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PubMedDate not supplied

[Val709-Glu724 streptokinase binding site on plasminogen interacts with streptokinase sequence Thr361-Arg372 during plasminogen-streptokinase complex formation].

Localization of the human plasminogen binding site on the streptokinase of complementary Val709-Glu724 plasminogen being crucial one in providing for the plasminogen streptokinase complex activity has been investigated. Experiments were performed with streptokinase fragments and synthetic decapeptides, antiplasminogen monoclonal anti-body IV-1c and synthetic peptide corresponding to Val709-Gly718 sequence of human plasminogen. It was found that plasminogen sequence Val709-Glu724 interacted with Thr361-Arg372 sequence of strepto-kinase.

Binding Sites↗
PubMed1979

Characterization of highly purified native streptokinase and altered streptokinase after alkaline treatment.

Physical and chemical data are reported for highly purified native streptokinase (staphylokinase, EC 3.4.99.22) (Kabikinase) and streptokinase treated with an alkaline agent (altered streptokinase). The mol. wts. were similar and were determined to be 50 200 by sedimentation equilibrium methods, polyacrylamide gradient gel electrophoresis and sodium dodecylsulphate-polyacrylamide gel electrophoresis. The sedimentation coefficient so20,w of native and altered streptokinase was found to be 3.37 S. The frictional ratio and the absorptivity (A1%1cm) at 280 nm of native streptokinase was found to be 1.29 and 7.5, respectively. Native streptokinase showed essentially a single band in the isoelectro-focusing pattern (pI 5.2), while altered streptokinase showed at least two separate bands. Polyacrylamide gel electrophoresis in the presence of Triton X-100 exhibited one band for native streptokinase but altered streptokinase showd two bands. At pH 12 the biological and immunological activity of streptokinase was markedly decreased in a time-dependent reaction. The amino-terminal amino acid of the two streptokinase forms was isoleucine and the carboxyl-terminal amino acid of native streptokinase was tyrosine. Peptide analysis showed that some peptides in altered streptokinase exhibited higher mobility compared to native streptokinase. The data suggest that streptokinase undergoes a conformational change when incubated in alkaline media, but no simultaneous loss of peptides was observed.

Amino Acids↗
PubMed1995

Mapping the antigenic regions of streptokinase in humans before and after streptokinase therapy.

Streptokinase saves lives in patients suffering a myocardial infarction. However, because nearly all humans tested show antibodies against streptokinase, allergic reactions to streptokinase are common and may be severe. In this report we have analysed antibodies purified from normal blood donors and patients, before and after streptokinase therapy, to identify antigenic regions of the streptokinase molecule. Antibody to streptokinase was seen in all subjects, but there were 20-30-fold differences between individuals in the antibody titer. These individual differences in titer persisted after SK treatment, though the titer for all patients rose an average of 7-fold 1 week after streptokinase therapy. To identify the regions of streptokinase to which the antibody bound, we employed a panel of well-characterized murine monoclonal antibodies and recombinant streptokinase truncated fragments. Antibodies to three discrete regions of streptokinase could be detected in all patients. Antibodies to two other regions, at the amino terminal and carboxyl terminus of the molecule, were found in many but not in all patients. However, antibodies to a sixth region of streptokinase were uncommon and of very low titer. Interestingly, individuals receiving streptokinase tended to show the same pattern of immunoreactivity after treatment as they had prior to streptokinase. We conclude that although individual differences exist in the titers of streptokinase antibody, certain regions of streptokinase appear to be more antigenic or immunodominant.

Animals↗
PubMed1993

Streptokinase neutralisation titres up to 866 days after intravenous streptokinase for acute myocardial infarction.

