Glucose transporter

Last updated
Sugar_tr
Identifiers
SymbolSugar_tr
Pfam PF00083
Pfam clan CL0015
InterPro IPR005828
PROSITE PDOC00190
TCDB 2.A.1.1
OPM superfamily 15
OPM protein 4gc0
CDD cd17315
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Glucose Beta-D-Glucose.svg
Glucose

Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these transporters are present in all phyla. The GLUT or SLC2A family are a protein family that is found in most mammalian cells. 14 GLUTS are encoded by the human genome. GLUT is a type of uniporter transporter protein.

Contents

Synthesis of free glucose

Most non-autotrophic cells are unable to produce free glucose because they lack expression of glucose-6-phosphatase and, thus, are involved only in glucose uptake and catabolism. Usually produced only in hepatocytes, in fasting conditions, other tissues such as the intestines, muscles, brain, and kidneys are able to produce glucose following activation of gluconeogenesis.

Glucose transport in yeast

In Saccharomyces cerevisiae glucose transport takes place through facilitated diffusion. [1] The transport proteins are mainly from the Hxt family, but many other transporters have been identified. [2]

NamePropertiesNotes
Snf3 low-glucose sensor; repressed by glucose; low expression level; repressor of Hxt6
Rgt2 high-glucose sensor; low expression level
Hxt1 Km: 100 mM, [3] 129 - 107 mM [1] low-affinity glucose transporter; induced by high glucose level
Hxt2 Km = 1.5 [1] - 10 mM [3] high/intermediate-affinity glucose transporter; induced by low glucose level [3]
Hxt3 Vm = 18.5, Kd = 0.078, Km = 28.6/34.2 [1] - 60 mM [3] low-affinity glucose transporter [3]
Hxt4 Vm = 12.0, Kd = 0.049, Km = 6.2 [1] intermediate-affinity glucose transporter [3]
Hxt5 Km = 10 mM [4] Moderate glucose affinity. Abundant during stationary phase, sporulation and low glucose conditions. Transcription repressed by glucose. [4]
Hxt6 Vm = 11.4, Kd = 0.029, Km = 0.9/14, [1] 1.5 mM [3] high glucose affinity [3]
Hxt7 Vm = 11.7, Kd = 0.039, Km = 1.3, 1.9, [1] 1.5 mM [3] high glucose affinity [3]
Hxt8 low expression level [3]
Hxt9 involved in pleiotropic drug resistance [3]
Hxt11 involved in pleiotropic drug resistance [3]
Gal2 Vm = 17.5, Kd = 0.043, Km = 1.5, 1.6 [1] high galactose affinity [3]

Glucose transport in mammals

GLUTs are integral membrane proteins that 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, [5] [6] [7] 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, it seems, located in transmembrane segments 9, 10, 11; [8] also, the DLS motif located in the seventh transmembrane segment could be involved in the selection and affinity of transported substrate. [9] [10]

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. [11] To date, 14 members of the GLUT/SLC2 have been identified. [12] 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. [13]

NameDistributionNotes
GLUT1 Is widely distributed in fetal tissues. In the adult, it is expressed at highest levels in erythrocytes and also in the endothelial cells of barrier tissues such as the blood–brain barrier. It is responsible for the low level of basal glucose uptake required to sustain respiration in all cells.Levels in cell membranes are increased by reduced glucose levels and decreased by increased glucose levels. GLUT1 expression is upregulated in many tumors.
GLUT2 Is a bidirectional transporter, allowing glucose to flow in 2 directions. Is expressed by renal tubular cells, liver cells and pancreatic beta cells. It is also present in the basolateral membrane of the small intestine epithelium. Bidirectionality is required in liver cells to uptake glucose for glycolysis and glycogenesis, and release of glucose during gluconeogenesis. In pancreatic beta cells, free flowing glucose is required so that the intracellular environment of these cells can accurately gauge the serum glucose levels. All three monosaccharides (glucose, galactose, and fructose) are transported from the intestinal mucosal cell into the portal circulation by GLUT2.Is a high-frequency and low-affinity isoform. [12]
GLUT3 Expressed mostly in neurons (where it is believed to be the main glucose transporter isoform), and in the placenta.Is a high-affinity isoform, allowing it to transport even in times of low glucose concentrations.
GLUT4 Expressed in adipose tissues and striated muscle (skeletal muscle and cardiac muscle).Is the insulin-regulated glucose transporter. Responsible for insulin-regulated glucose storage.
GLUT14 Expressed in testessimilarity to GLUT3 [12]

Classes II/III

Class II comprises:

Class III comprises:

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

The function of these new[ when? ] glucose transporter isoforms is still not clearly defined at present. Several of them (GLUT6, GLUT8) are made of 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.

