Glucose transporter

  Glucose transporters (GLUT or SLC2A family) are a family of membrane proteins found in most mammalian cells.

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Function

Glucose is an essential substrate for the metabolism of most cells. Because glucose is a polar molecule, transport through biological membranes requires specific transport proteins. Transport of glucose through the apical membrane of intestinal, choroid plexus and kidney epithelial cells depends on the presence of secondary active Na+/glucose symporters, SGLT-1 and SGLT-2, which concentrate glucose inside the cells, using the energy provided by cotransport of Na+ ions down their electrochemical gradient.^[1] Facilitated diffusion of glucose through the cellular membrane is otherwise catalyzed by glucose carriers (protein symbol GLUT, gene symbol SLC2 for Solute Carrier Family 2) that belong to a superfamily of transport facilitators (major facilitator superfamily) including organic anion and cation transporters, yeast hexose transporter, plant hexose/proton symporters, and bacterial sugar/proton symporters.^[2]

Mechanism

Molecule movement by glucose transporter proteins works by facilitating diffusion. [1] This makes them energy independent, unlike active transporters which often require the presence of ATP to drive their translocation mechanism and stall if ATP/ADP ratio drops too low.

Structure

GLUTs are integral membrane proteins which contain 12 membrane spanning helices with both the amino and carboxyl termini exposed on the cytoplasmic side of the plasma membrane. GLUT proteins transport glucose and related hexoses according to a model of alternate conformation,^[3][4][5] which predicts that the transporter exposes a single substrate binding site toward either the outside or the inside of the cell. Binding of glucose to one site provokes a conformational change associated with transport, and releases glucose to the other side of the membrane. The inner and outer glucose-binding sites are probably located in transmembrane segments 9, 10, 11;^[6] also, the QLS motif located in the seventh transmembrane segment could be involved in the selection and affinity of transported substrate.^[7][8]

Types

Each glucose transporter isoform plays a specific role in glucose metabolism determined by its pattern of tissue expression, substrate specificity, transport kinetics, and regulated expression in different physiological conditions.^[9] To date, 13 members of the GLUT/SLC2 have been identified.^[10] On the basis of sequence similarities, the GLUT family has been divided into three subclasses.

Class I

Class I comprises the well-characterized glucose transporters GLUT1-GLUT4.^[11]

Classes II/III

Class II comprises the fructose transporter GLUT5 (SLC2A5) and GLUT7 (SLC2A7), 9 (SLC2A9), 11 (SLC2A11).

Class III comprises GLUT6 (SLC2A6), 8 (SLC2A8), 10 (SLC2A10), and 12 (SLC2A12) and the H+/myoinositol transporter HMIT (SLC2A13).^[12]

Most members of classes II and III have been idenitified recently in homology searches of EST databases and the sequence information provided by the various genome projects.

The function of these new glucose transporter isoforms is still not clearly defined at present. Several of them (GLUT6, GLUT8) comprise motifs that help retain them intracellularly and therefore prevent glucose transport. Whether mechanisms exist to promote cell-surface translocation of these transporters is not yet known, but it has clearly been established that insulin does not promote GLUT6 and GLUT8 cell-surface translocation.

Synthesis of free glucose

Most cells are unable to produce free glucose because they lack expression of glucose-6-phosphatase and thus are only involved in glucose uptake and catabolism. Only hepatocytes and, in more severe fasting conditions, intestine and kidney, are able to produce glucose following activation of gluconeogenesis and glycogenolysis.

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