title: Inhibition of human GLUT1 and GLUT5 by plant carbohydrate products; insights into transport specificity.
abstract: 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.
authors: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
authors: Alayna M
authors: AM
authors: George Thompson
authors: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
authors: Cristina V
authors: CV
authors: Iancu
authors: The Institute of Food Industrialization, Institutes of Green Bio Science &Technology, Seoul National University, Pyeongchang-Gun, Gangwon-do, 232-916, South Korea.
authors: Thi Thanh Hanh
authors: TT
authors: Nguyen
authors: The Institute of Food Industrialization, Institutes of Green Bio Science &Technology, Seoul National University, Pyeongchang-Gun, Gangwon-do, 232-916, South Korea.|Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang-gun, Gangwon-do, 232-916, South Korea.
authors: Doman
authors: D
authors: Kim
authors: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL, 60064, USA.
authors: Jun-yong
authors: JY
authors: Choe
mesh_terms: D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D002241:Carbohydrates / Q000737:chemistry; D045786:Diterpenes, Kaurane / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051296:Glucose Transporter Type 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005960:Glucosides / Q000008:administration & dosage*; D006801:Humans; D044949:Kaempferols / Q000008:administration & dosage*; D010936:Plant Extracts / Q000008:administration & dosage*
chemical_list: D002241:Carbohydrates; D045786:Diterpenes, Kaurane; D051272:Glucose Transporter Type 1; D051296:Glucose Transporter Type 5; D005960:Glucosides; D044949:Kaempferols; D010936:Plant Extracts; C495677:SLC2A1 protein, human; C495726:SLC2A5 protein, human; C001579:astragalin; D005947:Glucose; C056177:rubusoside