Metal ions affect insulin-degrading enzyme activity

Insulin degradation is a finely tuned process that plays a major role in controlling insulin action andmost evidence supports IDE (insulin-degrading enzyme) as the primary degradative agent. However, thebiomolecular mechanisms involved in the interaction between IDE and its substrates are often obscure,rendering quite difficult to target the specific enzyme activity. On the other hand, biometals, such ascopper, aluminum and zinc, have an important role in pathological conditions such as Alzheimer’sdisease or diabetes mellitus. The metabolic disorders connected with the latter lead to somemetallostasis alterations in the human body and many studies point at a high level of interdependencebetween diabetes and several cations. We have previously reported (Grasso et al., Chem.- Eur. J. 17(2011) 2752–2762) that IDE activity towards Aβ peptides can be modulated by metal ions. Here, wehave investigated the effects of different metal ions on the IDE proteolytic activity towards insulin aswell as a designed peptide comprising a portion of the insulin B chain (B20-30), which has a very lowaffinity for metal ions. The results obtained by different experimental techniques clearly show that IDEis irreversibly inhibited by copper(I) but is still able to process its substrates when it is bound tocopper(II).