pepsin

Pepsinogen is synthesized and secreted by chief cells in the gastric fundic glands. Upon exposure to gastric acid (HCl, secreted by parietal cells), pepsinogen undergoes autocatalytic cleavage to form active pepsin. This conversion is optimal at pH < 3. Pepsin is an endopeptidase that preferentially cleaves peptide bonds adjacent to aromatic amino acids (phenylalanine, tryptophan, tyrosine), breaking down dietary proteins into smaller peptides and some free amino acids. This is the first step of protein digestion, which continues in the small intestine via pancreatic proteases (trypsin, chymotrypsin, carboxypeptidases). Pepsin secretion is stimulated by gastrin, acetylcholine (vagal input), and local reflexes triggered by the presence of food/protein in the stomach; histamine indirectly enhances acid secretion which supports pepsinogen activation. Clinically, pepsin has relevance in: (1) Peptic ulcer disease - excess acid/pepsin activity can damage gastric or duodenal mucosa, especially with H. pylori infection or NSAID use, which impair the mucosal protective barrier; (2) Laryngopharyngeal reflux (LPR) - pepsin refluxed into the pharynx/larynx can cause direct tissue damage even at less acidic pH, and pepsin detection in laryngeal tissue is used as a biomarker for reflux; (3) Barrett's esophagus and GERD complications - chronic exposure to acid and pepsin damages esophageal mucosa, contributing to metaplasia. Pharmacologically, proton pump inhibitors (PPIs) and H2 blockers reduce gastric acid production, indirectly reducing pepsin activation and activity, forming a mainstay of treatment for acid-peptic disorders. Understanding pepsin's dependence on an acidic environment explains why alkalinizing the stomach (antacids, PPIs) not only neutralizes acid but also diminishes pepsin's proteolytic activity, aiding mucosal healing.