Zymogens

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.


Activation of pepsinogen in the stomach


The peptidase in the stomach is pepsin. Pepsin works optimally in the acidic environment of the stomach, being active at pH 2-3, but becoming inactivated when the pH is above 5. The chief cells at the base of the gastric glands secrete the zymogen, which is called pepsinogen. Activation of pepsinogen starts when hydrocholoric acid (HCl), which is secreted by the parietal cells partially activates pepsinogen (pepsinogen* in figure). This partially active enzyme then cleaves the peptide from other pepsinogen molecules to form active pepsin. 



Activation of pancreatic zymogens in the small intestine

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. 

Quick Quiz


Fill-in Answer Correct False Correct Answer
1. Which cell secretes pepsinogen?
2. Pepsinogen is partially activated by ________.
3. Name the brush border enzyme responsible for activating trypsinogen.
4. What do acinar cells secrete that safeguards against inappropriate activation of zymogens in the pancreas?
5. What disorder occurs as a result of inappropriate activation of zymogens in the pancreas?
6. Name the chloride channel that is important for fluid secretion in the pancreatic ducts.


(Spelling must be correct)




Back to Home Page