Cleavage of peptide hormones by alpha 2-macroglobulin-trypsin complex and its relation to the pathogenesis and chemotherapy of acute pancreatitis.

Access to the active site of alpha 2-macroglobulin bound proteinases by macromolecular substrates and inhibitors is likely to be influenced by steric favourability and flexibility, as well as by molecular size. Hydrolysis of pure porcine cholecystokinin-pancreozymin 39, a flexible single chain peptide, by alpha 2-macroglobulin-trypsin complex resulted in a rapid up to 6-fold increase in cholecystokinin bioactivity; alpha 2-macroglobulin-trypsin rapidly abolished the bioactivity of endogenous parathormone in human plasma. Inhibition of both reactions was completed by low concentrations of antipain and leupeptin; Trasylol (aprotinin), a single chain peptide with three disulphide bonds, was an ineffective inhibitor even in massive molar excess. These findings may provide an explanation for the disordered calcium homeostasis in severe acute pancreatitis and for the failure of Trasylol to reduce mortality; they suggest that sterically favourable low molecular weight inhibitors may provide effective specific chemotherapy for the disease.