It acts by cleavingprothrombin in two places (anArg-Thr and then anArg-Ile bond), which yields the activethrombin. This process is optimized when factor Xa is complexed with activatedco-factor V in theprothrombinase complex.
Factor Xa is inactivated byprotein Z-dependent protease inhibitor (ZPI), aserine protease inhibitor (serpin). The affinity of this protein for factor Xa is increased 1000-fold by the presence ofprotein Z, while it does not require protein Z for inactivation offactor XI. Defects in protein Z lead to increased factor Xa activity and a propensity for thrombosis. The half life of factor X is 40–45 hours.
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 residuesAsp189,Ser195, andTyr228, 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.[7]
Inborn deficiency of factor X is very rare (1:1,000,000), and may present withepistaxis (nosebleeds),hemarthrosis (bleeding into joints) and gastrointestinal blood loss. Apart from congenital deficiency, low factor X levels may occur occasionally in a number of disease states. For example, factor X deficiency may be seen inamyloidosis, where factor X is adsorbed to the amyloid fibrils in the vasculature.
Deficiency of vitamin K or antagonism bywarfarin (or similar medication) leads to the production of an inactive factor X. In warfarin therapy, this is desirable to preventthrombosis. As of late 2007, four out of five emerginganti-coagulation therapeutics targeted this enzyme.[8]
Inhibiting Factor Xa would offer an alternate method for anticoagulation.Direct Xa inhibitors are popular anticoagulants.
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.[9]
Factor X is part offresh frozen plasma and the prothrombinase complex. There are two commercially available Factor X concentrates: "Factor X P Behring" manufactured byCSL Behring,[10] and high purity Factor XCoagadex produced byBio 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.[11][12][13][14]
Kcentra, manufactured by CSL Behring, is a concentrate containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S.[15]
The factor Xa protease can be used in biochemistry to cleave offprotein 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.
Traditional models of coagulation developed in the 1960s envisaged two separate cascades, the extrinsic(tissue factor (TF)) pathway and the intrinsic pathway. These pathways converge to a common point, the formation of the Factor Xa/Va complex which together withcalcium and bound on aphospholipids surface, generatethrombin (Factor IIa) fromprothrombin (Factor II).
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 theplatelet surface. Factor Xa plays a key role in all three of these stages.[16]
In stage 1,Factor VII binds to thetransmembrane protein TF on the surface of cells and is converted to Factor VIIa. The result is a Factor VIIa/TF complex, which catalyzes the activation of Factor X andFactor IX. Factor Xa formed on the surface of the TF-bearing cell interacts withFactor Va to form the prothrombinase complex which generates small amounts of thrombin on the surface of TF-bearing cells.
In stage 2, the amplification stage, if enough thrombin has been generated, then activation of platelets and platelet-associatedcofactors occurs.
In stage 3, thrombin generation,Factor XIa activates free Factor IX on the surface of activated platelets. The activated Factor IXa withFactor VIIIa forms the"tenase" complex. This "tenase" complex activates more Factor X, which in turn forms new prothrombinase complexes with Factor Va. Factor Xa is the prime component of the prothrombinase complex which converts large amounts ofprothrombin—the "thrombin burst". Each molecule of Factor Xa can generate 1000 molecules of thrombin. This large burst of thrombin is responsible forfibrinpolymerization to form athrombus.
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 ofcoumarin, is the most widely used oral anticoagulant in the US. In some European countries, other coumarin derivatives (phenprocoumon andacenocoumarol) are used. These agents known asvitamin K antagonists (VKA), inhibit the vitamin K-dependent carboxylation of Factors II (prothrombin), VII, IX, X in the hepatocyte. This carboxylation after the translation is essential for the physiological activity.[17]
Heparin (unfractionated heparin) and its derivativeslow molecular weight heparin (LMWH) bind to aplasma cofactor,antithrombin (AT) to inactivate several coagulation factors IIa, Xa, XIa and XIIa. The affinity of unfractionated heparin and the various LMWHs for Factor Xa varies considerably. The efficacy of heparin-based anticoagulants increases as selectivity for Factor Xa increases. LMWH shows increased inactivation of Factor Xa compared to unfractionated heparin, and fondaparinux, an agent based on the critical pentasacharide sequence of heparin, shows more selectivity than LMWH. This inactivation of Factor Xa by heparins is termed "indirect" since it relies on the presence of AT and not a direct interaction with Factor Xa.
Recently a new series of specific, direct acting inhibitors of Factor Xa has been developed. These include the drugsrivaroxaban,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.[18]
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.[19] 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.[20]
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[21] 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,[22] 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.”[23]
^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. Retrieved2008-01-06.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.
^Hoffman M, Monroe DM (February 2007). "Coagulation 2006: a modern view of hemostasis".Hematology/Oncology Clinics of North America.21 (1):1–11.doi:10.1016/j.hoc.2006.11.004.PMID17258114.
^Golan DE (2012).Principles of Pharmacology The Pathophysiologic Basis of Drug Therapy. Philadelphia: Lippincott Williams & Wilkins. p. 387.ISBN978-1-4511-1805-6.
