Effect of Steric Factors on Digestibility of Peptides Containing Aromatic Amino Acids by Cathepsin D and Pepsin

Of the oligomers of phenylalanine studied, tri‐ and tetra‐phenylalanine methyl esters were found to be cleaved by cathepsin D at the Phe‐Phe bond. Substitution of the amino group by the benzyloxycarbonyl group renders the substrate resistant to cleavage. By contrast pepsin readily cleaves di‐phenylalanine methyl ester and its action is not inhibited by the substitution of the amino group. In the hexapeptide Gly‐Phe‐Leu‐Gly‐Phe‐Leu, bonds 2–3, 3–4, and 5–6 are cleaved by pepsin. The same substrate is cleaved by cathepsin D only at bond 2–3, the value of the Michaelis constant for this reaction being Km= 3.3×10−4 M. A change in configuration of the amino acid involved in the sensitive bond completely inhibits the cleavage of the linear hexapeptide by both enzymes. Differences in the steric arrangement of diastereomeric substrates affect the action of cathepsin D considerably more than that of pepsin. d‐Isomers competitively inhibit the cleavage of the l‐isomer. The cyclic hexapeptide Gly‐Phe‐Leu‐Gly‐Phe‐Leu is cleaved neither with pepsin nor cathepsin and it does not inhibit the cleavage of the linear hexapeptide.