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

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Title
Inhibitory effect of Zn2+ on α-glucosidase: Inhibition kinetics and molecular dynamics simulation
Author(s)
Y F Zeng; Jinhyuk Lee; Y X Si; L Yan; T R Kim; G Y Qian; Z R Lu; Z M Ye; S J Yin
Bibliographic Citation
Process Biochemistry, vol. 47, no. 12, pp. 2510-2517
Publication Year
2012
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 Zn 2+-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 ± 0.001 mM) and directly induced the unfolding of α-glucosidase, resulting in a slight hydrophobic exposure. We also performed 10 ns 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 Zn 2+ could act as a potent inhibitor of α-glucosidase for the treatment of type 2 diabetes mellitus.
Keyword
α-GlucosidaseInhibition kineticsMolecular dynamicsUnfoldingZn2+
ISSN
0032-9592
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.procbio.2012.10.014
Type
Article
Appears in Collections:
Division of Biomedical Research > Genome Editing Research Center > 1. Journal Articles
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