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Role of thrombin in the blood coagulation cascade

Thrombin (EC 3.4.21.5, fibrinogenase, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, blood-coagulation factor IIa, factor IIa, E thrombin, beta-thrombin, gamma-thrombin) is a serine protease that, in humans, is encoded by the F2 gene.^[2]^[3] Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the coagulation cascade, the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

History

After the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.^[4]

Physiology

Synthesis

Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is co-translationally modified in a vitamin K-dependent reaction that converts ten glutamic acids on prothrombin to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.

In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life.^[5]

Mechanism of action

In the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa.

Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Thrombin interacts with thrombomodulin.^[6]^[7]

As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet.

Negative feedback

Thrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. Thrombin is also inactivated by antithrombin, a serine protease inhibitor.

Protein

Anchoring of bovine prothrombin to the membrane through its Gla domain.^[8]

The molecular weight of prothrombin is approximately 72,000 Da. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36,000 Da. Structurally, it is a member of the large PA clan of proteases.

Gene

The thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12).^[2]

There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency,^[9] which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.^[10]

Prothrombin G20210A is not usually accompanied by other factor mutations (i.e., the most common is factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), and is not related to gender or blood type. Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i.e., Crohn's disease or ulcerative colitis) and prothrombin G20210A or factor V Leiden mutation have been contradicted by research.^[11]

Role in disease

Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant also known as (antiphospholipid syndrome). Hyperprothrombinemia can be caused by the G20210A mutation.

Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke).

Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis.^[12]^[13]^[14]

Thrombin is implicated in the physiology of blood clots. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated iron oxide attached to "reporter chemicals". When a peptide binds to a thrombin molecule, the report is released and appears in the urine where it can be detected. Human testing has not been conducted.^[15]

Applications

Research tool

Due to its high proteolytic specificity, thrombin is a valuable biochemical tool. The thrombin cleavage site (Leu-Val-Pro-Arg-Gly-Ser) is commonly included in linker regions of recombinant fusion protein constructs. Following purification of the fusion protein, thrombin can be used to selectively cleave between the Arginine and Glycine residues of the cleavage site, effectively removing the purification tag from the protein of interest with a high degree of specificity.

Medicine and surgery

Prothrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Indications include intractable bleeding due to warfarin.

Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site.

Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding.^[16]^[17]^[18]

Food production

Thrombin is sold under the brand name Fibrimex for use as a binding agent for meat. The thrombin in Fibrimex derives from porcine or bovine blood.^[19] According to the manufacturer it can be used to produce new kinds of mixed meats (for example combining beef and fish seamlessly). The manufacturer also states that it can be used to combine whole muscle meat, form and portion these thus cutting down on production costs without a loss in quality.^[20]

General secretary Jan Bertoft of Swedish Consumers' Association has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat"^[19]

