Mechanism of Activation of Human Plasminogen by Streptokinase

Reddy, K.N.N.; Markus, Gabor

doi:10.1016/s0021-9258(19)45531-2

Cited by 223 publications

(45 citation statements)

References 27 publications

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“…As a consequence, the active site in HPG develops amidolytic and esterolytic potential even before the introduction of any proteolytic cleavage. This "virgin" enzyme complex is then converted rapidly to fully formed activator (either intact SK-HPG, as in the early phase after complex formation, or later, SK-HPN), which develops the capability to convert other "substrate" plasminogen molecules to plasmin by selective cleavage at the Arg560-Va1561 peptide bond (Markus & Werkheiser, 1964;Mc-Clintock & Bell, 1971;Reddy & Markus, 1972). Thus, the most intriguing aspects of the interaction of SK with HPG/HPN are (1) the structural basis of the activation of the cryptic active site in the zymogen, and (2) the conversion of this "nascent" activity to a highly specific proteolytic activity directed toward the scissile peptide bond in substrate PC.…”

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confidence: 99%

Role of the amino‐terminal region of streptokinase in the generation of a fully functional plasminogen activator complex probed with synthetic peptides

et al. 1998

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The mechanism whereby fragments of streptokinase (SK) derived from its N terminus (e.g., SK1-59 or SK1-63) enhance the low plasminogen (PG)-activating ability of other fragments, namely SK64-386, SK60-414, SK60-387, and SK60-333 (reported previously), has been investigated using a synthetic peptide approach. The addition of either natural SK1-59, or chemically synthesized SK16-59, at saturation (about 500-fold molar excess) generated amidolytic and PG activation capabilities in equimolar mixtures of human plasminogen (HPG) and its complementary fragment (either SK60-414 or SK56-414, prepared by expression of truncated SK gene fragments in Escherichia coli) that were approximately 1.2-and 2.5-fold, respectively, of that generated by equimolar mixtures of native SK and HPG. Although in the absence of SK1-59 equimolar mixtures of SK56-414 and HPG could generate almost 80% of amidolytic activity, albeit slowly, less than 2% level of PG activation could be observed under the same conditions, indicating that the contribution of the N-terminal region lay mainly in imparting in SK56-414 an enhanced ability for PG activation. The ability of various synthetic peptides derived from the amino-terminal region (SK16-51, SK16-45, SK37-59, SK1-36, SK16-36, and SK37-51) to (1) complement equimolar mixtures of SK56-414 and HPG for the generation of amidolytic and PG activation functions, (2) inhibit the potentiation of SK56-414 and HPG by SK16-59, and (3) directly inhibit PG activation by the 1:l SK-HPG activator complex was tested. Apart from SK16-59, SK16-51, and 16-45, the ability to rapidly generate amidolytic potential in HPG in the presence of SK56-414 survived even in the smaller SK-peptides, viz., SK37-59 and SK37-51. However, this ability was abolished upon specifically mutating the sequence -LTSRP-, present at position 42-46 in native SK. Although SK16-5 1 retained virtually complete ability for potentiation of PG activation in comparison to SK16-59 or SK1-59, this ability was reduced by approximately fourfold in the case of SK16-45, and completely abolished upon further truncation of the C-terminal residues to SK16-36 or SK1-36. Remarkably, however, these peptides not only displayed ability to bind PG, but also showed strong inhibition of PG activation by the native activator complex in the micromolar range of concentration; the observed inhibition, however, could be competitively relieved by increasing the concentration of substrate PG in the reaction, suggesting that this region in SK contains a site directed specifically toward interaction with substrate PG. This conclusion was substantiated by the observation that the potentiation of PG activating ability was found to be considerably reduced in a peptide (SK25-59) in which the sequence corresponding to this putative locus (residues 16-36) was truncated at the middle. On the other hand, fragments SK37-51 and SK37-59 did not show any inhibition of the PG activation by native activator complex. Taken together, these findings strongly support a model of SK acti...

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Role of the amino‐terminal region of streptokinase in the generation of a fully functional plasminogen activator complex probed with synthetic peptides

et al. 1998

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“…This complex possesses the ability to convert any species of plasminogen into plasmin (Blatt et al, 1964; Wulf and Mertz, 1969) and is called "plasminogen activator." It was also found that "activator" can form whether human plasminogen or plasmin is used as the starting material (McClintock and Bell, 1971; Reddy and Markus, 1972). A possible mechanism of activation of human plasminogen by streptokinase, employing all the above considerations, has been nicely formulated by Reddy and Markus (1972).…”

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Interaction of streptokinase and rabbit plasminogen