OBJECTIVE: To follow the change in streptokinase neutralisation titres in a group of patients after treatment with streptokinase for acute myocardial infarction. DESIGN: Venous blood samples suitable for analysis were obtained up to 866 days after treatment with 1.5 million units of streptokinase in 189 patients. The ability of the patient's plasma to inhibit lysis of a thrombin clot by streptokinase was assessed. SETTING: A coronary care unit in a district general hospital. PATIENTS: A retrospective review of coronary care records and the district health authority computer showed that 329 patients who had received streptokinase were alive. All were invited for venepuncture and 220 (67%) attended. Satisfactory samples were obtained from 189 patients. RESULTS: Raised titres of antibody sufficient to neutralise a standard dose of 1.5 million units of streptokinase were found in 90% of patients. There was a fall in streptokinase neutralisation titre with increasing time after administration of streptokinase (r = -0.35, P < 0.0001) and though there was considerable variation among the group the neutralisation titre was higher than in the general population in all patients, even those who had received streptokinase at least two years previously. CONCLUSION: The ability of streptokinase to lyse a thrombin clot was appreciably inhibited in vitro by the plasma from patients who had received 1.5 million units of streptokinase. High streptokinase neutralisation titres persisted for a long time after the use of streptokinase as thrombolytic treatment for acute myocardial infarction. Readministration of streptokinase may not be efficacious for considerably longer than the one year currently advocated. Until the in vivo effects of streptokinase readministration are known a non-antigenic thrombolytic agent should be used instead.

Antibodies↗
PubMed1992

Streptokinase resistance: when might streptokinase administration be ineffective?

OBJECTIVE: (a) To develop an assay for streptokinase resistance. (b) To determine the prevalence of streptokinase resistance in patients presenting with acute myocardial infarction for the first time. (c) To determine the prevalence of streptokinase resistance in patients after exposure to streptokinase or streptococcal infection. DESIGN: Open, prospective. PATIENTS: 30 healthy volunteers. 40 patients admitted to the coronary care unit at Addenbrooke's Hospital with suspected acute myocardial infarction, 12 patients 12 months after streptokinase treatment, eight patients 24 months after streptokinase treatment, and sera from 12 patients with raised anti-streptolysin O (ASO) titres. METHODS: Three assays were used; a dilution neutralisation assay, an enzyme linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) anti-streptokinase antibodies, and an in vitro fibrin plate lysis assay. All measurements were performed on venous blood samples. RESULTS: Neutralisation and IgG antibody titres were positively correlated. Mean (SEM) antistreptokinase concentrations in the 30 controls were 87 (10) U/ml (neutralisation assay) and 28 (6.3) U/ml (ELISA). Corresponding concentrations in patients before streptokinase were 68 (6.1) U/ml and 18 (4.5) U/ml with a mean fibrin plate assay 117 (7.1)% that of controls. Resistance to streptokinase was detectable in one patient after 72 hours and in all patients by day 10. By day 10 concentrations were 4388 (919) U/ml, 773 (109) U/ml, and 17 (5.4)%. At both 12 and 24 months resistance was present in 75% of patients. Similarly 66% of high ASO titre sera showed resistance. The fibrin plate lysis assay detected significantly reduced streptokinase dependent fibrinolysis in vitro in the absence of raised total concentrations of antistreptokinase antibodies. CONCLUSIONS: The prevalence of streptokinase resistance in patients presenting with their first myocardial infarction is low. Resistance develops early after treatment and is still present in 75% of patients after 24 months. Retreatment with streptokinase is likely to be suboptimal even after 24 months. The fibrin plate lysis assay detects resistance in patients with normal concentrations of streptokinase antibodies. Streptococcal infection is associated with a high incidence of streptokinase resistance.

Antibodies↗
PubMed1996

Anti-streptokinase antibodies and streptokinase resistance in an Aboriginal population in northern Australia.

BACKGROUND: Thrombolytic treatment with streptokinase in acute myocardial infarction has proven to be safe and effective in Caucasian populations with relatively low levels of anti-streptokinase IgG and streptokinase resistance. Higher levels of antibodies, as seen in previous recipients of streptokinase therapy, cause more adverse reactions and may result in lower efficacy. AIMS: To examine the levels of anti-streptokinase IgG and streptokinase resistance in a population subjected to endemic streptococcal infections. METHODS AND RESULTS: Thirty Aboriginal adults from a remote community in Northern Australia with endemic streptococcal infections and 15 non-Aboriginal adults from an urban community without endemic infections participated in this study. Aboriginal adults exhibited levels of anti-streptokinase IgG and streptokinase resistance that, respectively, were almost 20 and 15 times greater than the values of non-Aboriginal adults. At least 23% of Aboriginal adults had sufficiently high levels of streptokinase resistance to neutralise a standard 1.5 million unit dose of streptokinase. CONCLUSIONS: Aboriginal adults from a remote community had dramatically elevated levels of anti-streptokinase IgG and in vitro streptokinase resistance. Prospective studies are needed to assess the clinical relevance of streptokinase resistance in populations from areas with endemic streptococcal infection.