References

^ PDB: 2C93; Howard N, Abell C, Blakemore W, Chessari G, Congreve M, Howard S, Jhoti H, Murray CW, Seavers LC, van Montfort RL (February 2006). "Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors". J. Med. Chem. 49 (4): 1346–55. doi:10.1021/jm050850v. PMID 16480269.
^ ^a ^b Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL (May 1987). "Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively". Somat. Cell Mol. Genet. 13 (3): 285–92. doi:10.1007/BF01535211. PMID 3474786.
^ Degen SJ, Davie EW (September 1987). "Nucleotide sequence of the gene for human prothrombin". Biochemistry 26 (19): 6165–77. doi:10.1021/bi00393a033. PMID 2825773.
^ Schmidt A (1872). "Neue Untersuchungen ueber die Fasserstoffesgerinnung". Pflüger's Archiv für die gesamte Physiologie 6: 413–538. doi:10.1007/BF01612263.
^ Andrew M, Paes B, et al. (1987). "Development of the human coagulation system in the full-term infant". Blood 70 (1): 165–172. PMID 3593964.
^ Bajzar L, Morser J, Nesheim M (July 1996). "TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex". J. Biol. Chem. 271 (28): 16603–8. doi:10.1074/jbc.271.28.16603. PMID 8663147.
^ Jakubowski HV, Owen WG (July 1989). "Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin". J. Biol. Chem. 264 (19): 11117–21. PMID 2544585.
^ PDB: 1nl2; Huang M, Rigby AC, Morelli X, Grant MA, Huang G, Furie B, Seaton B, Furie BC (September 2003). "Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins". Nat. Struct. Biol. 10 (9): 751–6. doi:10.1038/nsb971. PMID 12923575.
^ Degen SJ, McDowell SA, Sparks LM, Scharrer I (February 1995). "Prothrombin Frankfurt: a dysfunctional prothrombin characterized by substitution of Glu-466 by Ala". Thromb. Haemost. 73 (2): 203–9. PMID 7792730.
^ Varga EA, Moll S (July 2004). "Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation)". Circulation 110 (3): e15–8. doi:10.1161/01.CIR.0000135582.53444.87. PMID 15262854.
^ Bernstein CN, Sargent M, et al. (2007). "Mutations in clotting factors and inflammatory bowel disease". Am. J. Gastroenterol. 102 (2): 338–343. doi:10.1111/j.1572-0241.2006.00974.x. PMID 17156138.
^ Borissoff JI, Spronk HM, Heeneman S, ten Cate H (June 2009). "Is thrombin a key player in the 'coagulation-atherogenesis' maze?". Cardiovasc. Res. 82 (3): 392–403. doi:10.1093/cvr/cvp066. PMID 19228706.
^ Borissoff JI, Heeneman S, Kilinç E, Kassák P, Van Oerle R, Winckers K, Govers-Riemslag JW, Hamulyák K, Hackeng TM, Daemen MJ, ten Cate H, Spronk HM (August 2010). "Early atherosclerosis exhibits an enhanced procoagulant state". Circulation 122 (8): 821–30. doi:10.1161/CIRCULATIONAHA.109.907121. PMID 20697022.
^ Borissoff JI, Spronk HM, ten Cate H (May 2011). "The hemostatic system as a modulator of atherosclerosis". N. Engl. J. Med. 364 (18): 1746–60. doi:10.1056/NEJMra1011670. PMID 21542745.
^ Economist (2013-11-05). "Nanomedicine: Particle physiology". The Economist. Retrieved 2013-12-15.
^ Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL, Reynolds TC, Murphy A, Weaver FA (August 2007). "A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis". J. Am. Coll. Surg. 205 (2): 256–65. doi:10.1016/j.jamcollsurg.2007.03.020. PMID 17660072.
^ Singla NK, Ballard JL, Moneta G, Randleman CD, Renkens KL, Alexander WA (July 2009). "A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis". J. Am. Coll. Surg. 209 (1): 68–74. doi:10.1016/j.jamcollsurg.2009.03.016. PMID 19651065.
^ Greenhalgh DG, Gamelli RL, Collins J, Sood R, Mozingo DW, Gray TE, Alexander WA (2009). "Recombinant thrombin: safety and immunogenicity in burn wound excision and grafting". J Burn Care Res 30 (3): 371–9. doi:10.1097/BCR.0b013e3181a28979. PMID 19349898.
^ ^a ^b "Sverige röstade ja till köttklister" [Sweden voted in favor of the meat paste] (in Swedish). Dagens Nyheter. 2010-02-09. Retrieved 2010-10-17.
^ "Welcome to Fibrimex". Fibrimex website. FX Technology. Retrieved 2010-10-17.

External links

The MEROPS online database for peptidases and their inhibitors: S01.217
GeneReviews/NCBI/NIH/UW entry on Prothrombin Thrombophilia
Anti-coagulation & proteases on YouTube by The Proteolysis Map-animation
[3] PMAP: The Proteolysis Map/Thrombin
Thrombin: RCSB PDB Molecule of the Month

Molecular and Cellular Biology portal

English Journal

HETEROLOGOUS EXPRESSION AND PURIFICATION OF DERMASEPTIN S4 FUSION IN Escherichia coli AND RECOVERY OF BIOLOGICAL ACTIVITY.

