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PubMed1994

Studies on the mechanisms of action of aprotinin and tranexamic acid as plasmin inhibitors and antifibrinolytic agents.

Both aprotinin and tranexamic acid are effective inhibitors of fibrinolysis in vitro and in vivo and both agents can act as plasmin inhibitors in purified systems, although there is some debate on their exact mechanism of action in vivo. The studies reported here using an in vitro clot lysis system designed to provide precise inhibition constants show that aprotinin remains a very potent inhibitor of plasmin even in the presence of fibrin with Ki = 2 nM. Plasmin-aprotinin interactions in solution are not affected by a number of kringle binding ligands, aminohexanoic acid, tranexamic acid or CNBr-fibrinogen fragments with Ki = 0.4 nM. The difference between these two Ki values is explained by competition for the plasmin active site between substrate (fibrin) and inhibitor (aprotinin). Inhibition of fibrinolysis by tranexamic acid is not readily analysed by a simple inhibition model which may be due to multiple overlapping ligand-kringle interactions or tranexamic-fibrin interactions. Experiments using combinations of aprotinin and tranexamic acid in the clot lysis system confirm the complementary nature of inhibitory mechanisms and suggest a slight synergism. These results support the idea that aprotinin inhibition of plasmin is a primary mode of action in vivo, and suggest that combination therapy of aprotinin with tranexamic acid might be more effective than either inhibitor alone.

Amino Acid Sequence↗
PubMed1993

PAM, a novel plasminogen-binding protein from Streptococcus pyogenes.

The ability of group A streptococci to bind human plasminogen and plasmin has attracted interest, because it could provide the bacteria with a mechanism for invasion. M or M-like proteins account for the binding of several plasma proteins to group A streptococci. To investigate whether M or M-like proteins were responsible for the binding of plasminogen to group A streptococci, acid-extracted material from a type M53 streptococcal isolate was tested for its ability to bind plasminogen. Indeed, a 42-kDa plasminogen-binding protein was solubilized. Two oligonucleotides homologous with conserved sequences in known M protein genes were used as primers in the polymerase chain reaction, with chromosomal DNA from the M53 isolate. When cloned and expressed in Escherichia coli, a resulting fragment encoded a 43-kDa plasminogen-binding protein. Nucleotide sequence determination of the gene fragment revealed an open reading frame encoding a polypeptide of 43,580 Da, which matched the amino-terminal amino acid sequence of the plasminogen-binding protein extracted from M53 streptococci. The DNA sequence data also proved the relationship of the encoded protein, named PAM, to the M proteins. The plasminogen-binding domain was mapped to the amino-terminal third of PAM. Plasminogen absorbed by M53 streptococci or by immobilized PAM could be activated by streptokinase. The results provide further evidence of the diversity of the M protein family and suggest a new mechanism whereby these proteins contribute to the virulence of group A streptococci.

Amino Acid Sequence↗
PubMed1993

Binding of anisoylated Lys-plasminogen streptokinase activator complex to cells in culture.

Anisoylated Lys-plasminogen streptokinase activator complex (APSAC) was purified from Eminase by chromatography on Superose-12. Purified APSAC did not significantly deacylate within 4 h at 4 degrees C in solution as determined by hydrolysis of D-Val-L-leu-L-lys-p-nitroanilide HCl (S-2251). At 37 degrees C, maximum amidase activity developed in 120 min; epsilon-amino-n-caproic acid (EACA) did not affect the apparent rate of APSAC deacylation but stabilized the streptokinase-plasmin(ogen) complex (SkPl) which formed. APSAC bound to C6 glioma cells and human umbilical vein endothelial cells (HUVECs) in culture. Binding as completely inhibited by EACA suggesting an essential role for the plasminogen kringle domains. Cell-associated APSAC deacylated to form active SkPl which hydrolyzed S-2251 and D-Val-Leu-Lys-7-amino-4-methyl coumarin. The rate of APSAC deacylation was increased when the APSAC was cell-associated. APSAC that was initially bound to C6 cells or HUVECs also activated 125I-plasminogen. This activity may have reflected cell-associated APSAC or APSAC but dissociated into solution. Plasmin was recovered bound to cells and in solution. These studies demonstrate that APSAC associates with cell-surfaces and retains activity. In the circulation, cell-surfaces may provide a significant pharmacologic compartment for intravenously administered APSAC.

Acylation↗