: 9014945 warfarin [Guide to Pharmacology:6853] warfarin Coumadin&reg; Marevan&reg; panwarfin Guide to Pharmacology 6853 Reactome Database ID Release 79 9014945 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014945 Reactome R-ALL-9014945 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9014945.2 ChEBI 10033 acenocoumarol Reactome DB_ID: 9603374 acenocoumarol [Guide to Pharmacology:9015] acenocoumarol Sinthrome&reg; Sintrom&reg; Guide to Pharmacology 9015 Reactome Database ID Release 79 9603374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9603374 Reactome R-ALL-9603374 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9603374.2 ChEBI 53766 Reactome Database ID Release 79 9035082 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9035082 Reactome R-HSA-9035082 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9035082.1 VKORC1 inhibitors:VKORC1 dimer Reactome DB_ID: 9035037 1 1 Reactome Database ID Release 79 9035037 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9035037 Reactome R-HSA-9035037 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9035037.1 Reactome Database ID Release 79 9026967 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9026967 Reactome R-HSA-9026967 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9026967.1 27941861 Pubmed 2017 Warfarin and vitamin K compete for binding to Phe55 in human VKOR Czogalla, Katrin J Biswas, Arijit Höning, Klara Hornung, Veit Liphardt, Kerstin Watzka, Matthias Oldenburg, J Nat. Struct. Mol. Biol. 24:77-85 25639072 Pubmed 2014 [On the history of vitamin K, dicoumarol and warfarin] Norn, Svend Permin, Henrik Kruse, Edith Kruse, Poul R Dan Medicinhist Arbog 42:99-119 4091996 Pubmed 1985 Vitamin K1 metabolism in relation to pharmacodynamic response in anticoagulated patients Choonara, I A Scott, A K Haynes, B P Cholerton, S Breckenridge, A M Park, B K Br J Clin Pharmacol 20:643-8 22315269 Pubmed 2012 Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Ageno, Walter Gallus, Alexander S Wittkowsky, Ann Crowther, Mark Hylek, Elaine M Palareti, Gualtiero Chest 141:e44S-e88S 3370190 Pubmed 1988 The relationship between inhibition of vitamin K1 2,3-epoxide reductase and reduction of clotting factor activity with warfarin Choonara, I A Malia, R G Haynes, B P Hay, C R Cholerton, S Breckenridge, A M Preston, F E Park, B K Br J Clin Pharmacol 25:1-7 24455237 Pubmed 2013 Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups Gómez-Outes, Antonio Terleira-Fernández, Ana Isabel Calvo-Rojas, Gonzalo Suárez-Gea, M Luisa Vargas-Castrillón, Emilio Thrombosis 2013:640723 12060134 Pubmed 2002 Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon Gadisseur, Alain P A van der Meer, Felix J M Adriaansen, Henk J Fihn, Stephan D Rosendaal, Frits R Br. J. Haematol. 117:940-6 646989 Pubmed 1978 Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition Whitlon, D S Sadowski, J A Suttie, J W Biochemistry 17:1371-7 23919835 Pubmed 2014 Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon Verhoef, Talitha I Redekop, William K Daly, Ann K van Schie, Rianne M F de Boer, Anthonius Maitland-van der Zee, Anke-Hilse Br J Clin Pharmacol 77:626-41 27918545 Pubmed 2017 Warfarin traps human vitamin K epoxide reductase in an intermediate state during electron transfer Shen, Guomin Cui, Weidong Zhang, Hao Zhou, Fengbo Huang, Wei Liu, Qian Yang, Yihu Li, Shuang Bowman, Gregory R Sadler, JE Gross, Michael L Li, Weikai Nat. Struct. Mol. Biol. 24:69-76 15743920 Pubmed 2005 Characterization of the T-cell response in a patient with phenindione hypersensitivity Naisbitt, Dean J Farrell, John Chamberlain, Peter J Hopkins, Josephine E Berry, Neil G Pirmohamed, Munir Park, B Kevin J. Pharmacol. Exp. Ther. 313:1058-65 LEFT-TO-RIGHT 1.17.4.4 MK4 epoxide => MK4 VKORC1 reduces vitamin K epoxide to MK4 (vitamin K hydroquinone) 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. 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 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).