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):161–172.doi:10.1055/s-0038-1657520.PMID9198147.S2CID27129058.
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):291–294.doi:10.1016/0378-1119(91)90141-W.PMID1902434.
España F, Berrettini M, Griffin JH (August 1989). "Purification and characterization of plasma protein C inhibitor".Thrombosis Research.55 (3):369–384.doi:10.1016/0049-3848(89)90069-8.PMID2551064.
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):517–519.doi:10.1016/0378-1119(89)90529-5.PMID2612918.
Kaul RK, Hildebrand B, Roberts S, Jagadeeswaran P (1986). "Isolation and characterization of human blood-coagulation factor X cDNA".Gene.41 (2–3):311–314.doi:10.1016/0378-1119(86)90112-5.PMID3011603.
Gilgenkrantz S, Briquel ME, André E, Alexandre P, Jalbert P, Le Marec B, et al. (1986). "Structural genes of coagulation factors VII and X located on 13q34".Annales de Génétique.29 (1):32–35.PMID3487272.
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):5098–5102.doi:10.1021/bi00366a018.PMID3768336.
McMullen BA, Fujikawa K, Kisiel W, Sasagawa T, Howald WN, Kwa EY, et al. (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):2875–2884.doi:10.1021/bi00281a016.PMID6871167.
Marchetti G, Castaman G, Pinotti M, Lunghi B, Di Iasio MG, Ruggieri M, et al. (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):910–915.doi:10.1111/j.1365-2141.1995.tb05214.x.PMID7669671.S2CID29324903.
Morgenstern KA, Sprecher C, Holth L, Foster D, Grant FJ, Ching A, et al. (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):3432–3441.doi:10.1021/bi00177a037.PMID8136380.
Padmanabhan K, Padmanabhan KP, Tulinsky A, Park CH, Bode W, Huber R, et al. (August 1993). "Structure of human des(1-45) factor Xa at 2.2 A resolution".Journal of Molecular Biology.232 (3):947–966.doi:10.1006/jmbi.1993.1441.PMID8355279.
1c5m: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR
1ezq: CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR128515
1f0r: CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR208815
1f0s: Crystal Structure of Human Coagulation Factor XA Complexed with RPR208707
1fax: COAGULATION FACTOR XA INHIBITOR COMPLEX
1fjs: CRYSTAL STRUCTURE OF THE INHIBITOR ZK-807834 (CI-1031) COMPLEXED WITH FACTOR XA
1g2l: FACTOR XA INHIBITOR COMPLEX
1g2m: FACTOR XA INHIBITOR COMPLEX
1hcg: STRUCTURE OF HUMAN DES(1-45) FACTOR XA AT 2.2 ANGSTROMS RESOLUTION
1ioe: Human coagulation factor Xa in complex with M55532
1iqe: Human coagulation factor Xa in complex with M55590
1iqf: Human coagulation factor Xa in complex with M55165
1iqg: Human coagulation factor Xa in complex with M55159
1iqh: Human coagulation factor Xa in complex with M55143
1iqi: Human coagulation factor Xa in complex with M55125
1iqj: Human coagulation factor Xa in complex with M55124
1iqk: Human coagulation factor Xa in complex with M55113
1iql: Human coagulation factor Xa in complex with M54476
1iqm: Human coagulation factor Xa in complex with M54471
1iqn: Human coagulation factor Xa in complex with M55192
1ksn: Crystal Structure of Human Coagulation Factor XA Complexed with FXV673
1kye: Factor Xa in complex with (R)-2-(3-adamantan-1-yl-ureido)-3-(3-carbamimidoyl-phenyl)-N-phenethyl-propionamide
1lpg: CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 79.
1lpk: CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 125.
1lpz: CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 41.
1lqd: CRYSTAL STRUCTURE OF FXA IN COMPLEX WITH 45.
