Inhibitory effect of Zn2+ on α-glucosidase: Inhibition kinetics and molecular dynamics simulation

Abstract

α-Glucosidase (EC 3.2.1.20) is a critical enzyme with clinical relevance to type 2 diabetes mellitus. Therefore, research on this enzyme's inhibition is important. In the present study, we investigated Zn2+-induced inhibition and the structural changes of α-glucosidase. α-Glucosidase activity was significantly inhibited by Zn2+ in a dose-dependent manner. The inhibition followed a multi-phase kinetic process with a first-order reaction. Zn2+ inhibited α-glucosidase in a parabolic mixed-type reaction (Ki=0.102±0.001mM) and directly induced the unfolding of α-glucosidase, resulting in a slight hydrophobic exposure. We also performed 10ns molecular dynamics simulations on α-glucosidase and Zn2+. The simulations suggest that ten Zn2+ ions possibly interact with 57 α-glucosidase residues. The molecular dynamics simulations also confirmed the binding mechanism of Zn2+ to α-glucosidase and suggest that the Zn2+ binding sites are not located in the glucose binding pocket of α-glucosidase. Our study provides insights into the mechanism of Zn2+-induced unfolding of α-glucosidase and inhibition of ligand binding and suggests that Zn2+ could act as a potent inhibitor of α-glucosidase for the treatment of type 2 diabetes mellitus.