Adult↗
PubMed1995

Identification of a plasminogen binding region in streptokinase that is necessary for the creation of a functional streptokinase-plasminogen activator complex.

Streptokinase is a plasminogen activator widely used to treat patients with myocardial infarction. However, streptokinase is not a protease, and must first bind and interact with plasminogen to form an enzymatic complex. By measuring the binding of recombinant streptokinase fragments to plasminogen, we have sought, first, to identify a plasminogen binding region in streptokinase and, second, to explore the relation between binding (via this region) and the generation of a functional streptokinase--plasminogen activator complex. Recombinant streptokinase bound in a saturable and specific manner to human Glu-plasminogen with a dissociation constant of 4.2 x 10(-10) M. Recombinant streptokinase fragments spanning amino acids 1-127 and 1-253 could not be shown to bind to Glu-plasminogen, whereas fragments spanning amino acids 1-352, 120-352, and 244-414 bound tightly to plasminogen and each fragment completely inhibited the binding of full-length streptokinase to plasminogen. Although these latter streptokinase fragments formed a complex with plasminogen, enzymatic assays indicated that none of them was capable of generating an active site. When the streptokinase region shared by these three fragments, spanning residues 244-352, was expressed, it also bound plasminogen and competitively inhibited the formation of a functional plasminogen activator complex by full-length streptokinase. Taken together, these data indicate that streptokinase binds to plasminogen with high affinity, that a primary binding region for plasminogen is located within amino acids 244-352, and that binding via this region is necessary for the generation of a functional plasminogen activator complex.

Base Sequence↗
PubMed2004

Inhibition of streptokinase-induced, antibody-mediated platelet aggregation with tirofiban after exposure to streptokinase or streptococcal infection.

STUDY OBJECTIVE: To evaluate the effect of tirofiban (a glycoprotein IIb-IIIa inhibitor) in preventing streptokinase-induced, antibody-mediated platelet aggregation after administration of streptokinase or development of a streptococcal infection. DESIGN: Prospective analysis. SETTING: Research center of a Canadian hospital. PARTICIPANTS: Forty-five healthy volunteers, 45 patients who had received streptokinase within the past 3 years, and 13 patients who had a severe streptococcal infection also within the past 3 years. INTERVENTION: Blood samples were drawn to measure the extent of inhibition of streptokinase-induced, antibody-mediated platelet activation and aggregation by tirofiban. MEASUREMENTS AND MAIN RESULTS: Platelet aggregation was measured by using a turbidimetric method. The extent of inhibition by tirofiban was measured by incubating tirofiban for 2 minutes before adding streptokinase 5000 U/ml. Also, tirofiban was added 2 minutes before adding adenosine 5'-diphosphate (ADP) 2 microM/L into the last tube as a comparison. Strepto-kinase-induced, antibody-mediated platelet aggregation was observed in 10 (22%) of the 45 patients treated with streptokinase, in 3 (23%) of the 13 patients with streptococcal infection, and in none of the 45 healthy volunteers. Tirofiban inhibited streptokinase-induced, antibody-mediated platelet aggregation by 89 +/- 14% (p<0.001). Similarly, ADP-induced platelet aggregation was inhibited by 92 +/- 6% (p<0.001) with tirofiban. CONCLUSION: Streptokinase-induced, antibody-mediated platelet aggregation occurred in 13 (22%) of 58 patients who received streptokinase or were exposed to a streptococcal infection in the past 3 years. Such patients may not benefit from streptokinase therapy. In these patients, tirofiban significantly decreased the extent of antistreptokinase antibody-mediated platelet aggregation. Hence, patients undergoing streptokinase therapy may benefit from tirofiban as adjunctive therapy.

Adult↗
PubMed1999

Streptokinase antibodies inhibit reperfusion during thrombolytic therapy with streptokinase in acute myocardial infarction.

