2.2.11: Zymogen Activation

A zymogen, also called a proenzyme, is an inactive precursor of an enzyme. A zymogen requires a biochemical change (such as a hydrolysis reaction that reveals the active site or a conformational change that exposes it) to become an active enzyme.

The pancreas initially synthesizes protease enzymes as zymogens to help prevent enzymes from inappropriately digesting proteins within the pancreatic cells . Enzymes like Trypsin are synthesized as proenzymes. For trypsin, trypsinogen is an inactive precursor translated by the rough endoplasmic reticulum and transported to the Golgi apparatus for sorting. Trypsinogen is always co-synthesized and packaged with a pancreatic secretory trypsin inhibitor (PSTI), which inhibits premature activation. Thus, there are two mechanisms in place to maintain the inactivity of the protease within the pancreas: (1) synthesis of the zymogen or proenzyme form, and (2) co-expression of a trypsin inhibitor protein that will bind and inhibit any prematurely cleaved trypsin until it has reached the small intestine. An animation showing structural differences between bovine trypsinogen (magenta) with just amino acids 10-15 of the pre-sequence (spacefill orange) and mature trypsin (cyan) is shown in Figure \(\PageIndex{23}\).

Figure \(\PageIndex{23}\): Animation showing structural differences between bovine trypsinogen (magenta) with just amino acids 10-15 of the pre-sequence (spacefill orange) and mature trypsin (cyan)

During packaging in the Golgi apparatus, trypsinogen and other digestive enzymes condense into core particles and are packed into zymogen granules. The condensed enzymes are stable, and minimal activation occurs within the zymogen granules. Once pancreatic cells receive secretory stimuli, zymogen granules are released into the pancreatic duct lumen, carrying digestive enzymes into the duodenum. Once in the duodenum, enteropeptidase activates trypsinogen by removing the 7-10 amino acid trypsinogen activation peptide (TAP) from the N-terminal region (see above). Removal of TAP induces a conformational change, resulting in active trypsin. TAP is immunologically distinct from the same sequence within trypsinogen, thereby allowing the detection of trypsinogen activation in situ.

Once activated, trypsin cleaves and activates other zymogen proteases and lipases in the duodenum. These include the activation of elastase, chymotrypsin, carboxypeptidase, and lipase, as shown in Figure \(\PageIndex{24}\). Zymogens are also found in other cellular processes. For example, caspases, intracellular proteases, are activated similarly during cellular apoptosis (programmed cell death). Blood clotting also involves the activation of zymogens.

Figure \(\PageIndex{24}\): Activation of proenzymes