Song D, Chen Y, Li X, Zhu M, Gu Q.Author information a Key Laboratory for Cell and Gene Engineering of Zhejiang Province , College of Life Sciences, Zhejiang University , Hangzhou , China.AbstractHeterologous expression of dermaseptin S4 (DS4), which has cytolytic activity in vitro against a broad spectrum of pathogenic microorganisms, was examined in Escherichia coli. The plasmid pGEX-4T-1, encoding DS4 fused with glutathione S-transferase (GST), was constructed and cloned into the E. coli strain BL21 (DE3). The fusion protein was overexpressed in this strain after induction with isopropyl-beta-D-thiogalactopyranoside (IPTG) and purified to homogeneity using GST affinity chromatography. To recover biologically active DS4, the purified fusion protein was cleaved using thrombin protease; the liberated DS4 was shown to be bactericidally active against an indicator strain. Since it is less expensive to obtain such a peptide biologically, in this study, we report for the first time a method to express purify DS4 in E. coli using a GST fusion system.
Preparative biochemistry & biotechnology.Prep Biochem Biotechnol.2014 Aug 18;44(6):598-607. doi: 10.1080/10826068.2013.835735.
Heterologous expression of dermaseptin S4 (DS4), which has cytolytic activity in vitro against a broad spectrum of pathogenic microorganisms, was examined in Escherichia coli. The plasmid pGEX-4T-1, encoding DS4 fused with glutathione S-transferase (GST), was constructed and cloned into the E. coli
PMID 24499364

Mediator-free triple-enzyme cascade electrocatalytic aptasensor with exonuclease-assisted target recycling and hybridization chain reaction amplification.

Peng K1, Zhao H1, Yuan Y2, Yuan R2, Wu X3.Author information 1Department of Kidney, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.2Key Laboratory on Luminescence and Real-Time Analysis, Ministry of Education, College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China.3Department of Kidney, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China. Electronic address: wuxfei@126.com.AbstractThe amplified sensitive detection of protein is essential to biomedical research as well as clinical diagnosis. Here, we developed an ultrasensitive mediator-free triple-enzyme cascade electrocatalytic aptasensor for thrombin detection on the basis of exonuclease-assisted target recycling and hybridization chain reaction (HCR) amplification strategy. The double strands constructed by the hybridization of thrombin binding aptamer (S1) with its complementary strand (S2) were firstly assembled on the electrode. Upon addition of target to the system, the S1 recognized thrombin and left off electrode to make space for assembly of hybrid-primer probe (H0). Then, the H0 triggered the HCR to form the multi-functional hemin/G-quadruplex DNAzyme nanowires. In the mediator-free triple-enzyme cascade electrocatalytic amplification system, the hemin/G-quadruplex DNAzyme nanowires here simultaneously played three roles: the redox probe, NADH oxidase and HRP-mimicking DNAzyme, respectively, which effectively avoided the fussy redox probe and enzyme labeling process, serving a useful alternative or supplement to conventional assays that typically suffer from complexity and poor sensitivity. Additionally, in order to improve the assembly amount of hemin/G-quadruplex DNAzyme nanowire, the exonuclease-assisted target recycling amplification was used for the continuous removal of S1. As a result, the proposed method can detect thrombin specifically with a detection limit as low as 20fM.
Biosensors & bioelectronics.Biosens Bioelectron.2014 May 15;55:366-71. doi: 10.1016/j.bios.2013.12.008. Epub 2013 Dec 10.
The amplified sensitive detection of protein is essential to biomedical research as well as clinical diagnosis. Here, we developed an ultrasensitive mediator-free triple-enzyme cascade electrocatalytic aptasensor for thrombin detection on the basis of exonuclease-assisted target recycling and hybrid
PMID 24419079

A novel electrochemiluminescence aptasensor based on in situ generated proline and matrix polyamidoamine dendrimers as coreactants for signal amplication.

