Effect of Ca(2+) on the activity and structure of α-glucosidase: inhibition kinetics and molecular dynamics simulations.

Abstract

Understanding the mechanism of inhibition of α-glucosidase (EC 3.2.1.20) is clinically important because of the involvement of this enzyme in type 2 diabetes mellitus. In this study, we conducted inhibition kinetics of α-glucosidase with Ca(2+) and 10-ns molecular dynamics simulations. We found that direct binding of Ca(2+) to the enzyme induced structural changes and inhibited enzyme activity. Ca(2+) inhibited α-glucosidase in a mixed-type reaction (Ki = 27.0 ± 2.0 mM) and directly induced the unfolding of α-glucosidase, which resulted in the exposure of hydrophobic residues. The simulations suggest that thirteen Ca(2+) ions may interact with α-glucosidase residues and that the Ca(2+) binding sites are associated with the structural changes in α-glucosidase. Our study provides insight into the mechanism of the Ca(2+)-induced structural changes in α-glucosidase and the inhibition of ligand binding. These results suggest that Ca(2+) could act as a potent inhibitor of α-glucosidase for the treatment of type 2 diabetes mellitus.

• Authors: Xin Zhang, Long Shi, Xuan Li, Qing Sheng, Ling Yao, Dong Shen, Zhi-Rong Lü, Hai-Meng Zhou, Yong-Doo Park, Jinhyuk Lee, Qian Zhang
• Journal: Journal of bioscience and bioengineering (J Biosci Bioeng) Vol. 117 Issue 6 Pg. 696-705 (Jun 2014) ISSN: 1347-4421 [Electronic] Japan
• PMID: 24457149 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Glucosides
• Glycoside Hydrolase Inhibitors
• Saccharomyces cerevisiae Proteins
• 4-nitrophenyl alpha-glucoside
• alpha-Glucosidases
• Calcium

Topics

• Amino Acid Sequence
• Binding Sites
• Calcium (chemistry)
• Catalytic Domain
• Diabetes Mellitus, Type 2 (complications, enzymology)
• Enzyme Inhibitors (chemistry)
• Glucosides (chemistry)
• Glycoside Hydrolase Inhibitors
• Humans
• Kinetics
• Molecular Dynamics Simulation
• Molecular Sequence Data
• Osteoporosis (drug therapy, etiology)
• Protein Binding
• Protein Structure, Secondary
• Saccharomyces cerevisiae Proteins (antagonists & inhibitors, chemistry)
• alpha-Glucosidases (chemistry)