Binding Interaction of Betulinic Acid to α-Glucosidase and Its Alleviation on Postprandial Hyperglycemia
Shaodan Chen,
Bing Lin,
Jiangyong Gu,
Tianqiao Yong,
Xiong Gao,
Yizhen Xie,
Chun Xiao,
Janis Yaxian Zhan,
Qingping Wu
Affiliations
Shaodan Chen
Guangdong Provincial Key Laboratory of Microbial Safety and Health, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Science, Guangzhou 510070, China
Bing Lin
School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
Jiangyong Gu
Research Centre for Integrative Medicine, School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
Tianqiao Yong
Guangdong Provincial Key Laboratory of Microbial Safety and Health, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Science, Guangzhou 510070, China
Xiong Gao
Guangdong Provincial Key Laboratory of Microbial Safety and Health, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Science, Guangzhou 510070, China
Yizhen Xie
Guangdong Provincial Key Laboratory of Microbial Safety and Health, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Science, Guangzhou 510070, China
Chun Xiao
Guangdong Provincial Key Laboratory of Microbial Safety and Health, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Science, Guangzhou 510070, China
Janis Yaxian Zhan
School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
Qingping Wu
Guangdong Provincial Key Laboratory of Microbial Safety and Health, Key Laboratory of Agricultural Microbiomics and Precision Application, Ministry of Agriculture and Rural Affairs, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Science, Guangzhou 510070, China
Inhibiting the intestinal α-glucosidase can effectively control postprandial hyperglycemia for type 2 diabetes mellitus (T2DM) treatment. In the present study, we reported the binding interaction of betulinic acid (BA), a pentacyclic triterpene widely distributed in nature, on α-glucosidase and its alleviation on postprandial hyperglycemia. BA was verified to exhibit a strong inhibitory effect against α-glucosidase with an IC50 value of 16.83 ± 1.16 μM. More importantly, it showed a synergistically inhibitory effect with acarbose. The underlying inhibitory mechanism was investigated by kinetics analysis, surface plasmon resonance (SPR) detection, molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. BA showed a non-competitive inhibition on α-glucosidase. SPR revealed that it had a strong and fast affinity to α-glucosidase with an equilibrium dissociation constant (KD) value of 5.529 × 10−5 M and a slow dissociation. Molecular docking and MD simulation revealed that BA bound to the active site of α-glucosidase mainly due to the van der Waals force and hydrogen bond, and then changed the micro-environment and secondary structure of α-glucosidase. Free energy decomposition indicated amino acid residues such as PHE155, PHE175, HIE277, PHE298, GLU302, TRY311 and ASP347 of α-glucosidase at the binding pocket had strong interactions with BA, while LYS153, ARG210, ARG310, ARG354 and ARG437 showed a negative contribution to binding affinity between BA and α-glucosidase. Significantly, oral administration of BA alleviated the postprandial blood glucose fluctuations in mice. This work may provide new insights into the utilization of BA as a functional food and natural medicine for the control of postprandial hyperglycemia.