OBJECTIVES: To evaluate the influence of pretreatment IgG against streptokinase on the outcome of streptokinase treatment in acute myocardial infarction. SETTING: Coronary care unit. DESIGN: From 88 patients admitted to the coronary care unit due to chest pain, blood samples were taken for determination of the pre-existing titre of antibodies against streptokinase. The patients were treated and monitored according to standard protocols. Fifty of the patients received thrombolytic therapy with streptokinase due to acute myocardial infarction and were monitored with continuous dynamic vectorcardiography, making possible the continuous analysis of ST- and QRS-vector changes and determination of the event of reperfusion. None of these 50 patients had been given streptokinase therapy previously. RESULTS: According to the vectorcardiographic criteria 21(42%) patients had signs of early (within 2 h) reperfusion after streptokinase therapy. These patients had lower pre-existing antibody titres than patients without signs of reperfusion (mean values 0.20 and 0.45 arbitrary units, P = 0.01). None of the patients with a titre higher than 0.50 arbitrary units (nine patients) had signs of early reperfusion. Of the 41 patients with a titre lower than 0.50 arbitrary units 52.5% had signs of early reperfusion. CONCLUSION: The present investigation indicates that pre-existing streptokinase antibodies play an important role in reperfusion failure during thrombolytic therapy with streptokinase in acute myocardial infarction. Therefore, the determination of streptokinase antibodies may differentiate between those patients who may benefit from streptokinase treatment and those who should be treated with some other regime.

Enzyme-Linked Immunosorbent Assay↗
PubMed1987

Electrocardiographic and enzymatic infarct size in a randomised study of intracoronary streptokinase and intravenous anisoylated plasminogen streptokinase activator complex in acute myocardial infarction.

The effect of thrombolytic therapy on ECG and enzymatic indices, including estimates of relative infarct size, was studied in 93 patients with acute myocardial infarction randomised to intracoronary streptokinase or intravenous anisoylated plasminogen streptokinase activator complex (APSAC) therapy within 6 hours of the onset of symptoms. 90 minutes after treatment, 49% (19/39) of the evaluable streptokinase patients and 44% (19/43) of the APSAC patients had reperfused (p = NS). The time from treatment to reperfusion was less in the streptokinase patients (30 +/- 18 minutes for streptokinase and 42 +/- 22 minutes for APSAC, p less than or equal to 0.02). Resolution of ST segment elevation, 90 minutes after treatment, was greater in the streptokinase patients (residual ST segment elevation 47 +/- 36% of initial value for streptokinase and 70 +/- 49% for APSAC, p less than or equal to 0.06) and in the patients reperfused by either agent (residual ST segment elevation 46 +/- 34% for reperfused and 68 +/- 52% for non-reperfused, p less than or equal to 0.10). ECG infarct size at discharge, determined by sum of Q waves and a 29-point QRS score, relative to the degree of initial ST segment elevation was similar in the streptokinase and APSAC patients, but smaller in reperfused than non-reperfused patients (p less than or equal to 0.01 for sigma Q). Peak serum creatine kinase and MB isoenzyme of creatine kinase levels were similar in the streptokinase and APSAC, and in reperfused and non-reperfused patients. Lower peak lactic acid dehydrogenase and especially lactic acid dehydrogenase isoenzyme values (by 16% and 22%, respectively) were observed in reperfused patients, but differences did not achieve significance. However, the time to peak enzyme levels was significantly shorter in the reperfused patients. Early intracoronary streptokinase and intravenous APSAC therapy have similar effects on ECG and enzymatic infarct size. Reperfusion by either agent, given at a mean of 3 hours 25 minutes, may reduce estimates of infarct size modestly.

Adult↗
PubMed1976

Isolation of a human plasmin-derived, functionally active, light (B) chain capable of forming with streptokinase an equimolar light (B) chain-streptokinase complex with plasminogen activator activity.

