Red wine and green tea flavonoids are cis-allosteric activators and competitive inhibitors of glucose transporter 1 (GLUT1)-mediated sugar uptake

Kenneth P Lloyd,Julie K De Zutter,Ogooluwa A Ojelabi,Anthony Carruthers

doi:10.1074/jbc.ra118.002326

Kenneth P Lloyd, Julie K De Zutter + Show 2 more

Open Access

https://doi.org/10.1074/jbc.ra118.002326

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Abstract

The antioxidant- and flavonoid-rich contents of red wine and green tea are 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, whereas higher concentrations competitively inhibit sugar uptake and noncompetitively inhibit sugar exit. Studies with heterologously expressed human GLUT1, -3, or -4 reveal that quercetin-GLUT1 and -GLUT4 interactions are stronger than quercetin-GLUT3 interactions, that epicatechin gallate (ECG) is more selective for GLUT1, and that epigallocatechin gallate (EGCG) is less GLUT 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 ECG 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 disease.

Highlights

The antioxidant- and flavonoid-rich contents of red wine and green tea are reported to offer protection against cancer, cardiovascular disease, and diabetes
We examined the effects of quercetin, epigallocatechin gallate (EGCG), and epicatechin gallate (ECG) (Fig. 1, B–D) on GLUT1-mediated, zero-trans uptake of 3-O-methylglucose (3MG; a transported but nonmetabolized sugar) in human red blood cells
Transport theory informs us [26, 27] that a ligand competing with sugar for binding at the exofacial sugar binding site serves as a competitive inhibitor of sugar uptake and as a noncompetitive inhibitor of sugar exit

Summary

To whom correspondence should be addressed

GLUT3, and GLUT4, leading to downstream effects on carbohydrate metabolism. The flavonoids are a large group of polyphenolic secondary metabolites with over 4,000 types identified in fruits, flowers, vegetables, and leaves [5, 6]. Show that quercetin, EGCG, and ECG inhibit GLUT1-mediated facilitative glucose transport [15, 16], raising the possibility that it is their interaction with GLUT1 and their downstream effects on carbohydrate metabolism that impact health. Whereas this may explain their actions in cancer, where GLUT1 expression and nonoxidative glucose metabolism are up-regulated [17], it is harder to understand how sugar transport inhibition would ameliorate diabetes and cardiovascular disease. Efits of flavonoids may derive from their antioxidant capacities, future studies should consider how the dual actions of flavonoids on glucose transport may influence downstream glucose metabolism in tumors, in insulin-secreting and responsive tissues, and in the CNS

Results

Discussion

Experimental procedures