Tissue plasminogen activator (abbreviated tPA or PLAT) is a protein involved in the breakdown of blood clots. Specifically, it is a serine protease (EC 3.4.21.68) found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Because it works on the clotting system, tPA is used in clinical medicine to treat only embolic or thrombolytic stroke. Use is contraindicated in hemorrhagic stroke and head trauma.
tPA may be manufactured using recombinant biotechnology techniques. tPA created this way may be referred to as recombinant tissue plasimogen activator or rtPA.
Function
A simplified illustration demonstrates clot breakdown (
fibrinolysis), with blue arrows denoting stimulation, and red arrows inhibition.
The classic role of tPA is in the clotting system. Specifically, tPA catalyzes the conversion of plasminogen into plasmin. It does so by cleaving the single-chained plasminogen into two chains. These two chains are linked by a disulfide bond and the resulting molecule is called plasmin.
Increased enzymatic activity causes hyperfibrinolysis, which manifests as excessive bleeding. Decreased activity leads to hypofibrinolysis which can result in thrombosis or embolism.
Tissue plasminogen activator also plays a role in cell migration and tissue remodeling.
Genetics
Tissue plasminogen activator is a protein encoded by the PLAT gene, which is located on chromosome 8. The primary transcript produced by this gene undergoes alternative splicing, producing three distinct messenger RNAs.
Clinical applications
tPA is used in diseases that feature blood clots, such as pulmonary embolism, myocardial infarction and stroke, in a medical treatment called thrombolysis. To be effective, tPA must be administered within the first three hours of the event to be given intravenously, or within six hours to be administered through an arterial catheter directly to the site of occlusion. The guideline in Ontario, Canada hospitals for ischemic strokes is that tPA must be given within 3 hours of the onset of symptoms.[citation needed] Because of this, only about 3% of patients qualify for this treatment.[citation needed] tPA appears to show benefit not only for large artery occlusions but also for lacunar strokes. Since tPA dissolves blood clots, there is risk of hemorrhage with its use.
Recently tPA has been used to dissolve thrombi associated with ischemic strokes and brain injury.[citation needed]
In addition, people with frostbite who were treated with tPA had fewer amputations than those who were not.[1]
In tPA overdose, aminocaproic acid works as an antidote.[2]
Interactions
Tissue plasminogen activator has been shown to interact with Fibrinogen alpha chain,[3][4] LRP1[5][6] and SERPINI1.[7]
See also
References
- ^ Bruen KJ, Ballard JR, Morris SE, Cochran A, Edelman LS, Saffle JR (June 2007). "Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy". Arch Surg 142 (6): 546–51; discussion 551–3. doi:10.1001/archsurg.142.6.546. PMID 17576891.
- ^ Quizlet > Toxins and Antidotes
- ^ Tsurupa, G; Medved L (Jan. 2001). "Identification and characterization of novel tPA- and plasminogen-binding sites within fibrin(ogen) alpha C-domains". Biochemistry (United States) 40 (3): 801-8. ISSN 0006-2960. PMID 11170397.
- ^ Ichinose, A; Takio K, Fujikawa K (Jul. 1986). "Localization of the binding site of tissue-type plasminogen activator to fibrin". J. Clin. Invest. (UNITED STATES) 78 (1): 163-9. doi:10.1172/JCI112546. ISSN 0021-9738. PMID 3088041.
- ^ Zhuo, M; Holtzman D M, Li Y, Osaka H, DeMaro J, Jacquin M, Bu G (Jan. 2000). "Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation". J. Neurosci. (UNITED STATES) 20 (2): 542-9. PMID 10632583.
- ^ Orth, K; Madison E L, Gething M J, Sambrook J F, Herz J (Aug. 1992). "Complexes of tissue-type plasminogen activator and its serpin inhibitor plasminogen-activator inhibitor type 1 are internalized by means of the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 89 (16): 7422-6. ISSN 0027-8424. PMID 1502153.
- ^ Parmar, Parmjeet K; Coates Leigh C, Pearson John F, Hill Rena M, Birch Nigel P (Sep. 2002). "Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells". J. Neurochem. (England) 82 (6): 1406-15. ISSN 0022-3042. PMID 12354288.
