Glucose transporter

Sugar_tr
Identifiers
Symbol Sugar_tr
Pfam PF00083
Pfam clan CL0015
InterPro IPR005828
PROSITE PDOC00190
TCDB 2.A.1.1
OPM superfamily 15
OPM protein 4gc0
Glucose

Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose over a plasma membrane. 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 human genome. GLUT is a type of uniporter transporter protein.

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]

Name Properties Notes
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-affinityglucose 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 QLS 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]

Name Distribution Notes
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. However, 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 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 Found in adipose tissues and striated muscle (skeletal muscle and cardiac muscle). Is the insulin-regulated glucose transporter. Responsible for insulin-regulated glucose storage.
GLUT14 testicle similarity 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 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][17]

See also

References

  1. 1 2 3 4 5 6 7 8 Maier A, Asano T, Volker A, Boles E, Fuhrmann GF (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): 539–550. PMID 12702270. doi:10.1111/j.1567-1364.2002.tb00121.x.
  2. ↑ uniprot list of possible glucose transporters in S. cerevisiae
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Boles E, Hollenberg CP (1997). "The molecular genetics of hexose transport in yeasts". FEMS Microbiology Reviews. 21 (1): 85–111. PMID 9299703. doi:10.1111/j.1574-6976.1997.tb00346.x.
  4. 1 2 Diderich JA, Schuurmans JM, Gaalen MC, Kruckeberg AL, Van Dam K (2001). "Functional analysis of the hexose transporter homologue HXT5 in Saccharomyces cerevisiae". Yeast. 18 (16): 1515–1524. PMID 11748728. doi:10.1002/yea.779.
  5. ↑ Oka Y, Asano T, Shibasaki Y, Lin J, Tsukuda K, Katagiri H, Akanuma Y, Takaku F (1990). "C-terminal truncated glucose transporter is locked into an inward-facing form without transport activity". Nature. 345 (6275): 550–3. PMID 2348864. doi:10.1038/345550a0.
  6. ↑ Hebert D, Carruthers A (1992). "Glucose transporter oligomeric structure determines transporter function. Reversible redox-dependent interconversions of tetrameric and dimeric GLUT1". J. Biol. Chem. 267 (33): 23829–38. PMID 1429721.
  7. ↑ Cloherty E, Sultzman L, Zottola R, Carruthers A (1995). "Net sugar transport is a multistep process. Evidence for cytosolic sugar binding sites in erythrocytes". Biochemistry. 34 (47): 15395–406. PMID 7492539. doi:10.1021/bi00047a002.
  8. ↑ Hruz P, Mueckler M (2001). "Structural analysis of the GLUT1 facilitative glucose transporter (review)". Mol. Membr. Biol. 18 (3): 183–93. PMID 11681785. doi:10.1080/09687680110072140.
  9. ↑ Seatter M, De la Rue S, Porter L, Gould G (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. PMID 9477959. doi:10.1021/bi972322u.
  10. ↑ Hruz P, Mueckler M (1999). "Cysteine-scanning mutagenesis of transmembrane segment 7 of the GLUT1 glucose transporter". J. Biol. Chem. 274 (51): 36176–80. PMID 10593902. doi:10.1074/jbc.274.51.36176.
  11. ↑ Thorens B (1996). "Glucose transporters in the regulation of intestinal, renal, and liver glucose fluxes". Am. J. Physiol. 270 (4 Pt 1): G541–53. PMID 8928783.
  12. 1 2 3 4 5 Thorens B, Mueckler M (2010). "Glucose transporters in the 21st Century". American Journal of Physiology. Endocrinology and Metabolism. 298 (2): E141–E145. doi:10.1152/ajpendo.00712.2009.
  13. ↑ Bell G, Kayano T, Buse J, Burant C, Takeda J, Lin D, Fukumoto H, Seino S (1990). "Molecular biology of mammalian glucose transporters". Diabetes Care. 13 (3): 198–208. PMID 2407475. doi:10.2337/diacare.13.3.198.
  14. ↑ Page 995 in: Walter F. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3.
  15. ↑ Robert K. Crane, D. Miller and I. Bihler. “The restrictions on possible mechanisms of intestinal transport of sugars”. In: Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22–27, 1960. Edited by A. Kleinzeller and A. Kotyk. Czech Academy of Sciences, Prague, 1961, pp. 439-449.
  16. ↑ Ernest M. Wright and Eric Turk. “The sodium glucose cotransport family SLC5”. Pflügers Arch 447, 2004, p. 510. “Crane in 1961 was the first to formulate the cotransport concept to explain active transport [7]. 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. ↑ Boyd, C A R. “Facts, fantasies and fun in epithelial physiology”. Experimental Physiology, Vol. 93, Issue 3, 2008, p. 304. “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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