MECHANISM OF ACTIVATION OF THE GASTRIC ASPARTIC PROTEINASES - PEPSINOGEN, PROGASTRICSIN AND PROCHYMOSIN

The gastric aspartic proteinases (pepsin A, pepsin B, gastricsin and c hymosin) are synthesized in the gastric mucosa as inactive precursors, known as zymogens. The gastric zymogens each contain a prosegment (i. e. additional residues at the N-terminus of the active enzyme) that se rves to stabilize the inactive form and prevent entry of the substrate to the active site. Upon ingestion of food, each of the zymogens is r eleased into the gastric lumen and undergoes conversion into active en zyme in the acidic gastric juice. This activation reaction is initiate d by the disruption of electrostatic interactions between the prosegme nt and the active enzyme moiety at acidic pH values. The conversion of the zymogen into its active form is a complex process, involving a se ries of conformational changes and bond cleavage steps that lead to th e unveiling of the active site and ultimately the removal and dissocia tion of the prosegment from the active centre of the enzyme. During th is activation reaction, both the prosegment and the active enzyme unde rgo changes in conformation, and the proteolytic cleavage of the prose gment can occur in one or more steps by either an intra- or inter-mole cular reaction. This variability in the mechanism of proteolysis appea rs to be attributable in part to the structure of the prosegment. Beca use of the differences in the activation mechanisms among the four typ es of gastric zymogens and between species of the same zymogen type, n o single model of activation can be proposed. The mechanism of activat ion of the gastric aspartic proteinases and the contribution of the pr osegment to this mechanism are discussed, along with future directions for research.