Further reading
- Rijken DC (1988). "Relationships between structure and function of tissue-type plasminogen activator". Klin. Wochenschr. 66 Suppl 12: 33–9. PMID 3126346.
- Bode W, Renatus M (1998). "Tissue-type plasminogen activator: variants and crystal/solution structures demarcate structural determinants of function". Curr. Opin. Struct. Biol. 7 (6): 865–72. doi:10.1016/S0959-440X(97)80159-5. PMID 9434908.
- Collen D, Billiau A, Edy J, De Somer P., Identification of the human plasma protein which inhibits fibrinolysis associated with malignant cells, Biochim Biophys Acta. 1977 Sep 29;499(2):194-201
- Anglés-Cano E, Rojas G (2003). "Apolipoprotein(a): structure-function relationship at the lysine-binding site and plasminogen activator cleavage site". Biol. Chem. 383 (1): 93–9. doi:10.1515/BC.2002.009. PMID 11928826.
- Ny T, Wahlberg P, Brändström IJ (2003). "Matrix remodeling in the ovary: regulation and functional role of the plasminogen activator and matrix metalloproteinase systems". Mol. Cell. Endocrinol. 187 (1-2): 29–38. doi:10.1016/S0303-7207(01)00711-0. PMID 11988309.
- Teesalu T, Kulla A, Asser T, et al. (2002). "Tissue plasminogen activator as a key effector in neurobiology and neuropathology". Biochem. Soc. Trans. 30 (2): 183–9. doi:10.1042/ (inactive 2008-06-21). PMID 12023848.
- Pang PT, Lu B (2005). "Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF". Ageing Res. Rev. 3 (4): 407–30. doi:10.1016/j.arr.2004.07.002. PMID 15541709.
- Sheehan JJ, Tsirka SE (2005). "Fibrin-modifying serine proteases thrombin, tPA, and plasmin in ischemic stroke: a review". Glia 50 (4): 340–50. doi:10.1002/glia.20150. PMID 15846799.
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1a5h: CATALYTIC DOMAIN OF HUMAN TWO-CHAIN TISSUE PLASMINOGEN ACTIVATOR COMPLEX OF A BIS-BENZAMIDINE
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1bda: CATALYTIC DOMAIN OF HUMAN SINGLE CHAIN TISSUE PLASMINOGEN ACTIVATOR IN COMPLEX WITH DANSYL-EGR-CMK (DANSYL-GLU-GLY-ARG CHLOROMETHYL KETONE)
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1pk2: SOLUTION STRUCTURE OF THE TISSUE-TYPE PLASMINOGEN ACTIVATOR KRINGLE 2 DOMAIN COMPLEXED TO 6-AMINOHEXANOIC ACID AN ANTIFIBRINOLYTIC DRUG
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1pml: KRINGLE-KRINGLE INTERACTIONS IN MULTIMER KRINGLE STRUCTURES
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1rtf: COMPLEX OF BENZAMIDINE WITH THE CATALYTIC DOMAIN OF HUMAN TWO CHAIN TISSUE PLASMINOGEN ACTIVATOR [(TC)-T-PA]
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1tpg: F1-G MODULE PAIR RESIDUES 1-91 (C83S) OF TISSUE-TYPE PLASMINOGEN ACTIVATOR (T-PA) (NMR, 298K, PH2.95, REPRESENTATIVE STRUCTURE)
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1tpk: CRYSTAL STRUCTURE OF THE KRINGLE-2 DOMAIN OF TISSUE PLASMINOGEN ACTIVATOR AT 2.4-ANGSTROMS RESOLUTION
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1tpm: SOLUTION STRUCTURE OF THE FIBRIN BINDING FINGER DOMAIN OF TISSUE-TYPE PLASMINOGEN ACTIVATOR DETERMINED BY 1H NUCLEAR MAGNETIC RESONANCE
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1tpn: SOLUTION STRUCTURE OF THE FIBRIN BINDING FINGER DOMAIN OF TISSUE-TYPE PLASMINOGEN ACTIVATOR DETERMINED BY 1H NUCLEAR MAGNETIC RESONANCE
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