Pepsinogen activation mechanisms

At pH 4, the pepsinogen concentration versus time did not decline exponentially. Consequently, we assumed that both the first-order and autocatalytic activation mechanisms were operative. The rate equation for this reaction is ... 

Figure 9. Mechanism of pepsinogen activation. The large circle is the main protein molecule the small square and circle are, respectively, undeveloped and developed active sites which each contain two carboxyl groups the line represents the activation peptide.

Thus, in the cases of bovine pepsinogen and calf prochymosin where the activation segment sequences are known, peptides were released corresponding to the NH2-terminal parts of the sequence only. For the canine and chicken proteins where no sequence data is available, it appears that inclusion of pepstatin stops the activations before all of the activation segment is released. Consequently, a sequential activation mechanism and not a one-step transformation must be operative with all five of these zymogens. 

By incubation of porcine, bovine, canine, or chicken pepsinogens and calf prochymosin with pepstatin at pH 2.5, the first active protein generated on activation is trapped in an inactive complex. The first activation peptide liberated from porcine pepsinogen has been identified as residues 1-16 whereas that from prochymosin is derived from residues 1-27. This suggests that pepsin and chymosin are not formed by one-step conversions from their zymogens, but by (different) sequential, activation mechanisms. 

The activation of pepsin from its zymogen pepsinogen occurs by a different mechanism. In this case, the pH of the environment plays a decisive role. In the strongly acidic milieu of the stomach cleavage of a 44 amino acid peptide occurs from the inactive precursor pepsinogen. The activation is intramolecular and depends on the pH of the solution. 

The activation of pepsinogen is thought to occur by two different mechanisms intramolecular, in which the ymogen aefs on itself to generate pepsin, and inter-molecular, in which one molecule of pepsin acts on a moiecule of pepsinogen to convert it to pepsin-... 

These latter synthesize ptyalin, an endoamylase which is also an a-amy-lase. When we come to the gastric mucosa, besides mucous cells we find present parietal cells specialized for the secretion of hydrochloric acid by a mechanism of active transport, and peptic cells which can synthesize pepsinogen, from which an endopeptidase, pepsin, is formed. 

For pepsin, activation from pepsinogen can occur via two different mechanisms. One is a bimolecular reaction (an intermolecular reaction), in which a pepsin molecule converts pepsinogen into pepsin the other is an unimolecular reaction (self-activation an intramolecular reaction), in which a pepsinogen molecule cleaves itself to yield a pepsin molecule (Herriott, 1939 Bustin and Conway-Jacobs, 1971 Al-Janabi et al., 1972 McPhie, 1974). 

A cartoon depicting the ligands and the transduction mechanisms activating the chief cell to secrete pepsinogen. Under acidic conditions, cleavage of the N-terminal sequence of pepsinogen results in autocatalytic catalysis and activation to pepsin. 

In view of the sequence homologies between pepsinogen and pro-chymosin (Fig.l) it was a little suprising that Al could not inhibit chymosin. This suggested that prochymosin might activate itself by a different mechanism that never generates a 16-residue peptide. 

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