Interaction of Streptokinase and Human Plasminogen. I. Combining of Streptokinase and Plasminogen Observed in the Ultracentrifuge under a Variety of Experimental Conditions.

The activation of human plasminogen by streptokinase has been the subject of extensive investigation (4-8). There appears to be general agreement that at least two enzymatic activities are demonstrable in streptokinase-plasminogen reaction mixtures. One is the proteolytic enzyme human plasmin, characterized in part by its ability to hydrolyze lysine and arginine esters and protein substrates such as casein and fibrin. The second enzyme, also active with basic amino acid esters, is chiefly distinguished by the property of enzymatically converting to plasmin a species of plasminogen which is refractory to activation by streptokinase alone. Bovine plasminogen is an example of such a species and has been used extensively as a substrate for detecting the “activator” activity in a streptokinase-human plasminogen reaction mixture. Bovine plasminogen is not activated by streptokinase alone, by human plasminogen alone, or by human plasmin alone. In their studies on bovine plasminogen activation, Mtillertz and Lassen (4, 5) postulated that streptokinase interacted with a substance, “proactivator,” invariably present in human plasminogen preparations, to produce an activator of bovine plasminogen. The same theory has been advanced by Troll and Sherry (9) for the activation of human plasminogen; i.e. a nonenzymatic reaction of streptokinase with “proactivator” has been postulated to precede the enzymatic conversion of human plasminogen to plasmin. The existence of “proactivator” distinct from human plasminogen remains largely hypothetical, and, in fact, evidence for their possible identity has been reported (10, 11). Little definitive work has been done to elucidate the chemical sequence of events in the interaction of streptokinase and human plasminogen. Virtually nothing is known about the molecular nature of the products formed in the interaction. Undoubtedly the chief reason for this is the fact that several reactions, viz. the generation of activator, activation of plasminogen, and autodigestion of the enzymes, are occurring simultaneously. Nevertheless, kinetic studies in several laboratories have indicated that the relative concentrations of human plasmin and bovine plasminogen activator demonstrable in a streptokinase-human plasminogen reaction mixture depend primarily upon the ratio of streptokinase and plasminogen. When streptokinase is present in high concentration relative to plasminogen, activator activity predominates, whereas an excess of human plasminogen favors the generation of plasmin activity (5-7, 12, 13).