Zymogens and proteolytic cleavage
A zymogen is an enzyme made in an inactive form (a precursor), then switched on when a protease (an enzyme that cuts other proteins) cuts part off its chain.
Remember
Digestive proteases are kept inactive as zymogens until proteolytic cleavage switches them on where they are needed, which protects the cells that make them.
Many digestive enzymes are proteases, enzymes that cut other proteins. Made in their active form, they would damage the cells that produce them, a problem called autodigestion (self-digestion).
To prevent this, the cell makes the enzyme as an inactive precursor called a zymogen, which is the form the enzyme has before it is switched on. Trypsinogen, for example, is the precursor of trypsin, which then activates other digestive zymogens. A zymogen is switched on by proteolytic cleavage: a protease cuts part off the chain. For digestive enzymes, this happens after the enzyme has been secreted, outside the cells that make it.
The cut cannot be undone, so the switch is irreversible, and the body controls the place and the moment at which an enzyme starts to work.
The same design is used in apoptosis (programmed cell death) and in blood clotting, where a rapid response is needed. Many of the activation steps form a cascade: each activated enzyme switches on the next zymogen in the chain, and one active molecule can switch on many, so a small trigger gives a large, quick response.
If trypsinogen is activated too early, inside the acinar cells (the cells of the pancreas that make and secrete the digestive enzymes), the gland begins to digest itself. This is the classic explanation of acute pancreatitis (inflammation of the pancreas), although other processes also drive the inflammation.
Key facts
- Zymogen
- an inactive precursor of an enzyme; for digestive proteases, it is made so that the cell producing the enzyme is not damaged by it.
- Stomach example
- pepsin, which digests protein, is made as inactive pepsinogen and activated in the stomach lumen (the hollow space inside the stomach).
- Pancreas example
- trypsinogen is normally converted to active trypsin only in the small intestine, and trypsin then activates other digestive zymogens.
- Switch
- proteolytic cleavage cannot be undone, so it acts as an irreversible switch.
- Other uses
- apoptosis (the caspases, proteases that dismantle the cell) and the clotting cascade also use inactive precursors.
- When it fails
- early activation of trypsinogen inside the acinar cells is the classic explanation of how autodigestion and inflammation start in acute pancreatitis, although other processes also drive the inflammation.
Exam traps
- Making an enzyme as a zymogen is not a way to keep it stable in stomach acid, because most pancreatic zymogens never encounter stomach acid and the inactive state prevents self-digestion.
- A zymogen is switched on by irreversible proteolytic cleavage, not by phosphorylation (the addition of a phosphate group), which is a separate and reversible way of controlling an enzyme.
- Cleavage does not let an enzyme be recycled (returned to an inactive form), because the cut cannot be reversed and proteolytic enzymes are generally broken down after use.
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