Insulysin: An allosteric enzyme as a target for Alzheimer's disease

That the zinc metalloendopeptidase insulysin (insulin-degrading enzyme IDE) is a major beta-amyloid (A beta) peptide-degrading enzyme in vivo is shown by the higher A beta peptide levels in the brain of an insulysin-deficient mouse. Insulysin was shown to initially cleave A beta(1-40)and A beta(1-42)at His(13)-Gln(14), His(14)-Gln(15), and Phe(19)-Phe(20). The insulysin-dependent cleavage of A beta prevents both the neurotoxic effects of the peptide as well as the ability of A beta to deposit onto synthetic amyloid plaques. The kinetics of the reaction of insulysin with the synthetic peptide substrate Abz-G-G-F-L-R-K-H-G-Q-EDDnp displays allosteric properties indicative of a regulated enzyme. Small peptide substrates increase the activity of insulysin toward the hydrolysis of A beta(1-40) without affecting the activity of the enzyme toward insulin. These studies indicate that insulysin is a target for drug development in which small-molecule peptide analogs can be used to increase the rate of A beta clearance without affecting insulin levels.