enteropeptidase

**Source and location:** Synthesized by enterocytes of the duodenum and proximal jejunum. It is a type II transmembrane serine protease anchored in the brush border. Secretion and activity are stimulated by bile salts and the presence of chyme.

**Function (digestive activation cascade):** - Enteropeptidase cleaves trypsinogen at Lys-Ile bond, removing the N-terminal hexapeptide (Val-Asp-Asp-Asp-Asp-Lys) to produce active trypsin. - Trypsin then autocatalytically activates more trypsinogen (positive feedback) and activates chymotrypsinogen → chymotrypsin, proelastase → elastase, procarboxypeptidase A/B → carboxypeptidase A/B, and prophospholipase A2 → phospholipase A2 (also colipase activation from procolipase). - Keeping these enzymes as zymogens until they reach the duodenal lumen prevents autodigestion of the pancreas. Pancreatic secretory trypsin inhibitor (SPINK1) offers an additional safeguard.

**Clinical significance:** - **Congenital enteropeptidase deficiency:** Rare autosomal recessive disorder (PRSS7 gene, also called TMPRSS15). Presents in infancy with chronic diarrhea, failure to thrive, hypoproteinemia, edema, and anemia due to protein malabsorption. Pancreas is structurally normal; duodenal aspirate shows low trypsin activity that normalizes when enteropeptidase is added. Treated with pancreatic enzyme replacement. - **Acquired deficiency:** Can occur with severe mucosal damage in the proximal small bowel (e.g., celiac disease, severe enteropathies), contributing to malabsorption. - **Pancreatitis:** Premature trypsinogen activation within the pancreas is central to pathogenesis. Hereditary pancreatitis involves PRSS1 gain-of-function mutations (trypsin resistant to inactivation/autolysis), SPINK1 loss-of-function (reduced trypsin inhibition), or CFTR mutations. Reflux of enteropeptidase-containing duodenal juice into the pancreatic duct has been proposed as a trigger in experimental models.

**High-yield board associations:** - Enteropeptidase = the "master switch" of pancreatic proteolytic enzymes; trypsin is the key activator. - Mnemonic: "Enteropeptidase turns on trypsin, trypsin turns on everything else." - Other brush-border enzymes (don't confuse): lactase, sucrase-isomaltase, maltase, aminopeptidases, dipeptidases. - Secretin → pancreatic bicarbonate; CCK → pancreatic enzyme release (and gallbladder contraction); CCK-releasing peptide mediates feedback via luminal trypsin. - Presentation with protein malabsorption in infancy and hypoalbuminemia/edema with normal fat absorption is a classic clue; stool contains undigested protein. Enteropeptidase deficiency differs from cystic fibrosis (thick secretions, steatorrhea, meconium ileus, positive sweat chloride) and from Shwachman-Diamond syndrome (pancreatic insufficiency with neutropenia).