Caffeine inhibits glucose transport by binding at the GLUT1 nucleotide-binding site

Glucose transporter1 ( GLUT1) is the primary glucose transportprotein of the cardiovascular system and astroglia. A recent study proposes that caffeineuncompetitive inhibition of GLUT1results from interactions at an exofacial GLUT1site. Intracellular ATP is also an uncompetitive GLUT1inhibitor and shares structural similarities with caffeine, suggesting that caffeineacts at the previously characterized endofacial GLUT1nucleotide-binding site. We tested this by confirming that caffeineuncompetitively inhibits GLUT1-mediated 3-O-methylglucose uptake in human erythrocytes [Vmax and Km for transport are reduced fourfold; Ki(app) = 3.5 mM caffeine]. ATP and AMP antagonize caffeineinhibition of 3-O-methylglucose uptake in erythrocyte ghosts by increasing Ki(app) for caffeineinhibition of transport from 0.9 ± 0.3 mM in the absence of intracellular nucleotides to 2.6 ± 0.6 and 2.4 ± 0.5 mM in the presence of 5 mM intracellular ATP or AMP, respectively. Extracellular ATP has no effect on sugar uptake or ...