Human plasma alpha 2-macroglobulin. An inhibitor of plasma kallikrein.
Activation of plasma kallikrein arginine esterase activity by kaolin resulted in peak activity at 1 min of incubation and a 50% reduction in activity at 5 min in normal plasma, and 30% reduction in the plasma of patients with hereditary angioneurotic edema who lacked the C1 inactivator. The peak esterolytic activity was inhibited by soybean trypsin inhibitor whereas the 5 min activity was resistant to this inhibitor. Acid treatment of normal and hereditary angioneurotic edema plasma destroyed the factor responsible for the fall in esterase activity at 5 min and the factor which rendered the esterase resistant to soybean trypsin inhibitor. Purified alpha(2)-macroglobulin inhibited approximately 50% of the TAMe esterase activity of purified plasma kallikrein without changing its activity toward basic amino acid esters. The interaction between the alpha(2)-macroglobulin and kallikrein resulted in alterations in the gel filtration chromatographic pattern of the TAMe esterase and biologic activity of kallikrein, indicating that kallikrein was bound to the alpha(2)-macroglobulin. The TAMe esterase activity of this complex, isolated by column chromatography, was resistant to C1 inactivator and SBTI. Studies of incubation mixtures of kallikrein, alpha(2)-macroglobulin and C1 inactivator suggested that these inhibitors compete for the enzyme, and that the alpha(2)-macroglobulin partially protects the esterase activity of kallikrein from C1 inactivator. The alpha(2)-macroglobulin isolated from kaolin-activated plasma possessed 240 times the esterolytic activity of the alpha(2)-macroglobulin purified from plasma treated with inhibitors of kallikrein and of its activation. The alpha(2)-macroglobulin blocked the uterine-containing activity and vascular permeability-inducing effects of plasma kallikrein. These studies suggest that the alpha(2)-macroglobulin is a major plasma inhibitor of kallikrein and provide a new example of an interrelationship between the coagulation, fibrinolytic, and kallikrein enzyme systems.
D000510:Alpha-Globulins / Q000302:isolation & purification* / Q000494:pharmacology; D000799:Angioedema / Q000097:blood; D007611:Aprotinin; D001120:Arginine; D001777:Blood Coagulation; D002199:Capillary Permeability / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D002845:Chromatography; D002850:Chromatography, Gel; D003165:Complement System Proteins / Q000032:analysis; D046508:Culture Techniques; D004586:Electrophoresis; D004950:Esterases / Q000097:blood; D005173:Factor XI Deficiency / Q000097:blood; D005260:Female; D006801:Humans; D006851:Hydrochloric Acid; D005779:Immunodiffusion; D007122:Immunoelectrophoresis; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D007616:Kaolin; D007705:Kinins / Q000032:analysis; D008259:Macroglobulins / Q000302:isolation & purification* / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects
D000510:Alpha-Globulins; D007705:Kinins; D008259:Macroglobulins; D007616:Kaolin; D003165:Complement System Proteins; D007611:Aprotinin; D001120:Arginine; D004950:Esterases; D007610:Kallikreins; D006851:Hydrochloric Acid