enterokinase

**Identity and location:** Enterokinase (also called enteropeptidase; gene PRSS7) is a type II transmembrane serine protease anchored in the brush border of duodenal and proximal jejunal enterocytes. Its expression is highest in the duodenum.

**Function:** It cleaves the N-terminal hexapeptide (trypsin activation peptide) from trypsinogen at a lysine-isoleucine bond (recognition sequence Asp-Asp-Asp-Asp-Lys). This produces active trypsin. Trypsin then does the following: - Autocatalytically activates more trypsinogen (positive feedback). - Activates the other pancreatic zymogens: chymotrypsinogen → chymotrypsin, proelastase → elastase, procarboxypeptidase A/B → carboxypeptidase A/B, and prophospholipase A2 → phospholipase A2. - Activates procolipase → colipase, which is needed for pancreatic lipase function.

Enterokinase is the first step in the cascade, and it is the only activator of trypsinogen that is physiologically "outside" the pancreas. This keeps proteolytic enzymes inactive while in the pancreas, which protects the gland from autodigestion.

**Clinical significance:** - **Congenital enteropeptidase deficiency** is a rare autosomal recessive disorder (PRSS7 mutations). Infants present with chronic diarrhea, failure to thrive, protein-losing/malabsorption picture (hypoproteinemia, edema, hypoalbuminemia), and sometimes anemia. Duodenal enterokinase activity is absent, while the pancreas itself is histologically normal. Treatment is pancreatic enzyme replacement. - **Pancreatitis:** Premature intrapancreatic activation of trypsinogen leads to autodigestion. Causes include hereditary pancreatitis (PRSS1 gain-of-function mutations, which make trypsin resistant to inactivation, and SPINK1 loss-of-function mutations, which cause loss of the trypsin inhibitor). Reflux of duodenal contents (with enterokinase) into the pancreatic duct is another proposed mechanism. - **Cystic fibrosis:** Thick secretions obstruct pancreatic ducts, causing pancreatic insufficiency. Enterokinase is intact, but enzymes and bicarbonate fail to reach the duodenum.

**Board pearls:** - Enterokinase → trypsinogen → trypsin → everything else (the rate-limiting "master switch"). - Secretin and CCK regulate pancreatic secretion, but enterokinase regulates enzyme activation. CCK also stimulates enterokinase secretion by the duodenal mucosa. - Do not confuse it with other brush-border enzymes (lactase, sucrase-isomaltase, maltase, peptidases), which are not part of the pancreatic zymogen cascade. - Enterokinase deficiency gives a low trypsin activity in duodenal fluid that is corrected by adding exogenous enterokinase. This differentiates it from isolated trypsinogen deficiency (where adding enterokinase does not correct it). - Isolated trypsinogen deficiency is a separate, rare entity with similar features (failure to thrive, hypoproteinemia). - Recombinant enterokinase is also used in molecular biology to cleave fusion proteins (e.g., removing tags at the Asp-Asp-Asp-Asp-Lys site).