Discovery of sodium-glucose cotransport

In August 1960, in Prague, Robert K. Crane presented for the first time his discovery of the sodium-glucose cotransport as the mechanism for intestinal glucose absorption. [15] Crane's discovery of cotransport was the first ever proposal of flux coupling in biology. [16] Crane in 1961 was the first to formulate the cotransport concept to explain active transport. Specifically, he proposed that the accumulation of glucose in the intestinal epithelium across the brush border membrane was [is] coupled to downhill Na+ transport cross the brush border. This hypothesis was rapidly tested, refined, and extended [to] encompass the active transport of a diverse range of molecules and ions into virtually every cell type. [17]

See also

Related Research Articles

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient. This process is in contrast to passive transport, which allows molecules or ions to move down their concentration gradient, from an area of high concentration to an area of low concentration, without energy.

<span class="mw-page-title-main">Mediated transport</span> Transportation of substances via membrane

Mediated transport refers to transport mediated by a membrane transport protein. Substances in the human body may be hydrophobic, electrophilic, contain a positively or negatively charge, or have another property. As such there are times when those substances may not be able to pass over the cell membrane using protein-independent movement. The cell membrane is imbedded with many membrane transport proteins that allow such molecules to travel in and out of the cell. There are three types of mediated transporters: uniport, symport, and antiport. Things that can be transported are nutrients, ions, glucose, etc, all depending on the needs of the cell. One example of a uniport mediated transport protein is GLUT1. GLUT1 is a transmembrane protein, which means it spans the entire width of the cell membrane, connecting the extracellular and intracellular region. It is a uniport system because it specifically transports glucose in only one direction, down its concentration gradient across the cell membrane.

A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion, active transport, osmosis, or reverse diffusion. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. Examples of channel/carrier proteins include the GLUT 1 uniporter, sodium channels, and potassium channels. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.

<span class="mw-page-title-main">Uniporter</span>

Uniporters, also known as solute carriers or facilitated transporters, are a type of membrane transport protein that passively transports solutes across a cell membrane. It uses facilitated diffusion for the movement of solutes down their concentration gradient from an area of high concentration to an area of low concentration. Unlike active transport, it does not require energy in the form of ATP to function. Uniporters are specialized to carry one specific ion or molecule and can be categorized as either channels or carriers. Facilitated diffusion may occur through three mechanisms: uniport, symport, or antiport. The difference between each mechanism depends on the direction of transport, in which uniport is the only transport not coupled to the transport of another solute.

<span class="mw-page-title-main">Cotransporter</span> Type of membrane transport proteins

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable coupled or cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

<span class="mw-page-title-main">GLUT2</span> Transmembrane carrier protein

Glucose transporter 2 (GLUT2) also known as solute carrier family 2, member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the principal transporter for transfer of glucose between liver and blood Unlike GLUT4, it does not rely on insulin for facilitated diffusion.

<span class="mw-page-title-main">GLUT4</span> Protein

Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.

<span class="mw-page-title-main">Ion transporter</span> Transmembrane protein that moves ions across a biological membrane

In biology, an ion transporter is a transmembrane protein that moves ions across a biological membrane to accomplish many different biological functions, including cellular communication, maintaining homeostasis, energy production, etc. There are different types of transporters including pumps, uniporters, antiporters, and symporters. Active transporters or ion pumps are transporters that convert energy from various sources—including adenosine triphosphate (ATP), sunlight, and other redox reactions—to potential energy by pumping an ion up its concentration gradient. This potential energy could then be used by secondary transporters, including ion carriers and ion channels, to drive vital cellular processes, such as ATP synthesis.

Method of glucose uptake differs throughout tissues depending on two factors; the metabolic needs of the tissue and availability of glucose. The two ways in which glucose uptake can take place are facilitated diffusion and secondary active transport. Active transport is the movement of ions or molecules going against the concentration gradient.

<span class="mw-page-title-main">GLUT1</span> Uniporter protein

Glucose transporter 1, also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene. GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells. This gene encodes a facilitative glucose transporter that is highly expressed in erythrocytes and endothelial cells, including cells of the blood–brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. GLUT1 accounts for 2 percent of the protein in the plasma membrane of erythrocytes.

