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Zymogens is a term referring to the precursors of an enzyme, usually inactive. So far, we have been discussing digestive enzymes. The reason behind a zymogen should be evident - if the digestive enzymes were active when synthesized, they would immediately start chewing up the organs and tissue that synthesized them. Acute pancreatitis is such a condition, in which there is premature activation of the digestive enzymes in the pancreas, resulting in self-digestion (autolysis). It also complicates postmortem investigations, as the pancreas often digests itself before it can be assessed visually.

Zymogens are large, inactive structures, which have the ability to break apart or change into the smaller activated enzymes. The difference between zymogens and the activated enzymes lies in the fact that the active site for catalysis of the zymogens is distorted. As a result, the substrate polypeptide cannot bind effectively, and proteolysis does not occur. Only after activation, during which the conformation and structure of the zymogen change and the active site is opened up, can proteolysis occur.

The zymogen for trypsin is trypsinogen. When trypsinogen enters the small intestine from the pancreas, secretions from the duodenal mucosa cleaves the lysine 15 - isoleucine 16 peptide bond of the zymogen. As a result, the zymogen trypsinogen breaks down into trypsin. Recall that trypsin is also responsible for cleaving lysine peptide bonds, and thus, once a small amount of trypsin is generated, it participates in cleavage of its own zymogen, generating even more trypsin. The process of trypsin activation can thus be called autocatalytic.

Chymotrypsinogen is the zymogen of chymotrypsin. After the Arg 15 - Ile 16 bond in the chymotrypsinogen zymogen is cleaved by trypsin, the newly generated structure called a pi-chymotrypsin undergoes autolysis (self digestion), yielding active chymotrypsin.

Proelastase is the zymogen of elastase, and it is activated by cleavage through trypsin.

As can be seen, trypsinogen activation to trypsin is essential, because it activates its own reaction, as well as the reaction of both chymotrypsin and elastase. It is therefore essential that this activation doesn't occur prematurely. There are several protective measures taken by the organism to prevent self-digestion:

  • The activation of trypsinogen by trypsin is relatively slow
  • The zymogens are stored in zymogen granules, capsules that have walls that are thought to be resistant to proteolysis.

A zymogen or a proenzyme, is an inactive enzyme precursor. A zymogen requires a biochemical change, such as a hydrolysis reaction revealing the active site, for it to become an active enzyme.

Examples of zymogens are trypsinogen, chymotrypsinogen, pepsinogen, most of the proteins of the coagulation system, some of the proteins of the complement system, the caspases.[1]