Schick¹

1973

Biochemistry

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The ability of rabbit plasminogen and plasmin to form complexes with streptokinase has been studied and compared to the human system. At 1 : l or 1O:l ratios of streptokinase to rabbit plasminogen, no complex was observed by sucrose density centrifugation; however, almost all the rabbit plasminogen was converted to plasmin. Under identical conditions with human plasminogen, a complex was formed which consisted of altered streptokinase and human plasmin. When the acylating agent p-nitrophenyl p'-guanidinobenzoate was added to either human or rabbit plasminogen prior to addition of a molar equivalent of streptokinase, reactive complexes were formed in each case which consisted of human or rabbit plasminogen and native streptokinase. Upon treatment of human plasmin with a molar equivalent of streptokinase, a complex is formed which consists of altered streptokinase and human plasmin. This complex possesses the ability to activate P lasminogen is a single-chain protein of mol wt 81,000-88,000, depending on the species (Barlow et al., 1969; Sodetz et ul., 1972), and plasmin is a two-chain molecule of approximately the same molecular weight, stabilized by disulfide bond(s) (Barlow et ul., 1969;Sodetz et al., 1972). Many agents mediate the conversion of plasminogen to plasmin, among which is the bacterial endotoxin streptokinase. The mechanism of activation of human plasminogen by streptokinase has been a widely studied subject. The problem resolves itself into the manner in which the nonproteolytic protein, streptokinase, catalyzes the proteolytic cleavage required for conversion of plasminogen into plasmin. Further, the fact that not all species of plasminogen are capable of activation by streptokinase raises other interesting questions.

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“…Plasminogen activity was determined using a chromogenic assay: Plasminogen is activated through reaction with an excess of Streptokinase in the presence of fibrinogen. The plasminogen-Streptokinase complex is determined by the rate of hydrolysis of the chromogenic substrate pyroGlu-Phe-Lys-pNA (HemosIL Plasminogen, Instrumentation Laboratory, Bedford, Mass., USA) [29]. The presence of the c.988A > G (p.K330E) PLG gene variant was tested as described elsewhere [8].…”

Section: Methodsmentioning

confidence: 99%

Treatment of patients with hereditary angioedema with the c.988A>G (p.Lys330Glu) variant in the plasminogen gene

Bork

Wulff

Witzke

et al. 2020

Orphanet J Rare Dis

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Background Hereditary angioedema (HAE) in patients with normal C1 inhibitor (C1-INH) and the c.988A > G (p.Lys330Glu; p.K330E) variant in the plasminogen gene (HAE-PLG) is associated with skin swellings, abdominal pain attacks, and the risk of asphyxiation due to upper airway obstruction. Aim of this observational, retrospective study is to report about the efficacy of various treatments for acute attacks and long-term prophylaxis. Results The study included 111 patients with HAE-PLG. Thirteen patients were treated with icatibant for 201 acute swelling attacks. The mean duration of the treated attacks (mean 4.3 h; standard deviation [SD] 2.6 h) was significantly shorter than that of the previous 149 untreated attacks (mean 44.7 h; SD 28.6 h, p < 0.0001). Twelve patients were treated with plasma-derived C1-INH for 74 acute swelling attacks. The duration of the treated attacks (mean 31.5 h; SD 18.6 h) was significantly shorter than that of the previous 129 untreated in the same patients (mean 48.2 h; SD 32.5 h, p < 0.0001). Corticosteroids alone showed good response in 61/268 attacks (8 patients), low response in 82/268 attacks (7 patients), and no response in 125/268 attacks (26 patients). Corticosteroids combined with antihistamines showed good response in 13/309 attacks (4 patients), low response in 150/309 attacks (7 patients), and no response in 146/309 attacks (17 patients). Antihistamines alone were ineffective in all 37 attacks of 5 patients. In 2 patients with imminent asphyxiation due to tongue swelling and partial obstruction of the upper airways fresh frozen plasma was used without clinical response. The mean reduction in attack frequency was 46.3% under progestins (6 patients), 93.9% under tranexamic acid (3 patients) and 83.3% under danazol (3 patients). Conclusions For patients with HAE-PLG various treatment options are available, which completely or at least partially reduce attack duration or attack frequency.

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Mechanism of Activation of Human Plasminogen by Streptokinase

Cited by 223 publications

References 27 publications

Role of the amino‐terminal region of streptokinase in the generation of a fully functional plasminogen activator complex probed with synthetic peptides

Role of the amino‐terminal region of streptokinase in the generation of a fully functional plasminogen activator complex probed with synthetic peptides

Interaction of streptokinase and rabbit plasminogen

Treatment of patients with hereditary angioedema with the c.988A>G (p.Lys330Glu) variant in the plasminogen gene

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