Yuan Y1, Gan X2, Chai Y1, Yuan R3.Author information 1Education Ministry Key Laboratory on Luminescence and Real-Time Analysis, College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People's Rebublic of China.2Education Ministry Key Laboratory on Luminescence and Real-Time Analysis, College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People's Rebublic of China; College of Chemistry and Chemical Engineering, Yibin University, Sichuan 644000, China.3Education Ministry Key Laboratory on Luminescence and Real-Time Analysis, College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People's Rebublic of China. Electronic address: yuanruo@swu.edu.cn.AbstractHere, an ultrasensitive electrochemiluminescence (ECL) aptasensor using in situ generated proline and polyamidoamine (PAMAM) dendrimers as coreactant for bis(2,2'-bipyridyl)(5-amino-1,10-phenanthroline) ruthenium(II) (Ru) was successfully constructed for detection of thrombin (TB). Firstly, PAMAM combined with PtNPs was used as platform to assemble substantial Ru, prolidase (GPDA) and avidin labeled thrombin aptamer (avidin-TBA) to form PAMAM-PtNPs-Ru-GDPA-TBA bioconjugate. With the double aptamer-based sandwich assay, the bioconjugate was successfully modified on the electrode surface. The proposed aptasensor possessed three attractive advantages: PAMAM, as a tertiary amine substance, not only served as a platform to immobilize the PtNPs for further assembling prolidase (GPDA) and avidin-TBA, but also used as a coreactant of Ru to amplify the ECL signal. Furthermore, putting the coreactant and luminescence reagent together onto the electrode surface could effectively shorten the reaction time, improve the efficiency of electron transfer, and enhance the ECL signal. Lastly, the in situ generated coreactant proline for Ru catalyzed by GPDA could rapidly increase the concentration of proline around the electrode surface, which could also greatly amplify the ECL signal. With the several amplification factors mentioned above, the proposed ECL aptasensor showed a wide linear range from 0.01pmolL(-1) to 10nmolL(-1) with the detection limit of 5.0fmolL(-1). The experimental results also indicated that the aptasensor exhibited excellent selectivity, stability and reproducibility.
Biosensors & bioelectronics.Biosens Bioelectron.2014 May 15;55:313-7. doi: 10.1016/j.bios.2013.12.010. Epub 2013 Dec 11.
Here, an ultrasensitive electrochemiluminescence (ECL) aptasensor using in situ generated proline and polyamidoamine (PAMAM) dendrimers as coreactant for bis(2,2'-bipyridyl)(5-amino-1,10-phenanthroline) ruthenium(II) (Ru) was successfully constructed for detection of thrombin (TB). Firstly, PAMAM co
PMID 24412428

Japanese Journal

Characterization and Identification of Partial Amino Acid Sequence of a Novel Elastase Inhibitor, Asnidin from Aspergillus nidulans

Medical mycology journal = / 日本医真菌学会 [編] 54(3), 279-284, 2013-07-31
NAID 10031187562

Isolation and Characterization of a Novel Elastase Inhibitor, AFLEI from Aspergillus flavus

日本医真菌学会雑誌 = Japanese journal of medical mycology 47(3), 219-224, 2006-07-31
NAID 10018225147

Purification and Annino Acid Sequence of Brevilysin L6, a Non-Hemorrhagic Metalloprotease from Agkistrodon halys brevicaudus Venom.

The Journal of Biochemistry 125(1), 64-69, 1999
NAID 130003533588

Related Pictures

Pourquoi le sperme coagule dans l’eau ? : Pharma - Anti-Thrombus - Fibrinogenase The Failed Sexual Assault Investigation 暗夜時空 Fibrinogenolytic activity of rf-subDJ 毒 phospholipase a2 及 fibrinogenase beta fibrinogenase brevinase chain a beta Thrombine (fibrinogenase)

