Inhibition of human GLUT1 and GLUT5 by plant carbohydrate products; insights into transport specificity.
Inhibition of human GLUT1 and GLUT5 by plant carbohydrate products; insights into transport specificity.
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DOI：
10.1038/srep12804
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发表时间：
2015-08-26
影响因子：
4.6
通讯作者：
Choe JY
中科院分区：
文献类型：
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作者：
George Thompson AM;Iancu CV;Nguyen TT;Kim D;Choe JY
葡萄糖转运蛋白GLUT1（运输葡萄糖）和GLUT5（运输果糖）除了在正常代谢中发挥作用外，还与包括癌症和糖尿病在内的几种疾病有关。虽然GLUT1有几种抑制剂，但尚未发现GLUT5的抑制剂。通过运输活性测定，我们发现两种植物产品，冬凌草苷（来自冬凌草）和黄芪苷-6-葡萄糖苷（来自美洲植物的黄芪苷的糖基化衍生物）可以抑制人的GLUT5。这些植物在传统医学中被用于减肥，美洲藜被用于治疗癌症，但这些产品的分子相互作用是未知的。鲁布冬苷对人的GLUT1也有抑制作用，而黄芪甲苷对GLUT1没有抑制作用。对冬冬苷的硅分析：蛋白质相互作用确定了这些转运体之间底物腔的主要差异，在GLUT1中是色氨酸，但在GLUT5中是丙氨酸。对突变蛋白的研究支持了该位置在配体特异性中的重要性。GLUT1W388A对黄芪苷-6-葡萄糖苷的抑制敏感，对冬冬苷产生抗性。GLUT5A396W不仅运输果糖，也运输葡萄糖，并保持了对冬凌草苷和黄芪甲苷-6-葡萄糖苷的抑制作用。黄芪苷-6-葡萄糖苷可以作为设计GLUT5特异性抑制剂的起点。讨论了这些研究在理解葡萄糖转运体及其与底物和配体相互作用方面的应用。
Glucose transporters GLUT1 (transports glucose) and GLUT5 (transports fructose), in addition to their functions in normal metabolism, have been implicated in several diseases including cancer and diabetes. While GLUT1 has several inhibitors, none have been described for GLUT5. By transport activity assays we found two plant products, rubusoside (from Rubus suavissimus) and astragalin-6-glucoside (a glycosylated derivative of astragalin, from Phytolacca americana) that inhibited human GLUT5. These plants are utilized in traditional medicine: R. suavissimus for weight loss and P. americana for cancer treatment, but the molecular interactions of these products are unknown. Rubusoside also inhibited human GLUT1, but astragalin-6-glucoside did not. In silico analysis of rubusoside:protein interactions pinpointed a major difference in substrate cavity between these transporters, a residue that is a tryptophan in GLUT1 but an alanine in GLUT5. Investigation of mutant proteins supported the importance of this position in ligand specificity. GLUT1W388A became susceptible to inhibition by astragalin-6-glucoside and resistant to rubusoside. GLUT5A396W transported fructose and also glucose, and maintained inhibition by rubusoside and astragalin-6-glucoside. Astragalin-6-glucoside can serve as a starting point in the design of specific inhibitors for GLUT5. The application of these studies to understanding glucose transporters and their interaction with substrates and ligands is discussed.