Factor X
F10 | |||
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Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process | |||
Sources:Amigo / QuickGO |
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RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 13: 113.12 – 113.15 Mb | Chr 8: 13.09 – 13.11 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Factor X, also known by the
for its synthesis.Factor X is activated, by hydrolysis, into factor Xa by both
It acts by cleaving
Factor Xa is inactivated by
The half life of factor X is 40–45 hours.
Structure
The first crystal structure of human factor Xa was deposited in May 1993. To date, 191 crystal structures of factor Xa with various inhibitors have been deposited in the protein data bank. The active site of factor Xa is divided into four subpockets as S1, S2, S3 and S4. The S1 subpocket determines the major component of selectivity and binding. The S2 sub-pocket is small, shallow and not well defined. It merges with the S4 subpocket. The S3 sub-pocket is located on the rim of the S1 pocket and is quite exposed to solvent. The S4 sub-pocket has three ligand binding domains: the "hydrophobic box", the "cationic hole" and the water site. Factor Xa inhibitors generally bind in an L-shaped conformation, where one group of the ligand occupies the anionic S1 pocket lined by residues Asp189, Ser195, and Tyr228, and another group of the ligand occupies the aromatic S4 pocket lined by residues Tyr99, Phe174, and Trp215. Typically, a fairly rigid linker group bridges these two interaction sites.[5]
Genetics
The human factor X gene is located on chromosome 13 (13q34).
Role in disease
Inborn deficiency of factor X is very rare (1:1,000,000), and may present with
Deficiency of vitamin K or antagonism by warfarin (or similar medication) leads to the production of an inactive factor X. In warfarin therapy, this is desirable to prevent thrombosis. As of late 2007, four out of five emerging anti-coagulation therapeutics targeted this enzyme.[6]
Inhibiting Factor Xa would offer an alternate method for anticoagulation.
Polymorphisms in Factor X have been associated with an increased prevalence in bacterial infections, suggesting a possible role directly regulating the immune response to bacterial pathogens.[7]
Therapeutic use
Factor X is part of fresh frozen plasma and the prothrombinase complex. There are two commercially available Factor X concentrates: "Factor X P Behring" manufactured by CSL Behring,[8] and high purity Factor X Coagadex produced by Bio Products Laboratory and approved for use in the United States by the FDA in October 2015, and in the EU in March 2016, after earlier acceptance by CHMP and COMP.[9][10][11][12]
Kcentra, manufactured by CSL Behring, is a concentrate containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S.[13]
Use in biochemistry
The factor Xa protease can be used in biochemistry to cleave off protein tags that improve expression or purification of a protein of interest. Its preferred cleavage site (after the arginine in the sequence Ile-Glu/Asp-Gly-Arg, IEGR or IDGR) can easily be engineered between a tag sequence and the protein of interest. After expression and purification, the tag is then proteolytically removed by factor Xa.
Factor Xa
Factor Xa is the activated form of the
Traditional models of coagulation developed in the 1960s envisaged two separate cascades, the extrinsic
A new model, the cell-based model of anticoagulation appears to explain more fully the steps in coagulation. This model has three stages: 1) initiation of coagulation on TF-bearing cells, 2) amplification of the procoagulant signal by thrombin generated on the TF-bearing cell and 3) propagation of thrombin generation on the platelet surface. Factor Xa plays a key role in all three of these stages.[14]
In stage 1,
In stage 2, the amplification stage, if enough thrombin has been generated, then activation of platelets and platelet-associated cofactors occurs.
In stage 3, thrombin generation,
Factor Xa also plays a role in other biological processes that are not directly related to coagulation, like wound healing, tissue remodelling, inflammation, angiogenesis and atherosclerosis.
Inhibition of the synthesis or activity of Factor X is the mechanism of action for many anticoagulants in use today. Warfarin, a synthetic derivative of
Heparin (unfractionated heparin) and its derivatives
Recently a new series of specific, direct acting inhibitors of Factor Xa has been developed. These include the drugs rivaroxaban, apixaban, betrixaban, LY517717, darexaban (YM150), edoxaban and 813893. These agents have several theoretical advantages over current therapy. They may be given orally. They have rapid onset of action. And they may be more effective against Factor Xa in that they inhibit both free Factor Xa and Factor Xa in the prothrombinase complex.[16]
History
American and British scientists described deficiency of factor X independently in 1953 and 1956, respectively. As with some other coagulation factors, the factor was initially named after these patients, a Mr Rufus Stuart (1921) and a Miss Audrey Prower (1934). At that time, those investigators could not know that the human genetic defect they had identified would be found in the previously characterized enzyme called thrombokinase.
