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Pathway Description
Ximelagatran Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2013-08-22
Last Updated: 2022-10-20
Ximelagatran is an anticoagulant drug used to prevent and treat blood clots, and was the first drug in the anticoagulant drug class to be able to be ingested orally. It was discontinued from distribution by its parent company AstraZeneca in 2006 as it was found to raise liver enzyme levels in patients and cause liver damage as a result. Ximelagatran inhibits prothrombin. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is inhibited by ximelagatran, and is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V and ximelagatran inhibits prothrombin. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced and inhibited by ximelagatran, which then uses fibrinogen alphabet, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator through plasminogen and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa. Prothrombin is inhibited by ximelagatran here as well. From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.
References
Ximelagatran Pathway References
Jennings LK, Saucedo JF: Antiplatelet and anticoagulant agents: key differences in mechanisms of action, clinical application, and therapeutic benefit in patients with non-ST-segment-elevation acute coronary syndromes. Curr Opin Cardiol. 2008 Jul;23(4):302-8. doi: 10.1097/HCO.0b013e3283021ad9.
Pubmed: 18520712
Walker CP, Royston D: Thrombin generation and its inhibition: a review of the scientific basis and mechanism of action of anticoagulant therapies. Br J Anaesth. 2002 Jun;88(6):848-63.
Pubmed: 12173205
Cool DE, MacGillivray RT: Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5'-flanking region. J Biol Chem. 1987 Oct 5;262(28):13662-73.
Pubmed: 2888762
Schmutz J, Martin J, Terry A, Couronne O, Grimwood J, Lowry S, Gordon LA, Scott D, Xie G, Huang W, Hellsten U, Tran-Gyamfi M, She X, Prabhakar S, Aerts A, Altherr M, Bajorek E, Black S, Branscomb E, Caoile C, Challacombe JF, Chan YM, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Lopez F, Lou Y, Martinez D, Medina C, Morgan J, Nandkeshwar R, Noonan JP, Pitluck S, Pollard M, Predki P, Priest J, Ramirez L, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wheeler J, Wu K, Yang J, Dickson M, Cheng JF, Eichler EE, Olsen A, Pennacchio LA, Rokhsar DS, Richardson P, Lucas SM, Myers RM, Rubin EM: The DNA sequence and comparative analysis of human chromosome 5. Nature. 2004 Sep 16;431(7006):268-74. doi: 10.1038/nature02919.
Pubmed: 15372022
Tripodi M, Citarella F, Guida S, Galeffi P, Fantoni A, Cortese R: cDNA sequence coding for human coagulation factor XII (Hageman). Nucleic Acids Res. 1986 Apr 11;14(7):3146. doi: 10.1093/nar/14.7.3146.
Pubmed: 3754331
Korkko J, Ala-Kokko L, De Paepe A, Nuytinck L, Earley J, Prockop DJ: Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfecta type I: identification of common sequences of null-allele mutations. Am J Hum Genet. 1998 Jan;62(1):98-110. doi: 10.1086/301689.
Pubmed: 9443882
D'Alessio M, Bernard M, Pretorius PJ, de Wet W, Ramirez F: Complete nucleotide sequence of the region encompassing the first twenty-five exons of the human pro alpha 1(I) collagen gene (COL1A1) Gene. 1988 Jul 15;67(1):105-15. doi: 10.1016/0378-1119(88)90013-3.
Pubmed: 2843432
Wallis GA, Starman BJ, Zinn AB, Byers PH: Variable expression of osteogenesis imperfecta in a nuclear family is explained by somatic mosaicism for a lethal point mutation in the alpha 1(I) gene (COL1A1) of type I collagen in a parent. Am J Hum Genet. 1990 Jun;46(6):1034-40.
Pubmed: 2339700
Chung DW, Fujikawa K, McMullen BA, Davie EW: Human plasma prekallikrein, a zymogen to a serine protease that contains four tandem repeats. Biochemistry. 1986 May 6;25(9):2410-7. doi: 10.1021/bi00357a017.
Pubmed: 3521732
Yu H, Anderson PJ, Freedman BI, Rich SS, Bowden DW: Genomic structure of the human plasma prekallikrein gene, identification of allelic variants, and analysis in end-stage renal disease. Genomics. 2000 Oct 15;69(2):225-34. doi: 10.1006/geno.2000.6330.
Pubmed: 11031105
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Kurachi K, Davie EW: Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6461-4. doi: 10.1073/pnas.79.21.6461.
Pubmed: 6959130
Jaye M, de la Salle H, Schamber F, Balland A, Kohli V, Findeli A, Tolstoshev P, Lecocq JP: Isolation of a human anti-haemophilic factor IX cDNA clone using a unique 52-base synthetic oligonucleotide probe deduced from the amino acid sequence of bovine factor IX. Nucleic Acids Res. 1983 Apr 25;11(8):2325-35. doi: 10.1093/nar/11.8.2325.