A functionally active human plasmin light (B) chain derivative, stabilized by the streptomyces plasmin inhibitor leupeptin, was isolated from a partially reduced and alkylated enzyme preparation by an affinity chromatography method with a L-lysine-substituted Sepharose column. This light (B) chain derivative was found to be relatively homogeneous by electrophoretic analysis in both an acrylamide gel/dodecyl sulfate system and on cellulose acetate. It possessed approximately 3% of the proteolytic activity (casein substrate) of the original enzyme, and it incorporated 0.09 mol of [3H]diisopropyl phosphorofluoridate per mol of protein. It contained 3.1 +/- 0.3 carboxymethylated cysteines per mol of protein and can be designated as a CmCys5-light (B) chain (CmCys)3. When this isolated light (B) chain derivative was mixed in equal molar amounts with streptokinase, the mixture developed both human and bovine plasminogen activator activities; the bovine activator activity was approximately 66% of the bovine activator activity of the equimolar human plasmin-streptokinase complex. Although this complex now incorporated 0.50 mol of [3H]diisopropyl phosphorofluoridate per mol of protein, its proteolytic activity, on a molar basis, was the same as the proteolytic activity of the isolated light (B) chain derivative. It was shown by electrophoretic analysis in both an acrylamide gel/epsilon-aminocaproic acid system and on cellulose acetate that the light (B) chain derivative and streptokinase forms an equimolar light (B) chain-streptokinase complex, indicating that the binding site for streptokinase is located on the light (B) chain of the enzyme. A functionally active equimolar light (B) chain-streptokinase complex was also isolated from a partially reduced and alkylated equimolar human plasmin-streptokinase complex by the affinity chromatography method. The plasminogen activator activities (human and bovine) of this light (B) chain-streptokinase complex were similar to those of the plasmin-streptokinase complex from which it was derived. Although this complex incorporated 0.70 mol of [3H]diisopropyl phosphorofluoridate per mol of protein, its proteolytic activity, on a molar basis, was only 14% of proteolytic activity of the plasmin-streptokinase complex.

Amino Acids↗
PubMed1976

Interaction of streptokinase with plasminogen. Isolation and characterization of a streptokinase degradation product.

When streptokinase is incubated with human or rabbit plasminogen, one event which occurs is a specific fragmentation of streptokinase. At least five major identifiable streptokinase fragments appear with time, and they possess molecular weights of approximately 40,000 (SK 1), 36,000 (SK 2), 31,000 (SK 3), 26,000 (SK 4), and 10,000 (SK 5) under denaturing conditions, as observed on calibrated sodium dodecyl sulfate-polyacrylamide gels, compared to native streptokinase of molecular weight 45,000. The amount of each of the fragments generated at given times of incubation of plasminogen and streptokinase depends upon the species of plasminogen employed. Utilizing rabbit plasminogen and streptokinase, the SK 4 fragment was purified. This fragment arises by proteolysis at both the NH2 and COOH regions of native streptokinase. However, when isolated utilizing dilute aqueous buffers, the SK 4 fragment contained a portion of the original NH2 terminus of native streptokinase noncovalently bound to the molecule (SK 4'). SK 4' is capable of activating human plasminogen to plasmin, albeit more slowly than native streptokinase. However, the SK 4'-human plasmin complex possess only very weak plasminogen-activating activity toward sheep plasminogen. Upon removal of the noncovalently bound small NH2-terminal peptide of native streptokinase from SK 4', SK 4 is formed. This particular fragment possesses practically no human plasminogen-activating activity and cannot be used as an activator of sheep plasminogen, even with added human plasminogen.

Amino Acid Sequence↗
PubMed1976

Kinetics of active center formation in dog plasminogin by streptokinase and activity of a modified streptokinase.

The rate of activation of dog plasminogen by excess streptokinase showed a significant delay as compared to the rate of activation with catalytic amounts of streptokinase. Studies of the reaction at high streptokinase levels with the active center reagent, p-nitrophenyl-p-guanidinobenzoate showed that only a fraction (13%) of the potential active centers were developed in a equimolar mixture of streptokinase and dog plasminogen in 15s and more than 10 min were required for the formation of 1 mol of active sites. In the first 15s, the yield of active sites could not be increased by increasing streptokinase 10-fold over the molar concentration of plasminogen, suggesting that active center development rather than complex formation was the rate-limiting step. The delayed reactivity seen in this system provides an interesting model for the study of conformationally induced active center formation. With catalytic amounts of streptokinase, the activation proceeded rapidly but reached a plateau, indicating the loss of activator activity in the reaction mixture. With successive additions of fresh streptokinase, complete activation was achieved. Polyacrylamide gel electorphoresis showed that a stable streptokinase-plasmin complex formed. However, in contrast to the human plasmin-steptokinase complex, a potent plasminogen activator in which streptokinase is found as a residue of 37,000 daltons, dog plasmin-streptokinase complex contained a residue of 25,700 daltons and the complex was inactive against canine and human plasminogen. The 25,700 fragment along, however, showed considerable activator activity when tested with human and dog plasminogens.

