Zymogen (Molecular Biology)

A zymogen is an enzymatically inactive precursor of an enzyme, often but not always a proteolytic enzyme (or proteinase). Some zymogens are named by adding the suffix -ogen to the name of the enzyme itself, as in trypsinogen or pepsinogen, whereas others are indicated by the prefix pro-, as in pro-collagenase or pro-carboxypeptidase. No strict rules of nomenclature pertain. Hence, pro-renin rather than reninogen, pre-kallikrein rather than pro-kallikrein, Factor X rather than proFactor Xa, etc. Also, some proteins are given the suffix -ogen even if they are not a proteinase (or even an enzyme) precursor—for example, fibrinogen or angiotensinogen.

Zymogens are one of Nature’s ways of ensuring that proteinase (or other) activity will be generated only at the most appropriate time and in the most appropriate place. Most of the digestive proteinases produced in the pancreas are synthesized as zymogens and stored as such in zymogen granules in the acinar cells. The contents of these granules are only released into the small intestine when food is eaten, and the zymogens are only activated once they enter the small intestine. This latter process is initiated by an intestinal proteinase, enterokinase. Inappropriate activation of these zymogens within the pancreas can cause pancreatitis and have devastating consequences.

Zymogen activation typically involves cleavage of a single peptide bond in the precursor protein. Sometimes, as in the case of pepsinogen, the proteinase responsible for cleaving that peptide bond is the zymogen itself. Briefly, in the acidic environment of the stomach the pepsinogen molecule unfolds enough to expose the active site, which then catalyzes a process of autoactivation by clipping off a peptide segment from the N-terminus of other pepsinogen molecules, thereby activating them and setting off a chain reaction. The pancreatic zymogens are activated by trypsin, which is itself generated from trypsinogen by enterokinase. Activation of trypsinogen involves removal of a six-residue peptide from its amino terminus, whereas activation of chymotrypsinogen involves cleavage of the peptide bond joining Arg15 and Ile16. The first 15 amino acids are linked to the rest of chymotrypsin by a disulfide bond, so there is no actual removal of a peptide. After activation, chymotrypsin undergoes some proteolytic fine-tuning and loses two internal dipeptides, but this is more for stabilization than for activation.


Many other strategies have evolved for zymogen activation, but basically they all come down to inducing a change in the conformation of the precursor by cleaving a peptide bond and thereby altering the primary structure (amino acid sequence) of the protein; or by interaction with another molecule, a cell surface, or some other type of structure.

Once a zymogen has been activated, Nature must resort to other means to control its activity, and in the case of proteinases there is no shortage of inhibitors (see Proteinase Inhibitors and Proteinase Inhibitors, Proteins). Moreover, proteinases being what they are, they can serve as their own substrates and their activities can be abolished by autolysis (self-digestion).

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