The galactose permease or GalP found in Escherichia coli is an integral membrane protein involved in the transport of monosaccharides, primarily hexoses, for utilization by E. coli in glycolysis and other metabolic and catabolic pathways (3,4). It is a member of the Major Facilitator Super Family (MFS) and is homologue of the human GLUT1 transporter (4). Below you will find descriptions of the structure, specificity, effects on homeostasis, expression, and regulation of GalP along with examples of several of its homologues.

Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron. They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron. If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

The Na–K–Cl cotransporter (NKCC) is a transport protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes. Two isoforms of the NKCC1/Slc12a2 gene result from keeping or skipping exon 21 in the final gene product.

The sodium/phosphate cotransporter is a member of the phosphate:Na+ symporter (PNaS) family within the TOG Superfamily of transport proteins as specified in the Transporter Classification Database (TCDB).

<span class="mw-page-title-main">Sodium/glucose cotransporter 1</span>

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the SLC5A1 gene which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and the epithelial cells of the kidney tubules of the nephron for the purpose of glucose uptake into cells. Recently, it has been seen to have functions that can be considered as promising therapeutic target to treat diabetes and obesity. Through the use of the sodium glucose cotransporter 1 protein, cells are able to obtain glucose which is further utilized to make and store energy for the cell.

<span class="mw-page-title-main">Robert K. Crane</span> American biochemist

Robert Kellogg Crane was an American biochemist best known for his discovery of sodium–glucose cotransport.

<span class="mw-page-title-main">SLC2A14</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 2, member 14 is a protein that in humans is encoded by the SLC2A14 gene.

The cation-chloride cotransporter (CCC) family is part of the APC superfamily of secondary carriers. Members of the CCC family are found in animals, plants, fungi and bacteria. Most characterized CCC family proteins are from higher eukaryotes, but one has been partially characterized from Nicotiana tabacum, and homologous ORFs have been sequenced from Caenorhabditis elegans (worm), Saccharomyces cerevisiae (yeast) and Synechococcus sp.. The latter proteins are of unknown function. These proteins show sequence similarity to members of the APC family. CCC family proteins are usually large, and possess 12 putative transmembrane spanners (TMSs) flanked by large N-terminal and C-terminal hydrophilic domains.

The anion exchanger family is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria. Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.

<span class="mw-page-title-main">Alpha Arrestin</span>

The arrestin family of proteins is subdivided into α-arrestins (also referred to as arrestin-related trafficking adaptors or arrestin-like yeast proteins in yeast or ARRDCs in mammals, β-arrestins and Vps26-like arrestins proteins. The α-Arrestins are an ancestral branch of the larger arrestin family of proteins and they are conserved across eukaryotes but are best characterized in the budding yeast Saccharomyces cerevisiae; to-date there are 6 α-arrestins identified in mammalian cells and 14 α-arrestins identified in the budding yeast Saccharomyces cerevisiae. The yeast α-arrestin family comprises Ldb19/Art1, Ecm21/Art2, Aly1/Art6, Aly2/Art3, Rod1/Art4, Rog3/Art7, Art5, Csr2/Art8, Rim8/Art9, Art10, Bul1, Bul2, Bul3 and Spo23. The best characterized α-arrestin function to date is their endocytic regulation of plasma membrane proteins, including G-protein coupled receptors and nutrient transporters. α-Arrestins control endocytosis of these membrane proteins in response to cellular stressors, including nutrient or metal ion excess.