Animals↗
PubMed1996

An Angiographic Study of Intracoronary Streptokinase versus Intravenous Tissue Plasminogen Activator After Failed Coronary Thrombolysis with Intravenous Streptokinase.

Objective: The medical treatment of failed intravenous streptokinase in patients with acute transmural myocardial infarction using angiographic endpoints. Design: Prospective open angiographic comparison of intracoronary streptokinase with intravenous tissue plasminogen activator. Setting: Single center study in a tertiary institution. Subjects: Eighty-five patients with acute myocardial infarction within 4 hours after symptom onset. Treatment regimens: The subjects received 1.5 million U intravenous streptokinase. Coronary angiography within 48 hours (median 19 hours) showed infarct-related vessel patency in 65 patients (76%). In the catheterization laboratory the 20 patients (24%) with failed intravenous streptokinase received repeat thrombolysis immediately after angiography. The first 10 patients with failed intravenous streptokinase received intracoronary streptokinase at a dose of 4000 U/min in the occluded infarct-related artery for a maximum of 1 hour. The subsequent 10 pati ents received high-dose front-loaded intravenous tissue plasminogen activator (100 mg in 1 hour). Results: In none of the patients receiving repeat streptokinase was reperfusion obtained. In 6 of 10 (60%) of the patients receiving tissue plasminogen activator, reperfusion was seen within 60 minutes (p < 0.005 vs. intracoronary streptokinase). One patient (5%) died and two refused follow-up angiography. Seventeen (88%) patients underwent angiography 3 months later according to the protocol. Two patients showed a persistently reperfused infarct-related artery, three reoccluded, four spontaneously reperfused, and eight had a persistently occluded infarct-related artery. The left ventricular ejection fraction was slightly higher at 3 months, and there were no differences between the patients with open vessels (increase +7.7 +/- 5.8%) and those with persistently occluded vessels (increase +5.8 +/- 6.8%). Conclusions: Repeat thrombolysis after failed intravenous streptokinase ca n be achieved with front-loaded intravenous tissue plasminogen activator but not with intracoronary streptokinase. Although patient numbers are small and repeat thrombolysis was performed rather late, this study leads the way to affordable optimization of thrombolysis, which needs large-scale testing.

Journal Article↗
PubMed2000

Intraventricular streptokinase after intraventricular hemorrhage in newborn infants.

BACKGROUND: Hydrocephalus following intraventricular hemorrhage (IVH) is still one of the most serious complications of premature birth. Ventriculoperitoneal shunt surgery cannot be carried out early and permanent dependence on a shunt is associated with several serious complications. OBJECTIVES: To determine whether intraventricular streptokinase after intraventricular hemorrhage reduces the risk of permanent shunt dependence, neurodevelopmental disability or death in neonates at risk of, or actually developing, post-hemorrhagic hydrocephalus (PHH). This form of therapy is based on the hypothesis that multiple blood clots in the CSF are the initial cause of post-hemorrhagic ventricular dilatation and lysis of clots could reopen the pathways of circulation and re-absorption of CSF. SEARCH STRATEGY: Pediatric, Neurosurgical and General Medical Journals were handsearched from 1976, as well as the Medline database. Personal contacts were used. SELECTION CRITERIA: One randomised trial evaluated intraventricular streptokinase in infants developing post-hemorrhagic ventricular dilatation. DATA COLLECTION AND ANALYSIS: Details of patient selection, patient allocation and the interventions were extracted. The end-points examined were: ventriculoperitoneal shunt, death, meningitis, and secondary hemorrhage. MAIN RESULTS: When intraventricular streptokinse was compared with conservative management of post-hemorrhagic ventricular dilatation, the numbers of deaths and babies with shunt dependence were identical in both groups. No information on the effect of intraventricular streptokinase on disability is available. There is cause for concern about meningitis and secondary intraventricular hemorrhage but numbers are insufficient to quantify the risks. REVIEWER'S CONCLUSIONS: Intraventricular fibrinolytic therapy with streptokinase, given when post-hemorrhagic ventricular dilatation is established, cannot be recommended for neonates following IVH. A conservative approach with CSF drainage applied only to symptomatic raised intracranial pressure seems appropriate.