1mq5: Crystal Structure of 3-chloro-N-[4-chloro-2-[[(4-chlorophenyl)amino]carbonyl]phenyl]-4-[(4-methyl-1-piperazinyl)methyl]-2-thiophenecarboxamide Complexed with Human Factor Xa
1mq6: Crystal Structure of 3-chloro-N-[4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]-6-methoxyphenyl]-4-[[(4,5-dihydro-2-oxazolyl)methylamino]methyl]-2-thiophenecarboxamide Complexed with Human Factor Xa
1nfu: CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR132747
1nfw: CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR209685
1nfx: CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR208944
1nfy: CRYSTAL STRUCTURE OF HUMAN COAGULATION FACTOR XA COMPLEXED WITH RPR200095
1p0s: Crystal Structure of Blood Coagulation Factor Xa in Complex with Ecotin M84R
1v3x: Factor Xa in complex with the inhibitor 1-[6-methyl-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridin-2-yl] carbonyl-2-carbamoyl-4-(6-chloronaphth-2-ylsulphonyl)piperazine
1wu1: Factor Xa in complex with the inhibitor 4-[(5-chloroindol-2-yl)sulfonyl]-2-(2-methylpropyl)-1-[[5-(pyridin-4-yl) pyrimidin-2-yl]carbonyl]piperazine
1xka: FACTOR XA COMPLEXED WITH A SYNTHETIC INHIBITOR FX-2212A,(2S)-(3'-AMIDINO-3-BIPHENYLYL)-5-(4-PYRIDYLAMINO)PENTANOIC ACID
1xkb: FACTOR XA COMPLEXED WITH A SYNTHETIC INHIBITOR FX-2212A,(2S)-(3'-AMIDINO-3-BIPHENYLYL)-5-(4-PYRIDYLAMINO)PENTANOIC ACID
1z6e: Crystal Structure of Factor Xa complexed to Razaxaban
2bmg: CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH 50
2boh: CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND ""1""
2bok: FACTOR XA - CATION
2bq6: CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH 21
2bq7: CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH 43
2bqw: CRYSTAL STRUCTURE OF FACTOR XA IN COMPLEX WITH COMPOUND 45
2cji: CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2d1j: Factor Xa in complex with the inhibitor 2-[[4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl] carbonyl]thieno[3,2-b]pyridine n-oxide
2fzz: Factor Xa in complex with the inhibitor 1-(3-amino-1,2-benzisoxazol-5-yl)-6-(2'-(((3r)-3-hydroxy-1-pyrrolidinyl)methyl)-4-biphenylyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7h-pyrazolo[3,4-c]pyridin-7-one
2g00: Factor Xa in complex with the inhibitor 3-(6-(2'-((dimethylamino)methyl)-4-biphenylyl)-7-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)benzamide
2gd4: Crystal Structure of the Antithrombin-S195A Factor Xa-Pentasaccharide Complex
2h9e: Crystal Structure of FXa/selectide/NAPC2 ternary complex
2j2u: CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j34: CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j38: CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j4i: CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j94: CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2j95: CRYSTAL STRUCTURE OF A HUMAN FACTOR XA INHIBITOR COMPLEX
2uwl: SELECTIVE AND DUAL ACTION ORALLY ACTIVE INHIBITORS OF THROMBIN AND FACTOR XA
2uwo: SELECTIVE AND DUAL ACTION ORALLY ACTIVE INHIBITORS OF THROMBIN AND FACTOR XA
![1mq5: Crystal Structure of 3-chloro-N-[4-chloro-2-[[(4-chlorophenyl)amino]carbonyl]phenyl]-4-[(4-methyl-1-piperazinyl)methyl]-2-thiophenecarboxamide Complexed with Human Factor Xa](/mt/?noimg=&dark=on&url=https%3a%2f%2fwikipedia.org%2fwiki%2fFile%3aPDB_1mq5_EBI.jpg)
![1mq6: Crystal Structure of 3-chloro-N-[4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]-6-methoxyphenyl]-4-[[(4,5-dihydro-2-oxazolyl)methylamino]methyl]-2-thiophenecarboxamide Complexed with Human Factor Xa](/mt/?noimg=&dark=on&url=https%3a%2f%2fwikipedia.org%2fwiki%2fFile%3aPDB_1mq6_EBI.jpg)
![1v3x: Factor Xa in complex with the inhibitor 1-[6-methyl-4,5,6,7-tetrahydrothiazolo(5,4-c)pyridin-2-yl] carbonyl-2-carbamoyl-4-(6-chloronaphth-2-ylsulphonyl)piperazine](/mt/?noimg=&dark=on&url=https%3a%2f%2fwikipedia.org%2fwiki%2fFile%3aPDB_1v3x_EBI.jpg)
![1wu1: Factor Xa in complex with the inhibitor 4-[(5-chloroindol-2-yl)sulfonyl]-2-(2-methylpropyl)-1-[[5-(pyridin-4-yl) pyrimidin-2-yl]carbonyl]piperazine](/mt/?noimg=&dark=on&url=https%3a%2f%2fwikipedia.org%2fwiki%2fFile%3aPDB_1wu1_EBI.jpg)
![2d1j: Factor Xa in complex with the inhibitor 2-[[4-[(5-chloroindol-2-yl)sulfonyl]piperazin-1-yl] carbonyl]thieno[3,2-b]pyridine n-oxide](/mt/?noimg=&dark=on&url=https%3a%2f%2fwikipedia.org%2fwiki%2fFile%3aPDB_2d1j_EBI.jpg)
![2fzz: Factor Xa in complex with the inhibitor 1-(3-amino-1,2-benzisoxazol-5-yl)-6-(2'-(((3r)-3-hydroxy-1-pyrrolidinyl)methyl)-4-biphenylyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydro-7h-pyrazolo[3,4-c]pyridin-7-one](/mt/?noimg=&dark=on&url=https%3a%2f%2fwikipedia.org%2fwiki%2fFile%3aPDB_2fzz_EBI.jpg)
![2g00: Factor Xa in complex with the inhibitor 3-(6-(2'-((dimethylamino)methyl)-4-biphenylyl)-7-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl)benzamide](/mt/?noimg=&dark=on&url=https%3a%2f%2fwikipedia.org%2fwiki%2fFile%3aPDB_2g00_EBI.jpg)
