If percutaneous coronary intervention (PCI) is not available within 90–120 minutes of first contact, streptokinase is recommended intravenously as soon as possible after the onset of a ST elevation myocardial infarction (STEMI). As streptokinase is a bacterial product, the body has the ability to build up an immunity to it. Therefore, it is recommended that this medication should not be used again after four days from the first administration, as it may not be as effective and can also cause an allergic reaction. For this reason, it is usually given only for a person's first heart attack. Further thrombotic events could be treated with tissue plasminogen activator (tPA). Overdose of streptokinase or tPA can be treated with aminocaproic acid.
Proposed counterion for Asp740 is Lys698 create salt-bridgeSubstrate Enzyme Mechanism Movie
Streptokinase belongs to a group of medications known as fibrinolytics, and complexes of streptokinase with human plasminogen can hydrolytically activate other unbound plasminogen by activating through bond cleavage to produce plasmin. There are three domains to streptokinase, denoted α (residues 1–150), β (residues 151–287), and γ (residues 288–414). Each domain binds plasminogen, although none can activate plasminogen independently.[10]
Plasmin is produced in the blood to break down fibrin, the major constituent of blood thrombi, thereby dissolving clots once they have fulfilled their purpose of stopping bleeding. Extra production of plasmin caused by streptokinase breaks down unwanted blood clots, for example, in the lungs (pulmonary embolism). The usual activation of plasminogen is by proteolysis of the Arg561—Val562 bond.[11] The amino group of Val562 then forms a salt-bridge with Asp740, which triggers a conformational change producing the active protease plasmin. When streptokinase is present, it binds to plasminogen to form a complex (streptokinase·plasminogen) that converts substrate plasminogen to plasmin. Residues 1–59 of streptokinase regulate its capacity to induce an active site in bound plasminogen by a nonproteolytic mechanism and to activate substrate plasminogen in a fibrin-independent manner. This complex subsequently rearranges to an active complex although the Arg561–Val562 bond remains intact. Therefore, another residue must substitute for the free amino group of Val562 and provide a counterion for Asp740 in this active complex.[12] Two candidates for this counterion have been suggested: Ile1 of streptokinase and Lys698 of plasminogen. Deletion of Ile1 of streptokinase markedly inhibits its capacity to induce an active site in plasminogen, which supports the hypothesis that establishment of a salt bridge between Ile1 of streptokinase and Asp740 of plasminogen is necessary for streptokinase to induce an active site in plasminogen by a nonproteolytic mechanism.[13] In contrast with the Ile1 substitutions, the Lys698 mutations also decreased the dissociation constant of the streptokinase complex by 15 to 50 fold. These observations suggest that Lys698 is involved in formation of the initial streptokinase·plasminogen complex.[14]
Biology
Streptokinase is naturally produced by Streptococci spp. bacteria, which use this enzyme to break up blood clots so that they can spread from the initial site of infection. It can also activate fibrin.[15]
It is similar, both in function and in structure, to staphylokinase (Sak) found in Staphylococcus aureus. Staphylokinase is considered a virulence factor,[16] although its presence after the establishment of infection actually decreases disease severity. Both enzymes are carried by phages.[17]
History
After many years of work along with his student Sol Sherry, William S. Tillett discovered streptokinase in 1933. Initially used in treatment of fibrinous pleural exudates, hemothorax and tuberculous meningitis, its role in acute myocardial infarction was serendipitous.[5]
Research
Streptokinase may find a use in helping to prevent postoperative adhesions, a common complication of surgery, especially abdominal surgery (appendectomy, gall stones, hysterectomy, etc.) One study using animal models (rats) found that when used with a PHBV membrane drug-delivery system, it was 90 percent effective in preventing adhesions.[18] However, it has not been shown to be effective in humans in a clinical trial.
Marketing
It is marketed in Chile as Streptase by Alpes Selection, under license of CSL Behring Germany.
Available in Vietnam under the name Mutose.
Available in Cuba, Venezuela, Ecuador and other Latin American countries under the trademark Heberkinasa, commercialized by Heber Biotech, Havana, Cuba.
Available in India under the name STPase by Cadila Pharmaceuticals, and Myokinase by Biocon Limited.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Rabijns A, De Bondt HL, De Ranter C (May 1997). "Three-dimensional structure of staphylokinase, a plasminogen activator with therapeutic potential". Nature Structural Biology. 4 (5): 357–360. doi:10.1038/nsb0597-357. PMID9145104. S2CID32914387.
^Loy JA, Lin X, Schenone M, Castellino FJ, Zhang XC, Tang J (December 2001). "Domain interactions between streptokinase and human plasminogen". Biochemistry. 40 (48): 14686–14695. doi:10.1021/bi011309d. PMID11724583.
^Wang S, Reed GL, Hedstrom L (April 1999). "Deletion of Ile1 changes the mechanism of streptokinase: evidence for the molecular sexuality hypothesis". Biochemistry. 38 (16): 5232–5240. doi:10.1021/bi981915h. PMID10213631.
^Wang X, Lin X, Loy JA, Tang J, Zhang XC (September 1998). "Crystal structure of the catalytic domain of human plasmin complexed with streptokinase". Science. 281 (5383): 1662–1665. doi:10.1126/science.281.5383.1662. PMID9733510.
^Wang H, Lottenberg R, Boyle MD (March 1995). "Analysis of the interaction of group A streptococci with fibrinogen, streptokinase and plasminogen". Microbial Pathogenesis. 18 (3): 153–166. doi:10.1016/S0882-4010(95)90013-6. PMID7565010.
^Bokarewa MI, Jin T, Tarkowski A (2006). "Staphylococcus aureus: Staphylokinase". The International Journal of Biochemistry & Cell Biology. 38 (4): 504–509. doi:10.1016/j.biocel.2005.07.005. PMID16111912.
^Yagmurlu A, Barlas M, Gursel I, Gokcora IH (2003). "Reduction of surgery-induced peritoneal adhesions by continuous release of streptokinase from a drug delivery system". European Surgical Research. 35 (1): 46–49. doi:10.1159/000067035. PMID12566787. S2CID37453555.
External links
"Streptokinase". Drug Information Portal. U.S. National Library of Medicine.
