zymogen activation

Meaning: A zymogen is made and stored in an inactive form so it cannot digest the cell that makes it or act at the wrong place or time. A protease cuts one or more peptide bonds, and the chain changes shape so a working active site forms or becomes accessible. Because a covalent backbone bond is broken, the step cannot be reversed. Examples: trypsinogen → trypsin (enteropeptidase in the small intestine) chymotrypsinogen → chymotrypsin (activated by trypsin) pepsinogen → pepsin (acidic pH, then pepsin itself) prothrombin → thrombin (clotting) Active trypsin also activates other zymogens, so one cleavage is amplified into a cascade.

On the MCAT: Passages ask you to sort regulation types: allosteric control, reversible covalent modification such as phosphorylation, or irreversible proteolytic cleavage. You may be told that a purified precursor has no activity until a protease is added, or shown a gel in which a band shifts to a smaller size after cleavage. You may also be asked to predict what happens downstream if the first activating protease is missing or if trypsin is added.

Common confusion: Students group zymogen activation with phosphorylation. Phosphorylation is reversible, since phosphatases remove the group. Proteolytic cleavage is not reversible, so the cell turns the enzyme off with inhibitors or by degrading it, not by re-forming the zymogen.