Mechanism of activation of the gastric aspartic proteinases: pepsinogen, progastricsin and prochymosin.
The gastric aspartic proteinases (pepsin A, pepsin B, gastricsin and chymosin) 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 serves to stabilize the inactive form and prevent entry of the substrate to the active site. Upon ingestion of food, each of the zymogens is released into the gastric lumen and undergoes conversion into active enzyme in the acidic gastric juice. This activation reaction is initiated by the disruption of electrostatic interactions between the prosegment and the active enzyme moiety at acidic pH values. The conversion of the zymogen into its active form is a complex process, involving a series of conformational changes and bond cleavage steps that lead to the unveiling of the active site and ultimately the removal and dissociation of the prosegment from the active centre of the enzyme. During this activation reaction, both the prosegment and the active enzyme undergo changes in conformation, and the proteolytic cleavage of the prosegment can occur in one or more steps by either an intra- or inter-molecular reaction. This variability in the mechanism of proteolysis appears to be attributable in part to the structure of the prosegment. Because of the differences in the activation mechanisms among the four types of gastric zymogens and between species of the same zymogen type, no single model of activation can be proposed. The mechanism of activation of the gastric aspartic proteinases and the contribution of the prosegment to this mechanism are discussed, along with future directions for research.
Richter
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Department of Food Science, University of Guelph, Guelph, ON N1G 2W1, Canada.
Tanaka
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Yada
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D000595:Amino Acid Sequence; D000818:Animals; D012085:Chymosin / Q000737:chemistry* / Q000378:metabolism*; D004063:Digestion; D004792:Enzyme Precursors / Q000737:chemistry* / Q000378:metabolism*; D005753:Gastric Mucosa / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020116:Pepsinogen A / Q000737:chemistry* / Q000378:metabolism*; D020115:Pepsinogen C / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D004792:Enzyme Precursors; D020115:Pepsinogen C; D020116:Pepsinogen A; C032443:prorennin; D012085:Chymosin