★リンクテーブル★

リンク元	「トロンビン」「フィブリノゲン分解酵素」

「トロンビン」

Coagulation factor II (thrombin)
	The structure of human thrombin in complex with the inhibitor hirudin.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1A2C, 1A3B, 1A3E, 1A46, 1A4W, 1A5G, 1A61, 1ABI, 1ABJ, 1AD8, 1AE8, 1AFE, 1AHT, 1AI8, 1AIX, 1AWF, 1AWH, 1AY6, 1B5G, 1B7X, 1BA8, 1BB0, 1BCU, 1BHX, 1BMM, 1BMN, 1BTH, 1C1U, 1C1V, 1C1W, 1C4U, 1C4V, 1C4Y, 1C5L, 1C5N, 1C5O, 1CA8, 1D3D, 1D3P, 1D3Q, 1D3T, 1D4P, 1D6W, 1D9I, 1DE7, 1DIT, 1DM4, 1DOJ, 1DWB, 1DWC, 1DWD, 1DWE, 1DX5, 1E0F, 1EB1, 1EOJ, 1EOL, 1FPC, 1FPH, 1G30, 1G32, 1G37, 1GHV, 1GHW, 1GHX, 1GHY, 1GJ4, 1GJ5, 1H8D, 1H8I, 1HAG, 1HAH, 1HAI, 1HAO, 1HAP, 1HBT, 1HDT, 1HGT, 1HLT, 1HUT, 1HXE, 1HXF, 1IHS, 1IHT, 1JMO, 1JOU, 1JWT, 1K21, 1K22, 1KTS, 1KTT, 1LHC, 1LHD, 1LHE, 1LHF, 1LHG, 1MH0, 1MU6, 1MU8, 1MUE, 1NM6, 1NO9, 1NRN, 1NRO, 1NRP, 1NRQ, 1NRR, 1NRS, 1NT1, 1NU7, 1NU9, 1NY2, 1NZQ, 1O0D, 1O2G, 1O5G, 1OOK, 1OYT, 1P8V, 1PPB, 1QBV, 1QHR, 1QJ1, 1QJ6, 1QJ7, 1QUR, 1RD3, 1RIW, 1SB1, 1SFQ, 1SG8, 1SGI, 1SHH, 1SL3, 1SR5, 1T4U, 1T4V, 1TA2, 1TA6, 1TB6, 1TBZ, 1THP, 1THR, 1THS, 1TMB, 1TMT, 1TMU, 1TOM, 1TQ0, 1TQ7, 1TWX, 1UMA, 1UVS, 1VR1, 1VZQ, 1W7G, 1WAY, 1WBG, 1XM1, 1XMN, 1YPE, 1YPG, 1YPJ, 1YPK, 1YPL, 1YPM, 1Z71, 1Z8I, 1Z8J, 1ZGI, 1ZGV, 1ZRB, 2A0Q, 2A2X, 2A45, 2AFQ, 2ANK, 2ANM, 2B5T, 2BDY, 2BVR, 2BVS, 2BVX, 2BXT, 2BXU, 2C8W, 2C8X, 2C8Y, 2C8Z, 2C90, 2C93, 2CF8, 2CF9, 2CN0, 2FEQ, 2FES, 2GDE, 2GP9, 2H9T, 2HGT, 2HNT, 2HPP, 2HPQ, 2HWL, 2JH0, 2JH5, 2JH6, 2OD3, 2PGB, 2PGQ, 2PKS, 2PW8, 2R2M, 2THF, 2UUF, 2UUJ, 2UUK, 2V3H, 2V3O, 2ZC9, 2ZDA, 2ZDV, 2ZF0, 2ZFF, 2ZFP, 2ZFQ, 2ZFR, 2ZG0, 2ZGB, 2ZGX, 2ZHE, 2ZHF, 2ZHQ, 2ZHW, 2ZI2, 2ZIQ, 2ZNK, 2ZO3, 3B23, 3B9F, 3BEF, 3BEI, 3BF6, 3BIU, 3BIV, 3BV9, 3C1K, 3C27, 3D49, 3DA9, 3DD2, 3DHK, 3DT0, 3DUX, 3E6P, 3EE0, 3EGK, 3EQ0, 3F68, 3GIC, 3GIS, 3HAT, 3HKJ, 3HTC, 3JZ1, 3JZ2, 3K65, 3LDX, 3LU9, 3NXP, 3P17, 3P6Z, 3P70, 3PMH, 3PO1, 3QDZ, 3QGN, 3QLP, 3QTO, 3QTV, 3QWC, 3QX5, 3R3G, 3RLW, 3RLY, 3RM0, 3RM2, 3RML, 3RMM, 3RMN, 3RMO, 3S7H, 3S7K, 3SHA, 3SHC, 3SI3, 3SI4, 3SQE, 3SQH, 3SV2, 3T5F, 3TU7, 3U69, 3U8O, 3U8R, 3U8T, 3U98, 3U9A, 3UTU, 3UWJ, 3VXE, 3VXF, 4AX9, 4AYV, 4AYY, 4AZ2, 4BAH, 4BAK, 4BAM, 4BAN, 4BAO, 4BAQ, 4BOH, 4CH2, 4CH8, 4DIH, 4DII, 4DT7, 4DY7, 4E05, 4E06, 4E7R, 4H6S, 4H6T, 4HFP, 4HTC, 4HZH, 4I7Y, 4LOY, 4LXB, 4LZ1, 4LZ4, 4MLF, 4N3L, 4NZE, 4NZQ, 4O03, 4RKJ, 4RKO, 4RN6, 4THN, 5GDS, 7KME, 8KME
Identifiers
Symbols	F2 ; PT; RPRGL2; THPH1
External IDs	OMIM: 176930 MGI: 88380 HomoloGene: 426 ChEMBL: 204 GeneCards: F2 Gene
EC number	3.4.21.5
Gene ontology
Molecular function	• serine-type endopeptidase activity; • receptor binding; • calcium ion binding; • protein binding; • growth factor activity; • thrombospondin receptor activity;
Cellular component	• extracellular region; • extracellular space; • endoplasmic reticulum lumen; • Golgi lumen; • cytosol; • plasma membrane; • extracellular matrix; • extracellular exosome; • blood microparticle;
Biological process	• positive regulation of protein phosphorylation; • proteolysis; • acute-phase response; • cell surface receptor signaling pathway; • multicellular organismal development; • blood coagulation; • blood coagulation, intrinsic pathway; • positive regulation of cell proliferation; • regulation of cell shape; • response to wounding; • regulation of gene expression; • negative regulation of platelet activation; • positive regulation of phosphatidylinositol 3-kinase signaling; • response to inactivity; • peptidyl-glutamic acid carboxylation; • platelet activation; • regulation of blood coagulation; • positive regulation of blood coagulation; • positive regulation of cell growth; • positive regulation of collagen biosynthetic process; • fibrinolysis; • post-translational protein modification; • cellular protein metabolic process; • negative regulation of proteolysis; • negative regulation of astrocyte differentiation; • leukocyte migration; • positive regulation of release of sequestered calcium ion into cytosol; • cytosolic calcium ion homeostasis; • negative regulation of fibrinolysis; • cellular response to mechanical stimulus; • positive regulation of phospholipase C-activating G-protein coupled receptor signaling pathway; • positive regulation of reactive oxygen species metabolic process;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

