US EPA

69088 

Journal Article 

The mechanism of the inhibition of plasmin activity by epsilon-aminocaproic acid 

Brockway, WJ; Castellino, FJ 

1971 

Yes 

Journal of Biological Chemistry
ISSN: 0021-9258
EISSN: 1083-351X 

246 

4641-4647 

The streptokinase-induced conversion of human plasminogen to plasmin is inhibited by concentrations of epsilon-aminocaproic acid which stimulates the esterolytic activity of plasmin on the synthetic substrate, tosyl-l-arginine methyl ester. The inhibitory effect of epsilon-aminocaproic acid decreases as its concentration is decreased and is eliminated upon incubation of plasminogen with streptokinase, regardless of the presence of epsilon-aminocaproic acid. At increased levels, epsilon-aminocaproic acid further functions as a competitive inhibitor of plasmin activity on tosyl-l-arginine methyl ester with a Ki of 0.32 m. In the presence of concentrations of epsilon-aminocaproic acid (0.05 m) sufficient to nearly saturate its inhibitory effect on the plasminogen to plasmin conversion, the sedimentation coefficient (S020,w) of plasminogen decreases from a native value of 5.0 +/- 0.1 S to 3.8 +/- 0.1 S without a decrease in molecular weight suggesting a gross conformational change in plasminogen induced by epsilon-aminocaproic acid. This conformational alteration is also evidenced in circular dichroism measurements. The effect of epsilon-aminocaproic acid on the conformation of plasminogen is readily reversible and restoration of the native structure is apparent after dialysis.
A mechanism for the inhibition of the plasminogen to plasmin conversion by epsilon-aminocaproic acid is postulated involving the formation of a plasminogen-epsilon-aminocaproic acid complex, which due to the altered conformation of plasminogen, is not acted upon by streptokinase. This inactive complex is rapidly reversible, yielding a fully streptokinase reactive plasminogen.