Metal ions affect insulin-degrading enzyme activity

Abstract

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).

The role of copper(ii) in the aggregation of human amylin

“…[31][32][33] The further role that copper(II) might have in modulating the degradation of amylin by these enzymes has not been studied, even if this metal ion has been proven to be able to tune the enzymatic activity of some of these metalloproteases. [34][35][36] The copper(II)-driven conformational changes on h-amylin ought to have a large impact on its in vivo homeostasis.…”

A neglected modulator of insulin-degrading enzyme activity and conformation: The pH

“…MS results confirm that such different binding features affect IDE capability to degrade insulin, as the enzyme is inactive toward the hormone at acidic pH. Moreover, the insulin fragments detected by MS at basic pH involve the C-terminal residues of the insulin A chain [A (14-21) and A (15)(16)(17)(18)(19)(20)(21)] and the fragments B (17-24) and B (17)(18)(19)(20)(21)(22)(23)(24)(25). The same set of insulin fragments are known to be produced in solutions containing IDE at high concentrations, where the equilibrium in the oligomerization state of the enzyme is mainly shifted toward the dimeric and/or tetrameric forms.…”

“…Interestingly, apart from the changes on the overall activity, it is possible to note that the insulin fragments detected at alkaline pH are different from the ones detected at physiological pH. Particularly, the insulin fragments involving the C-terminal residues of the insulin B (17)(18)(19)(20)(21)(22)(23)(24)(25) are mainly produced at alkaline pH [15]. The same set of insulin fragments are known to be produced in solutions containing IDE at high concentrations [15] and therefore it is easy to speculate that the pH, as well as the enzyme concentration, has an effect on IDE oligomerization state, acidic pH shifting the equilibrium toward the monomeric form.…”

“…Indeed, considerable evidence suggests that IDE inhibitors may hold therapeutic value, particularly for type 2 diabetes and other disorders involving impaired insulin signaling [12], while IDE activators could be used as possible drugs aiming at lowering Aβ levels in AD [13]. Moreover, the effect that other experimental factors such as oligomerization state [14][15][16], presence of metal ions [17][18][19][20] and oxidative stress [21][22][23] can have on IDE activity has also been widely investigated.…”

Effects of metal ions on the catalytic degradation of dicofol by cellulase

“…Catalysis with enzymes is one of the biodegradation pathways (Du et al, 2013;Pradub and Wattanachai, 2012). Research has shown that metal ions had impacts on enzyme activity and biological degradation efficiency (Jernejc and Legiša, 2002;Grasso et al, 2012;Madukasi et al, 2010;Gopinath et al, 2011). The co-occurrence of dicofol and heavy metal ions in farmland is common in China (Sun et al, 2012;Zhang and Shan, 2014).…”