Metal ions affect insulin-degrading enzyme activity

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

IDE activity in the presence of different metal ions toward insulin and a portion of the insulin B chain (B20–30) was investigated. The results obtained show that IDE is irreversibly inhibited by copper(I) but is still able to process its substrates when it is bound to copper(II).Figure optionsDownload as PowerPoint slideHighlights
► The effect of various metal ions on IDE activity toward insulin is investigated.
► B20-30 does not bind metal ions and is used in IDE enzymatic assays.
► The effect of direct metal-enzyme binding on IDE activity is assessed.
► IDE is irreversibly inhibited by copper(I).
► IDE is reversibly and only partially inhibited by copper(II).