Cathepsins S, B and L with aminopeptidases display β-secretase activity associated with the pathogenesis of Alzheimer's disease.

β-site APP-cleaving enzyme (BACE1) cleaves the wild type (WT) β-site very slowly (k(cat)/K(m): 46.6 m(-1) s(-1)). Therefore we searched for additional β-secretases and identified three cathepsins that split the WT β-site much faster.

Kinetic properties of cathepsin D and BACE 1 indicate the need to search for additional beta-secretase candidate(s).

Many studies suggest that BACE 1 is the genuine beta-secretase; however, this is not undisputed. The wild-type (WT) beta-site of the amyloid precursor protein (APP) present in the worldwide population is cleaved very slowly (kcat/Km: approx. 50 m(-1) s(-1)), while proteases acting on relevant substrates are much more efficient (kcat/Km: 10(4)-10(6) m(-1) s(-1)).

Inhibitors can activate proteases to catalyze the synthesis and hydrolysis of peptides.

Competitive inhibitors can activate proteases (papain, trypsin, and cathepsin S) to catalyze the synthesis of peptide bonds and accelerate the hydrolysis of poor substrates (from 1 to 99%). Reaction mixtures contained intermediate molecules that were formed by the coupling of the inhibitor with the poor substrate. This and other findings suggest the following chain of events.