Structure, function and regulation of mammalian glucose transporters of the SLC2 family

Abstract

The SLC2 genes code for a family of GLUT proteins that are part of the major facilitator superfamily (MFS) of membrane transporters. Crystal structures have recently revealed how the unique protein fold of these proteins enables the catalysis of transport. The proteins have 12 transmembrane spans built from a replicated trimer substructure. This enables 4 trimer substructures to move relative to each other, and thereby alternately opening and closing a cleft to either the internal or the external side of the membrane. The physiological substrate for the GLUTs is usually a hexose but substrates for GLUTs can include urate, dehydro-ascorbate and myo-inositol. The GLUT proteins have varied physiological functions that are related to their principal substrates, the cell type in which the GLUTs are expressed and the extent to which the proteins are associated with subcellular compartments. Some of the GLUT proteins translocate between subcellular compartments and this facilitates the control of their function over long-and shorttime scales. The control of GLUT function is necessary for a regulated supply of metabolites (mainly glucose) to tissues. Pathophysiological abnormalities in GLUT proteins are responsible for, or associated with, clinical problems including type 2 diabetes and cancer and a range of tissue disorders, related to tissue-specific GLUT protein profiles. The availability of GLUT crystal structures has facilitated the search for inhibitors and substrates and that are specific for each GLUT and that can be used therapeutically. Recent studies are starting to unravel the drug targetable properties of each of the GLUT proteins.

Excessive Intake of High-Fructose Corn Syrup Drinks Induces Impaired Glucose Tolerance

“…β-cells do not express Glut5, a fructose transporter; however, fructose is transported by Glut2 [ 49 , 50 ], and β-cells can metabolize fructose, albeit much less efficiently than glucose [ 26 ]. Glut2 transports glucose and fructose into β-cells and is important for insulin secretion [ 51 , 52 ]. The expression of Glut2 is significantly reduced in β-cells in mice with diabetes induced by a high-fat diet [ 53 ].…”

A Metabolic Landscape for Maintaining Retina Integrity and Function

“…Glucose supply of the retina is mainly mediated by glucose transporters (Hsu and Molday, 1991;Gospe et al, 2010), which are expressed in vasculature, RPE cells, PhRs and in MGCs (Watanabe et al, 1996;Wong-Riley, 2010;Veys et al, 2020; Figure 4). GLUTs are facilitative transporters and as such glucose follows a concentration gradient (Cheeseman and Long, 2015;Holman, 2020). Glucose from the blood supply leaves the choroidal endothelium and diffuses through RPE cells into the photoreceptor layer where photoreceptors take it up and readily metabolize it.…”

Identification of new GLUT2-selective inhibitors through in silico ligand screening and validation in eukaryotic expression systems

“…Human glucose transporters (GLUTs), proteins of the SLC2 gene family, facilitate the diffusion of hexoses into the cell and play a pivotal role in glucose homeostasis 1 . Important diseases, including cancer 2 and diabetes 3 , 4 , are related to the dysfunction or misregulation of these transporters, identifying them as potential drug targets 1 . The 14 GLUT isoforms present in humans show an amino acid identity of 19–65% (homology of 42–81%) 5 but differ in substrate specificity, affinity, and tissue distribution 6 .…”