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Opening Image: Porcine pepsin, shown here as the solvent-accessible surface model.
Pepsin is derived from its precursor pepsinogen by activation at acidic pH. Upon ingestion of food, pepsinogen is released into the lumen of the stomach and undergoes conversion into active enzyme in the acidic gastric juice. This activation reaction is initiated by the disruption of electrostatic interactions between the propeptide and the active enzyme moiety at acidic pH values.
The active site of pepsin is a large cleft that can bind hydrophobic peptides. The catalytic dyad (Asp 32 and Asp 215) is located at the bottom of the cleft. to the cleft.
the catalytic dyad CPK.
backbone trace model. A water molecule bridges the two aspartates. Though not shown, one Asp is protonated and is hydrogen-bonded to the other Asp. The water is also hydrogen-bonded to both side chain carboxyls.
As a result of gene duplication, all pepsin-like aspartic proteases have two homologous domains. Each domain contains one of the catalytic aspartyl residues. In this model, one domain is colored in shades of teal while the other is colored in shades of violet. The peptide connecting the two domains is colored white.
between cartoon and spacefill models. Note that three β strands from each domain form a continuous β sheet forming a rigid platform at the base of the molecule.
The atoms are now colored by formal charge. The net charge on pepsin below pH 4 is close to zero because the side chain carboxyls are mostly unionized. Consequently, pepsin is stable at pH 2.
the acidic residues Asp and Glu, in red.
the basic residues Arg, Lys, and His. How many positively charged side chains, shown in blue, can you find? Is pepsin stable at neutral pH? Explain.
Let's turn now to pepepsinogen and its distribution of charged residues.