Gastric zymogens

Having considered these difficulties, we have concluded that for the present purpose it is most rational to number the residues from the NH2-terminus of the longest known polypeptide chain of the gastric zymogens (prochymosin) and then continue by counting the longest completely sequenced chain of the active enzymes (porcine pepsin). 

The alignment in Table I includes sequences from 12 different zymogens and enzymes, only two of which are known completely and a third is almost completed. Despite the fragmentary data, we are able to deduct some general structure-function relationships of the aspartate proteinases and of the gastric zymogens. 

Throughout the 373 positions of amino acid residues in the gastric zymogens, 175 are found with identical residues in the presently known structures. This number will probably decrease somewhat when more structures are determined. If we compare the gastric enzymes with the microbial enzymes represented by penicillo-pepsin, and Mucor miehei proteinase, 63 positions are identical. 

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 (EC 3.4.23.1) is a typical aspartic proteinase produced in the gastric mucosa of vertebrates as a zymogen form [10], This enzyme has been extensively characterized, and its three-dimensional structure has been determined at high resolution. Porcine pepsin, in particular, has been studied as model to analyze the structure-function relationship of the aspartic proteinases. Although the aspartic proteinases including mammalian and fungal enzymes are quite similar in their three-dimentional structures, there are drastic differences in the catalytic properties, especially in substrate specificities. 

Aspartic proteases include the gastric proteases pepsin A, pepsin B, gastricsin and chymosin that are secreted as inactive zymogens and are activated through removal of autoinhibitory domains in the low pH conditions of the stomach [7-9]. Oesophagitis is caused by undue... 

The entry of protein into the stomach stimulates the release of a hormone, gastrin, which then causes the release of hydrochloric acid from the parietal cells, and pepsinogen from the chief cells (Fig. 15-5). Pepsinogen is another zymogen (they all start with pro- or end in -ogen) that is converted in the gastric juice to the active enzyme pepsin. 

T3. Tang, J., and Tang, K. 1., Purification and properties of a zymogen from human gastric mucosa. J. Biol. Chem. 238, 606-612 (1963). 

Before turning to the strategy adopted in our work, a few of the characteristics of the two proteins are reviewed. The physical and chemical properties of these proteins have been discussed in detail 11, 14). As first shown by Langley, pepsin is present in its inactive form, pepsinogen, in the gastric mucosa. At acid pH, the zymogen is transformed by an autocat-alytic reaction into pepsin, a proteolytic enzyme with an activity optimum at pH 2.0 and a wide specificity 9, 10, 19). Pepsin is rapidly inactivated above pH 6.0, whereas pepsinogen is stable at neutrality 1 If). 

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