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Why does pepsin work effectively in the acidic environment of the stomach?

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A multi-panel diagram illustrates how a substrate binds to an enzyme's active site through induced fit, leading to product formation, and shows how non-substrates and allosteric regulators can alter enzyme activity by binding to different sites on the enzyme. — Enzyme In the induced-fit theory of enzyme-substrate binding, a substrate approaches the surface of an enzyme (step 1 in box A, B, C) and causes a change in the enzyme shape that results in the correct alignment of the catalytic groups (triangles A and B; circles C and D represent substrate-binding groups on the enzyme that are essential for catalytic activity). The catalytic groups react with the substrate to form products (step 2). The products then separate from the enzyme, freeing it to repeat the sequence (step 3). Boxes D and E represent examples of molecules that are too large or too small for proper catalytic alignment. Boxes F and G demonstrate binding of an inhibitor molecule (I and I′) to an allosteric site, thereby preventing interaction of the enzyme with the substrate. Box H illustrates binding of an allosteric activator (X), a nonsubstrate molecule capable of reacting with the enzyme.

Pepsin is a proteolytic enzyme that functions most effectively in the highly acidic environment of the stomach, specifically at a pH range of 1.5 to 2.5.1

While most biological systems maintain a neutral pH of approximately 7 to ensure enzyme stability, pepsin is uniquely adapted to operate within an acid milieu. This acidity is provided by hydrochloric acid, which is secreted by parietal cells in the gastric glands. When the inactive precursor pepsinogen is released into the stomach, it mixes with this acid and is rapidly converted into its active, mature form.213

The enzyme's digestive power is greatest under these acidic conditions; conversely, when gastric contents move into the small intestine and the environment is neutralized to a pH of 7, pepsin becomes ineffective. To prevent the stomach from digesting its own tissues, the gastric lining is protected by a thick layer of mucus and a membrane rich in lipoproteins, which are resistant to acid and enzymatic attack.143