Human Plasminogen Variant Chicago III

Abstract

SummaryA new abnormal, variant, plasminogen Chicago III has been isolated from a patient with recurring deep vein thrombosis. Studies on the plasma fibrinolytic system of four family members showed no inheritance pattern. Kinetics of activation parameters of Chicago III plasminogen with different activators showed lowered catalytic rate constants from 159fold with urokinase, to 3fold with light (B) chain ‧ streptokinase complex, to 1.3fold with streptokinase. The Michaelis constants of activation of Chicago III plasminogen were 16fold higher with streptokinase, 6fold higher with light (B) chain ‧ streptokinase complex, and similar with urokinase. Each of the three activators exhibited different interaction characteristics with this variant zymogen, as they did with variant Chicago I and Chicago II plasminogens (previously reported). However, the latter variants were characterized by having normal catalytic rate constants of activation, with higher than normal apparent Michaelis constants of activation. Chicago III plasminogen, as well as Chicago I and II plasminogens, has a homogeneous population of molecules; the interpretation of the kinetic data was possible only in terms of a single population of molecules. The plasmins derived from Chicago I plasminogen, and also Chicago II and Chicago III plasminogens, have 100% active sites with normal amidase parameters. Basically, a single population of normal isoelectric forms were found in the Chicago III plasma, with three minor forms, about 11% of the total.The kinetic parameters have permitted us to classify the four known plasminogen variants into three different classes. The Class A homozygote (Tochigi) has both an active center defect and a charge mutation difference with normal cleavage of the Arg560-Val peptide bond; the Class B homozygote (Chicago I and Chicago II) has a Km of activation defect with impaired activator binding and normal cleavage of the Arg560-Val peptide bond; and, the Class C homozygote (Chicago III) has both a Km of activation defect with impaired activator binding and a kcat of activation defect, and impaired Arg560-Val peptide bond cleavage.