Li Xin-Yu, Wang Tian, Wu Sheng-Li, Huang Xiao-Yan, Ma Yun-Bao, Geng Chang-An
Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.
Int J Biol Macromol. 2025 Mar;295:139496. doi: 10.1016/j.ijbiomac.2025.139496. Epub 2025 Jan 6.
Diabetes mellitus (DM) is a chronic metabolic disorder characterized by elevated blood glucose levels, generally due to defects of insulin action or secretion. Inhibition of α-glucosidase, an enzyme responsible for carbohydrate degradation, is a promising strategy for managing postprandial hyperglycemia in diabetic patients. In this study, two new C-linked diarylheptanoid dimers, kaemgalanganols A (1) and B (2), were isolated from K. galanga, which showed obvious inhibitory activity on α-glucosidase but weak activity on protein tyrosine phosphatase 1B (PTP1B). Kaemgalanganol B had an IC value of 35.1 μM against α-glucosidase, obviously more potent than kaemgalanganol A (IC = 78.5 μM) and acarbose (IC = 363.0 μM). Enzyme kinetic study indicated that 2 was a reversible mixed-type inhibitor of α-glucosidase via non-competitive and anti-competitive inhibition modes. Fluorescence quenching and UV-visible spectroscopic study revealed that fluorescence quenching mechanism of 2 on α-glucosidase is a combination of dynamic quenching and static quenching, accompanied by non-radiative energy transfer. Compound 2 formed complex with α-glucosidase closer to the Tyr residue, and induced changes in both the microenvironment and peptide backbone. Surface hydrophobicity and CD spectra measurement indicated that 2 affected the function of α-glucosidase by decreasing the surface hydrophobicity of α-glucosidase as well as altering the secondary structure instead of the overall three-dimensional framework, which is consistent with the results of fluorescence experiment. Molecular docking manifested that compound 2 had a strong binding affinity (-7.27 kcal/mol) with α-glucosidase, higher than 1 (-9.82 kcal/mol) and acarbose (-4.48 kcal/mol), consistent with the enzyme inhibitory assay. Besides hydrogen bonds, electrostatic interactions and hydrophobic interactions played important roles in the binding of 2 with α-glucosidase. This study disclosed the inhibitory activity and mechanism of 2 against α-glucosidase, which provides a theoretical basis for the development of new antidiabetic drugs form K. galanga.
糖尿病（DM）是一种慢性代谢紊乱疾病，其特征为血糖水平升高，通常是由于胰岛素作用或分泌缺陷所致。抑制α-葡萄糖苷酶（一种负责碳水化合物降解的酶）是控制糖尿病患者餐后高血糖的一种有前景的策略。在本研究中，从高良姜中分离出两种新的C-连接二芳基庚烷二聚体，即高良姜醇A（1）和高良姜醇B（2），它们对α-葡萄糖苷酶表现出明显的抑制活性，但对蛋白酪氨酸磷酸酶1B（PTP1B）的活性较弱。高良姜醇B对α-葡萄糖苷酶的IC值为35.1 μM，明显比高良姜醇A（IC = 78.5 μM）和阿卡波糖（IC = 363.0 μM）更有效。酶动力学研究表明，2是α-葡萄糖苷酶的可逆混合型抑制剂，通过非竞争性和反竞争性抑制模式起作用。荧光猝灭和紫外-可见光谱研究表明，2对α-葡萄糖苷酶的荧光猝灭机制是动态猝灭和静态猝灭的结合，伴有非辐射能量转移。化合物2与α-葡萄糖苷酶形成的复合物更靠近酪氨酸残基，并引起微环境和肽主链的变化。表面疏水性和圆二色光谱测量表明，2通过降低α-葡萄糖苷酶的表面疏水性以及改变二级结构而非整体三维框架来影响α-葡萄糖苷酶的功能，这与荧光实验结果一致。分子对接表明，化合物2与α-葡萄糖苷酶具有很强的结合亲和力（-7.27 kcal/mol），高于1（-9.82 kcal/mol）和阿卡波糖（-4.48 kcal/mol），与酶抑制试验结果一致。除了氢键外，静电相互作用和疏水相互作用在2与α-葡萄糖苷酶的结合中也起重要作用。本研究揭示了2对α-葡萄糖苷酶的抑制活性和作用机制，为从高良姜中开发新型抗糖尿病药物提供了理论依据。
