Pepsin works best in the stomach (pH ~2) but fails in the small intestine (pH ~8). Why?

Core Concept

Pepsin functions best under strongly acidic conditions because the ionization states and conformation of active-site residues are suited to low pH. At the much higher pH of the small intestine, those charge states change and catalytic activity falls sharply. Extreme pH can sometimes contribute to denaturation, but loss of activity at pH 8 should not automatically be described as irreversible denaturation.