<br><br>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). Authored: D'Eustachio, P, 2005-03-17 16:24:57 Reviewed: Jassal, Bijay, 2015-11-02 Edited: D'Eustachio, P, 0000-00-00 00:00:00 H+ hydron Reactome DB_ID: 156540 hydron [ChEBI:15378] hydron ChEBI CHEBI:15378 Reactome Database ID Release 79 156540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=156540 Reactome R-ALL-156540 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-156540.3 COMPOUND C00080 2 MK4 epoxide metatetrenone epoxide 2,3-epoxymenatetrenone Reactome DB_ID: 6806366 2,3-epoxymenatetrenone [ChEBI:90152] 2,3-epoxymenatetrenone ChEBI CHEBI:90152 Reactome Database ID Release 79 6806366 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806366 Reactome R-ALL-6806366 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6806366.5 ACTIVATION GENE ONTOLOGY GO:0047057 Reactome Database ID Release 79 159727 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=159727 Reactome Database ID Release 79 159790 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=159790 Reactome R-HSA-159790 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-159790.5 14765195 Pubmed 2004 Identification of the gene for vitamin K epoxide reductase Li, T Chang, CY Jin, DY Lin, PJ Khvorova, A Stafford, DW Nature 427:541-4 3932474 Pubmed 1985 Vitamin K-dependent carboxylation and vitamin K metabolism in liver. Effects of warfarin. Wallin, R Martin, LF J Clin Invest 76:1879-84 14765194 Pubmed 2004 Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2 Rost, S Fregin, A Ivaskevicius, V Conzelmann, E Hortnagel, K Pelz, HJ Lappegard, K Seifried, E Scharrer, I Tuddenham, EG Müller, Clemens R Strom, TM Oldenburg, J Nature 427:537-41 14765176 Pubmed 2004 Medicine: K is for koagulation Sadler, JE Nature 427:493-4 INHIBITION Reactome Database ID Release 79 9014943 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9014943 Reactome R-HSA-9014943 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9014943.3 LEFT-TO-RIGHT 1.17.4.4 MK4 epoxide => MK4 VKORC1L1 reduces vitamin K epoxide to MK4 (vitamin K hydroquinone) 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). Authored: D'Eustachio, Peter, 2015-11-02 Reviewed: Jassal, Bijay, 2015-11-02 Edited: D'Eustachio, Peter, 2015-11-02 2 ACTIVATION VKORC1L1 Vitamin K epoxide reductase complex subunit 1-like protein 1 VKORL_HUMAN Reactome DB_ID: 2980944 UniProt:Q8N0U8 VKORC1L1 VKORC1L1 FUNCTION Involved in vitamin K metabolism. Can reduce inactive vitamin K 2,3-epoxide to active vitamin K (in vitro), and may contribute to vitamin K-mediated protection against oxidative stress. Plays a role in vitamin K-dependent gamma-carboxylation of Glu residues in target proteins.ACTIVITY REGULATION Inhibited by warfarin (coumadin).INDUCTION Up-regulated in response to oxidative stress induced by hydrogen peroxide treatment.MISCELLANEOUS The location of two cysteine active-site residues within a proposed transmembrane is consistent both with the known hydrophobic environment of the thiol redox site of the enzyme and with the lipophilicity of vitamin K and warfarin (coumadin).SIMILARITY Belongs to the VKOR family. UniProt Q8N0U8 1 EQUAL 176 EQUAL Reactome Database ID Release 79 2980944 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2980944 Reactome R-HSA-2980944 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2980944.1 Reactome Database ID Release 79 6806682 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806682 Reactome Database ID Release 79 6806647 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806647 Reactome R-HSA-6806647 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6806647.2 23928358 Pubmed 2013 VKORC1L1, an enzyme rescuing the vitamin K 2,3-epoxide reductase activity in some extrahepatic tissues during anticoagulation therapy Hammed, Abdessalem Matagrin, Benjamin Spohn, Gabriele Prouillac, Caroline Benoit, Etienne Lattard, Virginie J. Biol. Chem. 288:28733-42 21367861 Pubmed 2011 Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular antioxidant function Westhofen, Philipp Watzka, Matthias Marinova, Milka Hass, Moritz Kirfel, Gregor Müller, Jens Bevans, Carville G Müller, Clemens R Oldenburg, J J. Biol. Chem. 286:15085-94 24532791 Pubmed 2014 Conserved loop cysteines of vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) are involved in its active site regeneration Tie, Jian-Ke Jin, DY Stafford, DW J. Biol. Chem. 289:9396-407 Reactome Database ID Release 79 6806664 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6806664 Reactome R-HSA-6806664 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6806664.3 22516726 Pubmed 2012 Vitamin K nutrition, metabolism, and requirements: current concepts and future research Shearer, Martin J Fu, Xueyan Booth, Sarah L Adv Nutr 3:182-95 24489112 Pubmed 2014 Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis Shearer, Martin J Newman, Paul J. Lipid Res. 55:345-62 25753038 Pubmed 2015 GGCX and VKORC1 inhibit osteocalcin endocrine functions Ferron, Mathieu Lacombe, Julie Germain, Amélie Oury, Franck Karsenty, Gerard J. Cell Biol. 208:761-76 9845520 Pubmed 1998 A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors Brenner, B Sanchez-Vega, B Wu, SM Lanir, N Stafford, DW Solera, J Blood 92:4554-9 GENE ONTOLOGY GO:0042373 gene ontology term for cellular process MI MI:0359