Digestive System > Stomach

Pepsinogens and Pepsins

Pepsins are the principal proteases in gastric secretions of adult mammals. They are members of the family of aspartic proteases, and closely related to chymosin, another gastric protease expressed particularly in young animals. These enzymes are synthesized and secreted predominantly by chief cells in the gastric mucosa.

At least 8 isozymes of pepsinogen have been identified in gastric epithelial cells, and these have been categorized into two immunologically-separable types (pepsins A and C). The mature, active enzymes are roughly 325 amino acids with a mass of approximately 35 kDa.

Pepsins are synthesized as inactive pre-proenzymes, consisting of a signal peptide, activation peptide and active enzyme. The signal peptide is cleaved as the protein is inserted into endoplasmic reticulum and the resulting proenzyme - pepsinogen - is transported to the Golgi and condensed into secretory granules.

Pepsinogens are secreted in a form such that the activation peptide assumes a compact structure that occludes the active site. On exposure to an acidic pH the activation peptide is cleaved, thereby unmasking the active site and generating catalytically-active pepsin. Optimal activity of pepsins is at pH of 1.8 to 3.5, depending on the isoform. They are reversibly inactivated at about pH 5 and irreversibly inactivated at pH 7 to 8.

In general, secretion of pepsinogens is coupled to secretion of acid from the parietal cell. In vitro studies have demonstrated that secretion is effectively stimulated by agents that stimulate either of two conditions:

Receptors for many of the hormones listed above have been demonstrated on chief cells and pepsinogen secretion has been stimulated or blocked by exposure to these agents or their antagonists, respectively. At the present time it seems safe to say that the principal physiologic secretagogue(s) regulating pepsinogen secretion has not been clearly deliniated.

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