Tissue Plasminogen Activator
Title: Tissue Plasminogen Activator
Additional Names: Fibrinokinase; extrinsic plasminogen activator; t-PA; TPA
Literature References: Serine protease catalyzing the enzymatic conversion of plasminogen to plasmin, q.q.v. Component of the mammalian fibrinolytic system; major physiological function is to provide plasmin that will dissolve fibrin clots. Shows high affinity and specificity for fibrin-bound plasminogen and weak affinity for circulating plasminogen. Plasminogen activation and fibrinolysis are therefore localized to the clot site, with limited systemic enzymatic activity. t-PA exists as 2 bioactive structural variants and can be isolated in either form depending on method of purification. Synthesized in vascular endothelial cells and released into circulation as the native single chain form, 527 amino acids, mol wt ~70,000. Converted to the two chain form by cleavage of Arg275-Ile276 bond to form two polypeptides connected by a disulfide bond. Discovery of in vitro plasminogen-activating ability in tissue fragments: T. Astrup, P. M. Permin, Nature 159, 681 (1947); H. J. Tagnon, M. L. Petermann, Proc. Soc. Exp. Biol. Med. 70, 359 (1949). Review of early literature: T. Astrup, Fed. Proc. 25, 42-51 (1966). Purifn from human tissue: D. C. Rijken et al., Biochim. Biophys. Acta 580, 140 (1979). Identification and purifn of 2 forms: P. Wallen et al., Biochim. Biophys. Acta 719, 318 (1982); and comparison of biological activity: D. C. Rijken et al., J. Biol. Chem. 257, 2920 (1982). Review of role in fibrinolytic system: D. Collen, Thromb. Haemostasis 43, 77-89 (1980); of pharmacology and clinical efficacy: S. D. Rogers et al., Pharmacotherapy 7, 111-121 (1987); D. Collen et al., Drugs 38, 346-388 (1989); of production by cell cultures: J. B. Griffiths, A. Electricwala, Adv. Biochem. Eng. Biotechnol. 34, 147-166 (1987).
Properties: Practically insol in solns of low ionic strength at neutral pH. Sol in 1.6M KSCN at neutral pH; 0.3M K-acetate at pH 4.2.
 
Derivative Type: Alteplase
CAS Registry Number: 105857-23-6
Additional Names: rt-PA
Trademarks: Actilyse (Boehringer, Ing.); Actiplas (Domp?; Activase (Genentech)
Literature References: Recombinant form of human t-PA; purified glycoprotein of 527 amino acids with a sequence identical to the naturally occurring form. Cloning and expression of cDNA: D. Pennica et al., Nature 301, 214 (1983). Review of pharmacokinetics: P. Tanswell et al., Arzneim.-Forsch. 41, 1310-1319 (1991). Comparative clinical trial in myocardial infarction: C. P. Cannon et al., J. Am. Coll. Cardiol. 24, 1602 (1994); in acute ischemic stroke: The Natl. Inst. Neurological Disorders and Stroke rt-PA Stroke Study Group, N. Engl. J. Med. 333, 1581 (1995).
 
Derivative Type: Duteplase
CAS Registry Number: 120608-46-0
CAS Name: 245-L-Methionine-plasminogen activator (human tissue-type 2-chain form protein moiety)
Trademarks: Solclot (Sumitomo)
Literature References: Two-chain form of recombinant human t-PA. Clinical pharmacokinetics: R. W. Koster et al., Clin. Pharmacol. Ther. 50, 267 (1991). Clinical efficacy in myocardial infarction: Z. G. Turi et al., Am. J. Cardiol. 71, 1009 (1993).
 
Therap-Cat: Thrombolytic.
Keywords: Thrombolytic.

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