Active center differences between cathepsins L and B: The S1 binding region

Abstract

The substrate peptide bond cleaved by cathepsins B and L is determined not by the amino acid contributing the carboxyl group to this bond as in the case of serine proteases but rather by the presence of a neighboring amino acid with a large hydrophobic side chain. From a study of the inhibitory potency in a series, Cbz-Phe-X-CHN₂, in which Phe promotes binding at S₂ (terminology of [(1968) Biochem. Biophys. Res. Commun. 32, 898–902]) while the amino acid X probes S₁, it is shown that this region of cathepsin L also has the ability to accommodate large hydrophobic side chains. In this respect cathepsin L differs from cathepsin B. Thus Cbz-Phe-Tyr(O-t-Bu)CHN₂ inactivates cathepsin L with a rate 2.5 × 10⁴ greater than that for cathepsin B.