英: thrombin
同: 第IIa因子 factor IIa、F IIa、フィブリノゲン分解酵素 fibrinogenase
商: アナクト、アンスロビン、タココンブ、タコシール、ノイアート、ノンスロン、ベリプラストP、ボルヒール
関: 血液凝固因子、Thrombinar, Thrombogen, Thrombostat

「フィブリノゲン分解酵素」

　　[★]

英: fibrinogenase
関: トロンビン

[pmid16480269-1] PDB: 2C93; Howard N, Abell C, Blakemore W, Chessari G, Congreve M, Howard S, Jhoti H, Murray CW, Seavers LC, van Montfort RL (February 2006). "Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors". J. Med. Chem. 49 (4): 1346–55. doi:10.1021/jm050850v. PMID 16480269.

[pmid3474786-2] Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL (May 1987). "Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively". Somat. Cell Mol. Genet. 13 (3): 285–92. doi:10.1007/BF01535211. PMID 3474786.

[pmid2825773-3] Degen SJ, Davie EW (September 1987). "Nucleotide sequence of the gene for human prothrombin". Biochemistry 26 (19): 6165–77. doi:10.1021/bi00393a033. PMID 2825773.

[4] Schmidt A (1872). "Neue Untersuchungen ueber die Fasserstoffesgerinnung". Pflüger's Archiv für die gesamte Physiologie 6: 413–538. doi:10.1007/BF01612263.

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[dn-19] "Sverige röstade ja till köttklister" [Sweden voted in favor of the meat paste] (in Swedish). Dagens Nyheter. 2010-02-09. Retrieved 2010-10-17.

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