Cerebral Hemorrhage↗
PubMed1996

ATP-regulated activity of the plasmin-streptokinase complex: a novel mechanism involving phosphorylation of streptokinase.

Streptokinase, an extracellular protein produced by Streptococci, is capable of activating the human fibrinolytic zymogen plasminogen. The rate of amidolytic activity of the plasminogen-streptokinase complex is greatly diminished by micromolar concentrations of ATP and heparin oligosaccharides. In addition, the plasminogen activator activity of the plasminogen-streptokinase complex is also inhibited by these effectors. ATP and heparin oligosaccharides show structural similarity, suggesting that the inhibition is caused by binding of these molecules to a common newly formed binding pocket in streptokinase, which appears after interaction with plasminogen. Addition of the bivalent cations Ca2+ and Mg2+ reverses the inhibition caused by ATP and heparin. In the presence of ATP and bivalent cations, the complex between plasminogen and streptokinase develops an autophosphorylating activity whose target is the sequence LTSRPAHG in the 4.5 kDa streptokinase N-terminal peptide, which is an early autolysis peptide. This streptokinase N-terminal peptide, which is essential for streptokinase activating activity, may serve, once phosphorylated, in mechanisms related to the pathogenicity of Streptococci. These studies suggest a critical role for plasminogen in regulating the activity of the streptokinase molecule.

Adenosine Triphosphate↗
PubMed1982

Catabolic pathways for streptokinase, plasmin, and streptokinase activator complex in mice. In vivo reaction of plasminogen activator with alpha 2-macroglobulin.

The catabolic pathways of streptokinase, plasmin, and activator complex prepared with human plasminogen were studied in mice. (125)I-streptokinase clearance occurred in the liver and was 50% complete in 15 min. Incubation with mouse plasma had no effect on the streptokinase clearance rate. Complexes of plasmin and alpha(2)-plasmin inhibitor were eliminated from the plasma by a specific and saturable pathway. Competition experiments demonstrated that this pathway is responsible for the clearance of injected plasmin. Streptokinase-plasminogen activator complex formed with either (125)I-plasminogen or (125)I-streptokinase cleared in the liver at a significantly faster rate than either of the uncomplexed proteins (50% clearance in <3 min). Streptokinase incubated with human plasma also demonstrated this accelerated clearance. p-Nitrophenyl-p'-guanidinobenzoate-HCl or pancreatic trypsin inhibitor-treated complex cleared slowly compared with untreated complex independent of which protein was radiolabeled. Significant competition for clearance was demonstrated between alpha(2)-macroglobulin-trypsin and activator complex only when the plasmin(ogen) was the radiolabeled moiety. Large molar excesses of alpha(2)-plasmin inhibitor-plasmin failed to retard the clearance of activator complex. Hepatic binding of streptokinase-plasmin, in liver perfusion experiments, was dependent upon prior incubation with plasma (8-10% uptake compared to a background of approximately 2.5%). Substitution of human alpha(2)-macroglobulin for plasma also resulted in binding when the incubation was performed for 10 min at 37 degrees C (7.5%). Electrophoresis experiments confirmed the transfer of 0.8 mol plasmin/mol alpha(2)-macroglobulin when activator complex was incubated at 37 degrees C with alpha(2)-macroglobulin for 40 min. Streptokinase transfer from activator complex to alpha(2)-macroglobulin was negligible. The in vivo clearance of activator complex is proposed to involve active attack of the complex on the alpha(2)-macroglobulin "bait region," resulting in facilitated plasmin transfer. Dissociated streptokinase is rapidly bound and cleared by sites in the liver.

Animals↗