Pepsinogen active site

The proteases are secreted as inactive zymogens the active site of the enzyme is masked by a small region of its peptide chain, which is removed by hydrolysis of a specific peptide bond. Pepsinogen is activated to pepsin by gastric acid and by activated pepsin (autocatalysis). In the small intestine, trypsinogen, the precursor of trypsin, is activated by enteropeptidase, which is secreted by the duodenal epithelial cells trypsin can then activate chymotrypsinogen to chymotrypsin, proelas-tase to elastase, procarboxypeptidase to carboxypepti-dase, and proaminopeptidase to aminopeptidase. 

Pepsin is secreted as the inactive pepsinogen, which is activated by H+ ions at a pH below 5. Determination of its crystal structure revealed that in the proenzyme the N-terminal 44-residue peptide segment lies across the active site, blocking it.384 At low pH the salt bridges that stabilize the proenzyme are disrupted and the active site is opened up to substrates. 

The inactive precursors are called trypsinogen, pepsinogen, chymotrypsino-gen, and procarboxypeptidase. These precursors are converted to the active enzymes by hydrolytic cleavage of a few specific peptide bonds under the influence of other enzymes (trypsin, for example, converts chymotrypsinogen to chymotrypsin). The digestive enzymes do not appear to self-destruct, probably because they are so constructed that it is sterically impossible to fit a part of one enzyme molecule into the active site of another. In this connection, it is significant that chymotrypsin attacks denatured proteins more rapidly than natural proteins with their compact structures of precisely folded chains. 

The most obvious differences between pepsin and pepsinogen are found in the prosegment portion. Not only does the prosegment cover the active-site cleft, but it contains a large number of positively charged residues [i.e.,... 

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.

The activation of zymogens involves the cleavage of one or more peptide bonds. In the case of pepsinogen, when the catalytic site is exposed by lowering the pH, it hydrolyzes the peptide bond between the percursor and pepsin moities. Note that this activation is autocatalytic. Therefore, the time required for activation of half the pepsinogen molecules is independent of the total number of the molecules present. 

Molecular-weight estimates for pepsinogens from various species, including amphibians, fish, and mammals, range from 29 to 65 kDa. Some of this heterogeneity arises from differences in the NHz-terminal activation sequence, but significant differences exist in the catalytic peptide as well. Despite such differences, the catalytic site appears to be similar in all species. 

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