Thrombokinase was the name coined by Paul Morawitz in 1904 to describe the substance that converted prothrombin to thrombin and caused blood to clot.[17] That name embodied an important new concept in understanding blood coagulation – that an enzyme was critically important in the activation of prothrombin. Morawitz believed that his enzyme came from cells such as platelets yet, in keeping with the state of knowledge about enzymes at that time, he had no clear idea about the chemical nature of his thrombokinase or its mechanism of action. Those uncertainties led to decades during which the terms thrombokinase and thromboplastin were both used to describe the activator of prothrombin and led to controversy about its chemical nature and origin.[18]
In 1947, J Haskell Milstone isolated a proenzyme from bovine plasma which, when activated, converted prothrombin to thrombin. Following Morawitz’s designation, he called it prothrombokinase [19] and by 1951 had purified the active enzyme, thrombokinase. Over the next several years he showed that thrombokinase was a proteolytic enzyme that, by itself, could activate prothrombin. Its activity was greatly enhanced by addition of calcium, other serum factors, and tissue extracts,[20] which represented the thromboplastins that promoted the conversion of prothrombin to thrombin by their interaction with thrombokinase. In 1964 Milstone summarized his work and that of others: “There are many chemical reactions which are so slow that they would not be of physiological use if they were not accelerated by enzymes. We are now confronted with a reaction, catalyzed by an enzyme, which is still too slow unless aided by accessory factors.” [21]
Interactions
Factor X has been shown to
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000126218 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031444 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Presentation on Direct Factor Xa Inhibitors". Archived from the original on 2016-03-03. Retrieved 2010-04-08.
- ^ Ron Winslow, Avery Johnson (2007-12-10). "Race Is on for the Next Blood Thinner". The Wall Street Journal. p. A12. Archived from the original on 2016-03-10. Retrieved 2008-01-06.
The flurry of interest reflects increasing understanding of what doctors call the coagulation cascade... Four new blood thinners target an enzyme called factor Xa, one of several enzymes that play an important role in the cascade.
- PMID 30782860.
- ^ Mark Brooker (2008): "Registry of Clotting Factor Concentrates". Eighth Edition, 2008, World Federation of Hemophilia
- ^ "FDA approves first Factor X concentrate to treat patients with rare hereditary bleeding disorder" (Press release). US FDA. October 20, 2015. Archived from the original on October 21, 2015. Retrieved October 21, 2015.
Until today's orphan drug approval, no specific coagulation factor replacement therapy was available for patients with hereditary Factor X deficiency.
- ^ "Coagadex". U.S. Food and Drug Administration. 28 June 2017. Archived from the original on 22 July 2017. Retrieved 2 April 2020.
{{cite web}}
: CS1 maint: unfit URL (link) - ^ "Coagadex". U.S. Food and Drug Administration. 21 September 2018. Archived from the original on 17 December 2019. Retrieved 2 April 2020.
- ^ "Coagadex EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 30 December 2019. Retrieved 21 April 2020.
- ^ "Kcentra- prothrombin, coagulation factor vii human, coagulation factor ix human, coagulation factor x human, protein c, protein s human, and water kit". DailyMed. 22 October 2018. Archived from the original on 25 March 2021. Retrieved 21 April 2020.
- PMID 17258114.
- ISBN 978-1-4511-1805-6.
- S2CID 2998452.
- ^ Morawitz P. "Beitrage zur Kenntnis der Blutgerinnung". Deutsches Archiv für Klinische Medizin. 79: 432–442.
- PMID 13012730.
- S2CID 35643683.
- S2CID 231682954.
- PMID 14080818.
- PMID 3422166.
External links
- The MEROPS online database for peptidases and their inhibitors: S01.216 Archived 2020-05-29 at the Wayback Machine
- med/3495 at eMedicine
- Factor X deficiency
Further reading
- Cooper DN, Millar DS, Wacey A, Pemberton S, Tuddenham EG (July 1997). "Inherited factor X deficiency: molecular genetics and pathophysiology". Thrombosis and Haemostasis. 78 (1): 161–72. S2CID 27129058.
- Hassan HJ, Leonardi A, Chelucci C, Mattia G, Macioce G, Guerriero R, Russo G, Mannucci PM, Peschle C (September 1990). "Blood coagulation factors in human embryonic-fetal development: preferential expression of the FVII/tissue factor pathway". Blood. 76 (6): 1158–64. PMID 1698100.
- Messier TL, Pittman DD, Long GL, Kaufman RJ, Church WR (March 1991). "Cloning and expression in COS-1 cells of a full-length cDNA encoding human coagulation factor X". Gene. 99 (2): 291–4. PMID 1902434.
