Pepsinogen Activation to Pepsin: The Role of Gastric Acid and Autocatalysis

Pepsinogen (zymogen) → Pepsin (active protease) occurs in the stomach lumen:

1. Protonation: H⁺ binds specific aspartate residues → conformational change exposing active site.
2. Autocatalytic Cleavage: Activated pepsinogen cleaves its own N-terminal peptide (44 aa) → mature pepsin.
3. Positive Feedback: Newly formed pepsin activates additional pepsinogen molecules exponentially.

This pH-dependent mechanism ensures proteolytic activity only in the acidic gastric environment, preventing autodigestion of chief cells.