References

  1. 1 2 3 4 5 6 7 8 Maier A, Völker B, Boles E, Fuhrmann GF (December 2002). "Characterisation of glucose transport in Saccharomyces cerevisiae with plasma membrane vesicles (countertransport) and intact cells (initial uptake) with single Hxt1, Hxt2, Hxt3, Hxt4, Hxt6, Hxt7 or Gal2 transporters". FEMS Yeast Research. 2 (4): 539–50. doi: 10.1111/j.1567-1364.2002.tb00121.x . PMID   12702270.
  2. ↑ "List of possible glucose transporters in S. cerevisiae". UniProt.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Boles E, Hollenberg CP (August 1997). "The molecular genetics of hexose transport in yeasts". FEMS Microbiology Reviews. 21 (1): 85–111. doi:10.1111/j.1574-6976.1997.tb00346.x. PMID   9299703.
  4. 1 2 Diderich JA, Schuurmans JM, Van Gaalen MC, Kruckeberg AL, Van Dam K (December 2001). "Functional analysis of the hexose transporter homologue HXT5 in Saccharomyces cerevisiae". Yeast. 18 (16): 1515–24. doi:10.1002/yea.779. PMID   11748728. S2CID   22968336.
  5. ↑ Oka Y, Asano T, Shibasaki Y, Lin JL, Tsukuda K, Katagiri H, Akanuma Y, Takaku F (June 1990). "C-terminal truncated glucose transporter is locked into an inward-facing form without transport activity". Nature. 345 (6275): 550–3. Bibcode:1990Natur.345..550O. doi:10.1038/345550a0. PMID   2348864. S2CID   4264399.
  6. ↑ Hebert DN, Carruthers A (November 1992). "Glucose transporter oligomeric structure determines transporter function. Reversible redox-dependent interconversions of tetrameric and dimeric GLUT1". The Journal of Biological Chemistry. 267 (33): 23829–38. doi: 10.1016/S0021-9258(18)35912-X . PMID   1429721.
  7. ↑ Cloherty EK, Sultzman LA, Zottola RJ, Carruthers A (November 1995). "Net sugar transport is a multistep process. Evidence for cytosolic sugar binding sites in erythrocytes". Biochemistry. 34 (47): 15395–406. doi:10.1021/bi00047a002. PMID   7492539.
  8. ↑ Hruz PW, Mueckler MM (2001). "Structural analysis of the GLUT1 facilitative glucose transporter (review)". Molecular Membrane Biology. 18 (3): 183–93. doi: 10.1080/09687680110072140 . PMID   11681785.
  9. ↑ Seatter MJ, De la Rue SA, Porter LM, Gould GW (February 1998). "QLS motif in transmembrane helix VII of the glucose transporter family interacts with the C-1 position of D-glucose and is involved in substrate selection at the exofacial binding site". Biochemistry. 37 (5): 1322–6. doi:10.1021/bi972322u. PMID   9477959.
  10. ↑ Hruz PW, Mueckler MM (December 1999). "Cysteine-scanning mutagenesis of transmembrane segment 7 of the GLUT1 glucose transporter". The Journal of Biological Chemistry. 274 (51): 36176–80. doi: 10.1074/jbc.274.51.36176 . PMID   10593902.
  11. ↑ Thorens B (April 1996). "Glucose transporters in the regulation of intestinal, renal, and liver glucose fluxes". The American Journal of Physiology. 270 (4 Pt 1): G541-53. doi:10.1152/ajpgi.1996.270.4.G541. PMID   8928783.
  12. 1 2 3 4 5 Thorens B, Mueckler M (February 2010). "Glucose transporters in the 21st Century". American Journal of Physiology. Endocrinology and Metabolism. 298 (2): E141-5. doi:10.1152/ajpendo.00712.2009. PMC   2822486 . PMID   20009031.
  13. ↑ Bell GI, Kayano T, Buse JB, Burant CF, Takeda J, Lin D, Fukumoto H, Seino S (March 1990). "Molecular biology of mammalian glucose transporters". Diabetes Care. 13 (3): 198–208. doi:10.2337/diacare.13.3.198. PMID   2407475. S2CID   20712863.
  14. ↑ Boron WF (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 995. ISBN   978-1-4160-2328-9.
  15. ↑ Crane RK, Miller D, Bihler I (1961). "The restrictions on possible mechanisms of intestinal transport of sugars". In Kleinzeller A, Kotyk A (eds.). Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22–27, 1960. Prague: Czech Academy of Sciences. pp. 439–449.
  16. ↑ Wright EM, Turk E (February 2004). "The sodium/glucose cotransport family SLC5". Pflügers Archiv. 447 (5): 510–8. doi:10.1007/s00424-003-1063-6. PMID   12748858. S2CID   41985805.
  17. ↑ Boyd CA (March 2008). "Facts, fantasies and fun in epithelial physiology". Experimental Physiology. 93 (3): 303–14. doi: 10.1113/expphysiol.2007.037523 . PMID   18192340. S2CID   41086034. The insight from this time that remains in all current text books is the notion of Robert Crane published originally as an appendix to a symposium paper published in 1960 (Crane et al. 1960). The key point here was 'flux coupling', the cotransport of sodium and glucose in the apical membrane of the small intestinal epithelial cell. Half a century later this idea has turned into one of the most studied of all transporter proteins (SGLT1), the sodium–glucose cotransporter.
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