New Glucosidase Inhibitors from an Ayurvedic Herbal Treatment for Type 2 Diabetes: Structures and Inhibition of Human Intestinal Maltase-Glucoamylase with Compounds from Salacia reticulata
New Glucosidase Inhibitors from an Ayurvedic Herbal Treatment for Type 2 Diabetes: Structures and Inhibition of Human Intestinal Maltase-Glucoamylase with Compounds from Salacia reticulata
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DOI：
10.1021/bi9016457
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发表时间：
2010-01-26
期刊：
影响因子：
2.9
通讯作者：
Rose, David R.
中科院分区：
文献类型：
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作者：
Sim, Lyann;Jayakanthan, Kumarasamy;Rose, David R.
控制2型糖尿病患者血糖水平的一种方法是使用α -葡萄糖苷酶抑制剂阿卡波糖和米格糖醇靶向α -淀粉酶和肠道葡萄糖苷酶。肠道糖苷酶的靶点之一是麦芽糖酶-葡萄糖分析酶（ntMGAM）的n端催化结构域，麦芽糖酶-葡萄糖分析酶（ntMGAM）是四种肠道糖苷水解酶31活性之一，负责将末端淀粉产物水解成葡萄糖。在这里，我们展示了ntMGAM与一类新的α -葡萄糖苷酶抑制剂复合物的x射线晶体学研究，这些抑制剂来自于网状Salacia reticulata的天然提取物，这种植物传统上用于阿育吠陀医学治疗2型糖尿病。这些提取物中包括活性化合物salacinol， kotalanol，和去氧磺化kotalanol。本研究表明，去氧磺化的草柳醇是迄今为止报道的最有效的ntMGAM抑制剂（Ki = 0.03 μ M），比目前临床使用的化合物要好2000倍左右，并突出了草柳醇类抑制剂作为未来候选药物的潜力。
An approach to controlling blood glucose levels in individuals with type 2 diabetes is to target alpha-amylases and Intestinal glucosidases using alpha-glucosidase Inhibitors acarbose and miglitol. One of the intestinal glucosidases targeted is the N-terminal catalytic domain of maltase-glucoanlylase (ntMGAM), one of the four intestinal glycoside hydrolase 31 enzyme activities responsible for the hydrolysis of terminal starch products into glucose. Here we present the X-ray crystallographic studies of ntMGAM in complex with a new class of alpha-glucosidase inhibitors derived from natural extracts of Salacia reticulata, a plant used traditionally in Ayurvedic medicine for the treatment of type 2 diabetes. Included in these extracts are the active Compounds salacinol, kotalanol, and de-O-sulfonated kotalanol. This study reveals that de-O-sulfonated kotalanol is the most potent ntMGAM inhibitor reported to date (Ki = 0.03 mu M), some 2000-fold better than the compounds currently used in the clinic, and highlights the potential of the salacinol class of inhibitors as future drug candidates.