Monosaccharides enter cells by slow translipid bilayer diffusion by rapid, protein-mediated, cation-dependent cotransport and by rapid, protein-mediated equilibrative transport. This review addresses protein-mediated, equilibrative glucose transport catalyzed by GLUT1, the first equilibrative glucose transporter to be identified, purified, and cloned. GLUT1 is a polytopic, membranespanning protein that is one of 13 members of the human equilibrative glucose transport protein family. We review GLUT1 catalytic and ligand-binding properties and interpret these behaviors in the context of several putative mechanisms for protein-mediated transport. We conclude that no single model satisfactorily explains GLUT1 behavior. We then review GLUT1 topology, subunit architecture, and oligomeric structure and examine a new model for sugar transport that combines structural and kinetic analyses to satisfactorily reproduce GLUT1 behavior in human erythrocytes. We next review GLUT1 cell biology and the transcriptional and posttranscriptional regulation of GLUT1 expression in the context of development and in response to glucose perturbations and hypoxia in blood-tissue barriers. Emphasis is placed on transgenic GLUT1 overexpression and null mutant model systems, the latter serving as surrogates for the human GLUT1 deficiency syndrome. Finally, we review the role of GLUT1 in the absence or deficiency of a related isoform, GLUT3, toward establishing the physiological significance of coordination between these two isoforms. glucose transport; facilitated diffusion; major facilitator superfamily protein; bloodbrain barrier; placenta; diabetes; glucose transporter 1 deficiency syndrome; development MOST CELLS TRANSPORT SUGARS rapidly down the prevailing concentration gradient into or out of the cell. This equilibrative transport process is mediated by a family of sugar transporters called GLUTs. GLUT1 was the first glucose transporter isoform to be identified, purified (66, 132), and cloned (93) and is one of 13 proteins that comprise the human equilibrative glucose transporter family (63). GLUT1 is a membrane-spanning glycoprotein containing 12 transmembrane domains with a single N-glycosylation site, and its gene is located on chromosome 1 (1p35-31.3) (93). GLUT1 is expressed at the highest levels in the plasma membranes of proliferating cells forming the early developing embryo, in cells forming the blood-tissue barriers, in human erythrocytes and astrocytes, and in cardiac muscle (86). Having a catalytic turnover of ϳ1,200/s (115), glucose transporter 1 (GLUT1) provides an efficient pathway for cellular import and export of glucose. In addition, GLUT1 transports galactose and ascorbic acid (81,107). This review examines the catalytic properties, structure, molecular regulation, and physiology of GLUT1. GLUT1 CATALYTIC PROPERTIES Facilitated DiffusionThe cytoplasm of most cells equilibrates rapidly with nonmetabolizable extracellular sugars. This process is mediated by sugar transport proteins that catalyze unidirectional sugar up...

GLUT1‐mediated cellular glucose transport is required to fuel anaerobic metabolism in proliferating cancer cells. Accordingly, GLUT1 inhibition by small molecules is a viable strategy to halt the proliferation of cancers. However, GLUT1 is presently not targeted therapeutically in cancers because of lack of potent and specific inhibitors. Recently, a novel small molecule, WZB117, was shown to kill lung and breast cancer cells by inhibiting GLUT1‐mediated glucose transport, without affecting non‐tumorigenic cells. Here, we studied the detailed kinetics of WZB117 inhibition of GLUT1, and found that WZB117 inhibits uptake of the non‐metabolizable sugar, 3‐O‐methylglucose, by red blood cells with an inhibition constant of 2.83 μM. Our data show that WZB117 is a competitive inhibitor of GLUT1‐mediated zero‐trans sugar uptake and exchange transport but is a non‐competitive inhibitor of zero‐trans exit. These results, together with our docking studies, suggest that WZB117 binds at or near the exofacial sugar‐binding site of GLUT1. In addition, our preliminary data on the specificity of WZB117 for GLUT1 suggests that, while WZB117 inhibits GLUT1 with a high affinity, it is also a potent inhibitor of the skeletal muscle and adipose specific transporter GLUT4 and the neuronal glucose transporter GLUT3. We conclude that the ability of WZB117 to serve as a tumor‐specific inhibitor derives, not from specificity of transport inhibition but rather, from the absolute dependence of tumor cells on anaerobic metabolism and glucose‐dependent anabolism.Support or Funding InformationThis work is supported by NIH grant DK 44888.