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Zymogens: Activation of Pepsinogen in The Stomach
Zymogens: Activation of Pepsinogen in The Stomach
Digestive enzymes are released in inactive forms called zymogens. This is necessary to
prevent the digestive enzymes from digesting the cells that produce them. In a zymogen, a
peptide blocks the active site of the enzyme. Cleaving off this peptide activates the enzyme.
Pancreatic zymogens are normally only activated after they reach the small intestine. A brush
border enzyme, enterokinase, cleaves a peptide from trypsinogen, forming the active
enzyme trypsin. Trypsin then activates the other enzymes. ("Brush border" is another term
for the microvilli at the apical surface of enterocytes, where brush border enzymes are
located).
A dangerous situation occurs if there is inappropriate formation of trypsin in the pancreas.
This can cause pancreatitis, where trypsin digests pancreatic tissue and triggers an
inflammatory response. Acinar cells synthesize and secrete a trypsin inhibitor that acts as a
safeguard against trypsin activation within the pancreas. Another protective mechanism is
that trypsin has a mechanisms of autolysis (self-digestion). Genetic mutations that decrease
the activity of the pancreatic trypsin inhibitor increase the risk for pancreatitis, as do
mutations that affect trypsinogen so that it is more likely to become prematurely activated or
is resistant to autolysis.
A further important mechanism to protect against pancreatitis is fluid secretion by duct cells
to flush zymogens (or active enzymes) out of the pancreas and into the duodenum. Blockage
of the pancreatic duct (for instance, by a gallstone) will prevent flow out of the pancreas and
can be a cause of acute pancreatitis. Fluid secretion in the pancreas depends upon the
chloride channel CFTR (as does fluid secretion in the lungs and small intestine). Patients
with mutations in the CFTR gene (which causes cystic fibrosis) have an increased risk for
the development of pancreatitis.
Two other factors that increase the risk for the development of pancreatitis are excessive
alcohol consumption and hyperlipidemia. Alcohol and fatty acids cause inappropriate
intracellular activation of trypsin via mechanisms that are still being elucidated.