- Krishnaswamy S (March 1990). "Prothrombinase complex assembly. Contributions of protein-protein and protein-membrane interactions toward complex formation". The Journal of Biological Chemistry. 265 (7): 3708–18. PMID 2303476.
- España F, Berrettini M, Griffin JH (August 1989). "Purification and characterization of plasma protein C inhibitor". Thrombosis Research. 55 (3): 369–84. PMID 2551064.
- Fung MR, Hay CW, MacGillivray RT (June 1985). "Characterization of an almost full-length cDNA coding for human blood coagulation factor X". Proceedings of the National Academy of Sciences of the United States of America. 82 (11): 3591–5. PMID 2582420.
- Jagadeeswaran P, Reddy SV, Rao KJ, Hamsabhushanam K, Lyman G (December 1989). "Cloning and characterization of the 5' end (exon 1) of the gene encoding human factor X". Gene. 84 (2): 517–9. PMID 2612918.
- Reddy SV, Zhou ZQ, Rao KJ, Scott JP, Watzke H, High KA, Jagadeeswaran P (October 1989). "Molecular characterization of human factor XSan Antonio". Blood. 74 (5): 1486–90. PMID 2790181.
- Kaul RK, Hildebrand B, Roberts S, Jagadeeswaran P (1986). "Isolation and characterization of human blood-coagulation factor X cDNA". Gene. 41 (2–3): 311–4. PMID 3011603.
- Broze GJ, Warren LA, Novotny WF, Higuchi DA, Girard JJ, Miletich JP (February 1988). "The lipoprotein-associated coagulation inhibitor that inhibits the factor VII-tissue factor complex also inhibits factor Xa: insight into its possible mechanism of action". Blood. 71 (2): 335–43. PMID 3422166.
- Gilgenkrantz S, Briquel ME, André E, Alexandre P, Jalbert P, Le Marec B, Pouzol P, Pommereuil M (1986). "Structural genes of coagulation factors VII and X located on 13q34". Annales de Génétique. 29 (1): 32–5. PMID 3487272.
- Leytus SP, Foster DC, Kurachi K, Davie EW (September 1986). "Gene for human factor X: a blood coagulation factor whose gene organization is essentially identical with that of factor IX and protein C". Biochemistry. 25 (18): 5098–102. PMID 3768336.
- Leytus SP, Chung DW, Kisiel W, Kurachi K, Davie EW (June 1984). "Characterization of a cDNA coding for human factor X". Proceedings of the National Academy of Sciences of the United States of America. 81 (12): 3699–702. PMID 6587384.
- McMullen BA, Fujikawa K, Kisiel W, Sasagawa T, Howald WN, Kwa EY, Weinstein B (June 1983). "Complete amino acid sequence of the light chain of human blood coagulation factor X: evidence for identification of residue 63 as beta-hydroxyaspartic acid". Biochemistry. 22 (12): 2875–84. PMID 6871167.
- Marchetti G, Castaman G, Pinotti M, Lunghi B, Di Iasio MG, Ruggieri M, Rodeghiero F, Bernardi F (August 1995). "Molecular bases of CRM+ factor X deficiency: a frequent mutation (Ser334Pro) in the catalytic domain and a substitution (Glu102Lys) in the second EGF-like domain". British Journal of Haematology. 90 (4): 910–5. S2CID 29324903.
- Morgenstern KA, Sprecher C, Holth L, Foster D, Grant FJ, Ching A, Kisiel W (March 1994). "Complementary DNA cloning and kinetic characterization of a novel intracellular serine proteinase inhibitor: mechanism of action with trypsin and factor Xa as model proteinases". Biochemistry. 33 (11): 3432–41. PMID 8136380.
- Heeb MJ, Rosing J, Bakker HM, Fernandez JA, Tans G, Griffin JH (March 1994). "Protein S binds to and inhibits factor Xa". Proceedings of the National Academy of Sciences of the United States of America. 91 (7): 2728–32. PMID 8146182.
- Inoue K, Morita T (November 1993). "Identification of O-linked oligosaccharide chains in the activation peptides of blood coagulation factor X. The role of the carbohydrate moieties in the activation of factor X". European Journal of Biochemistry. 218 (1): 153–63. PMID 8243461.
- Padmanabhan K, Padmanabhan KP, Tulinsky A, Park CH, Bode W, Huber R, Blankenship DT, Cardin AD, Kisiel W (August 1993). "Structure of human des(1-45) factor Xa at 2.2 A resolution". Journal of Molecular Biology. 232 (3): 947–66. PMID 8355279.
- Sinha U, Wolf DL (February 1993). "Carbohydrate residues modulate the activation of coagulation factor X". The Journal of Biological Chemistry. 268 (5): 3048–51. PMID 8428982.