Department of Medicine, Division of Infectious Diseases and Immunology; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences, Biochemistry and Molecular Pharmacology Program
Amino Acids, Peptides, and Proteins | Biochemistry | Carbohydrates | Cellular and Molecular Physiology | Molecular Biology | Structural Biology
The anti-oxidant, flavonoid-rich content of red wine and green tea is reported to offer protection against cancer, cardiovascular disease and diabetes. Some studies, however, show that flavonoids inhibit GLUT1-mediated, facilitative glucose transport raising the possibility that their interaction with GLUT1 and subsequent, downstream effects on carbohydrate metabolism may also impact health. The present study explores the structure/function relationships of flavonoid-GLUT1 interactions. We find that low concentrations of flavonoids act as cis-allosteric activators of sugar uptake while higher concentrations competitively inhibit sugar uptake and noncompetitively inhibit sugar exit. Studies with heterologously expressed human GLUTs 1, 3 and 4 reveal that quercetin-GLUT1 and -GLUT4 interactions are stronger than quercetin-GLUT3 interactions, that ECG is more selective for GLUT1 while EGCG is less isoform-selective. Docking studies suggest that only one flavonoid can bind to GLUT1 at any instant, but sugar transport and ligand binding studies indicate that human erythrocyte GLUT1 can bind at least two flavonoid molecules simultaneously. Quercetin and EGCG are each characterized by positive, cooperative binding whereas EGC shows negative cooperative binding. These findings support recent studies suggesting that GLUT1 forms an oligomeric complex of interacting, allosteric, alternating access transporters. We discuss how modulation of facilitative glucose transporters could contribute to the protective actions of the flavonoids against diabetes and Alzheimer's.
allosteric regulation, glucose transport, membrane transport, oligomerization, structure-function
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DOI of Published Version
J Biol Chem. 2018 Oct 25. pii: RA118.002326. doi: 10.1074/jbc.RA118.002326. [Epub ahead of print] Link to article on publisher's site
The Journal of biological chemistry
Ojelabi OA, Lloyd KP, De Zutter JK, Carruthers A. (2018). Red wine and green tea flavonoids are cis-allosteric activators and competitive inhibitors of GLUT1-mediated sugar uptake. Open Access Publications by UMass Chan Authors. https://doi.org/10.1074/jbc.RA118.002326. Retrieved from https://escholarship.umassmed.edu/oapubs/3637