Pubmed: 6687940
Anson DS, Choo KH, Rees DJ, Giannelli F, Gould K, Huddleston JA, Brownlee GG: The gene structure of human anti-haemophilic factor IX. EMBO J. 1984 May;3(5):1053-60.
Pubmed: 6329734
Coagulation References
van der Meijden PE, Munnix IC, Auger JM, Govers-Riemslag JW, Cosemans JM, Kuijpers MJ, Spronk HM, Watson SP, Renne T, Heemskerk JW: Dual role of collagen in factor XII-dependent thrombus formation. Blood. 2009 Jul 23;114(4):881-90. doi: 10.1182/blood-2008-07-171066. Epub 2009 Apr 16.
Pubmed: 19372258
Norris LA: Blood coagulation. Best Pract Res Clin Obstet Gynaecol. 2003 Jun;17(3):369-83.
Pubmed: 12787532
Cool DE, MacGillivray RT: Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5'-flanking region. J Biol Chem. 1987 Oct 5;262(28):13662-73.
Pubmed: 2888762
Schmutz J, Martin J, Terry A, Couronne O, Grimwood J, Lowry S, Gordon LA, Scott D, Xie G, Huang W, Hellsten U, Tran-Gyamfi M, She X, Prabhakar S, Aerts A, Altherr M, Bajorek E, Black S, Branscomb E, Caoile C, Challacombe JF, Chan YM, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Lopez F, Lou Y, Martinez D, Medina C, Morgan J, Nandkeshwar R, Noonan JP, Pitluck S, Pollard M, Predki P, Priest J, Ramirez L, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wheeler J, Wu K, Yang J, Dickson M, Cheng JF, Eichler EE, Olsen A, Pennacchio LA, Rokhsar DS, Richardson P, Lucas SM, Myers RM, Rubin EM: The DNA sequence and comparative analysis of human chromosome 5. Nature. 2004 Sep 16;431(7006):268-74. doi: 10.1038/nature02919.
Pubmed: 15372022
Tripodi M, Citarella F, Guida S, Galeffi P, Fantoni A, Cortese R: cDNA sequence coding for human coagulation factor XII (Hageman). Nucleic Acids Res. 1986 Apr 11;14(7):3146. doi: 10.1093/nar/14.7.3146.
Pubmed: 3754331
Korkko J, Ala-Kokko L, De Paepe A, Nuytinck L, Earley J, Prockop DJ: Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfecta type I: identification of common sequences of null-allele mutations. Am J Hum Genet. 1998 Jan;62(1):98-110. doi: 10.1086/301689.
Pubmed: 9443882
D'Alessio M, Bernard M, Pretorius PJ, de Wet W, Ramirez F: Complete nucleotide sequence of the region encompassing the first twenty-five exons of the human pro alpha 1(I) collagen gene (COL1A1) Gene. 1988 Jul 15;67(1):105-15. doi: 10.1016/0378-1119(88)90013-3.
Pubmed: 2843432
Wallis GA, Starman BJ, Zinn AB, Byers PH: Variable expression of osteogenesis imperfecta in a nuclear family is explained by somatic mosaicism for a lethal point mutation in the alpha 1(I) gene (COL1A1) of type I collagen in a parent. Am J Hum Genet. 1990 Jun;46(6):1034-40.
Pubmed: 2339700
Chung DW, Fujikawa K, McMullen BA, Davie EW: Human plasma prekallikrein, a zymogen to a serine protease that contains four tandem repeats. Biochemistry. 1986 May 6;25(9):2410-7. doi: 10.1021/bi00357a017.
Pubmed: 3521732
Yu H, Anderson PJ, Freedman BI, Rich SS, Bowden DW: Genomic structure of the human plasma prekallikrein gene, identification of allelic variants, and analysis in end-stage renal disease. Genomics. 2000 Oct 15;69(2):225-34. doi: 10.1006/geno.2000.6330.
Pubmed: 11031105
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Kurachi K, Davie EW: Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6461-4. doi: 10.1073/pnas.79.21.6461.
Pubmed: 6959130
Jaye M, de la Salle H, Schamber F, Balland A, Kohli V, Findeli A, Tolstoshev P, Lecocq JP: Isolation of a human anti-haemophilic factor IX cDNA clone using a unique 52-base synthetic oligonucleotide probe deduced from the amino acid sequence of bovine factor IX. Nucleic Acids Res. 1983 Apr 25;11(8):2325-35. doi: 10.1093/nar/11.8.2325.
Pubmed: 6687940
Anson DS, Choo KH, Rees DJ, Giannelli F, Gould K, Huddleston JA, Brownlee GG: The gene structure of human anti-haemophilic factor IX. EMBO J. 1984 May;3(5):1053-60.
Pubmed: 6329734
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