Glucose transporter

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Glucose transporter
Identifier
Gene name (s) SLC2A1 , SLC2A2 , SLC2A3 , SLC2A4 , SLC2A5 , SLC2A6 , SLC2A7 , SLC2A8 , SLC2A9 , SLC2A10 , SLC2A11 , SLC2A12 , SLC2A14
Transporter classification
TCDB 2.A.1.1
designation Sugar truck family
Occurrence
Parent taxon Eukaryotes

β- D -glucose (grape sugar) molecule

Glucose transporter (GLUT, SLC2A) are specific transmembrane transporter proteins that transport of glucose or fructose by the cell membrane catalyze . These are carrier protein-mediated Uniports , with the concentration gradient of glucose providing the energy required for transport.

All GLUTs are members of the sugar transporters in the major facilitator superfamily of membrane transport proteins. They have twelve transmembrane domains.

structure

So far, 14 different transporters of the GLUT type are known, which are divided into three classes. Each GLUT consists of a total of twelve amphiphilic transmembrane domains , which are arranged in the plasma membrane in such a way that the hydrophobic components bind to the outside of the membrane and a hydrophilic pore for glucose is created in the middle. The amino terminus and carboxyl terminus are on the cytosolic side (intracellular). The binding of glucose causes a conformational change through which the molecule is transported to the other side (“rocker switch”, tilting movement). The transport cycle can be described using the two-state four-step model .

Types and development

Due to similarities in the amino acid sequence , the GLUTs are divided into three classes. GLUT1 and GLUT3 are also permeable to dehydroascorbate . GLUT5 mainly transports fructose and GLUT9 uric acid.

Based on the amino acid sequences of now known GLUTs, it can be concluded that GLUTs of type 3 are the oldest GLUTs; they probably originated with the eukaryotes and orthologues of them can also be found in plants. With the development of the chordates , the GLUTs of type 2 were also created by copying the genes. Another gene duplication in the course of the Euteleostomi finally resulted in GLUTs of type 1, with GLUT-14 being the most recent development with the primates from a copy of GLUT-3.

Type 1

designated
voltage 		description gene Phenotypes
GLUT1 GLUT1 is the most common type and is found in many mammalian cells . This type is particularly common in the cells of the CNS and the erythrocytes , which is why it is assumed that it has a special function in the supply of nutrients to these glucose-dependent cells. It is an insulin-independent transporter, its K M value is 1.5 mmol·l −1 . It therefore shows a high affinity for glucose and is almost saturated under physiological conditions. This ensures a constant uptake of glucose into the cell.

Up until now, many textbooks have held the wrong opinion that human β cells of the pancreas express GLUT2 like those of the rat or mouse. In fact, it is the glucose transporter GLUT1. The uptake of glucose activates insulin synthesis and release in the β cells. This happens through an ATP-mediated inhibition (glucose breakdown leads to ATP build-up) of potassium channels with subsequent depolarization, which opens voltage-dependent calcium channels. The influx of calcium leads to exocytosis of the insulin vesicles.

SLC2A1 Dystonia type 9,

GLUT1 deficit syndrome 1,

GLUT1 deficit syndrome 2,

Cryohydrocytosis with reduced stomatin ,

Idiopathic generalized epilepsy

GLUT2 It occurs in hepatocytes , in the intestinal mucosa and in the epithelial cells of the kidney. The transporter is also insulin-independent, but has only a low affinity for glucose (K M between 17 and 66 mmol·l −1 ). As a result, glucose uptake is dependent on blood sugar levels. This inhibits the breakdown of glycogen in the liver. SLC2A2 Fanconi-Bickel syndrome ,

Non-insulin dependent diabetes mellitus

GLUT3 GLUT3 occurs mainly, but not only, in nerve cells in the brain. The lower K M compared to GLUT2 ensures sufficient glucose uptake even with low blood sugar levels. It is insulin-independent and serves as the basic supply for the CNS. SLC2A3
-
GLUT4 GLUT4 occurs in fat cells and in all striated muscle cells ( skeletal muscle cells and cardiac muscle cells ). The transporter is insulin-dependent, has a high affinity and is stored intracellularly in the membrane of vesicles . When the blood sugar level rises, the insulin level rises too. Insulin mediates the fusion of the vesicles with the plasma membrane , so that the blood sugar level can be lowered again by the absorption of glucose into the cells. The transporters are then resumed by endocytosis and can be used again. In the fat cells, the glucose can then be converted into triacylglycerol , and stored in muscle cells in the form of glycogen . GLUT4 therefore has the function of a demand-oriented glucose supply. SLC2A4
-
GLUT14 Only occurs in the testes and is structurally very similar to GLUT3. SLC2A14
-

Type 2

designated
voltage 		description gene Phenotypes
GLUT5 This type is not a pure glucose, but a fructose transporter and occurs mainly in the spermatozoa , in the intestinal tract and in the kidneys. SLC2A5
-
GLUT7 This transporter is used to transport the glucose produced in gluconeogenesis in the liver from the cells into the blood. To do this, glucose-6-phosphate must first be dephosphorylated by the glucose-6-phosphatase located on the endoplasmic reticulum . SLC2A7
-
GLUT9 GLUT-9 is mainly found in the renal tubules, where it reabsorbs uric acid . To a lesser extent, two isoforms are expressed in several other tissue types and can additionally transport small amounts of fructose and glucose. SLC2A9 Hypouricemia
GLUT11 All that is known about this glucose transporter is that it is expressed in three isoforms in heart and skeletal muscle cells. SLC2A11
-

Type 3

designated
voltage 		description gene Phenotypes
GLUT6 GLUT-6 is expressed in the brain, spleen and peripheral leukocytes. SLC2A6
-
GLUT8 GLUT-8 competitively transports glucose and fructose in testicular cells. Its expression is inhibited by estrogen. SLC2A8
-
GLUT10 Expressed in many tissue types, but especially in the liver and pancreas, this GLUT has a K m = 0.28 mM for 2-deoxy- D -glucose. SLC2A10 Arterial Tortuosity Syndrome
GLUT12 GLUT-12 is a membrane protein in the perinuclear region of muscle cells as long as insulin is absent. SLC2A12
-

function

Monosaccharides such as glucose are readily soluble ( polar ) in both water and blood and can therefore be transported to the target cells via the blood without any problems. The (apolar) lipid bilayer of the cells is difficult for glucose to permeate, which is why there are glucose transporters in the plasma membranes that allow easier diffusion . You work without energy consumption purely due to the chemical gradient for glucose.

In order to maintain this necessary concentration gradient between the intracellular and extracellular spaces, the glucose reacts to glucose-6-phosphate (G6P) after entering the cytosol , which is catalyzed by the hexokinase (various isoforms ). G6P is the starting product of glycolysis , the pentose phosphate pathway and glycogen synthesis .

GLUT1, GLUT3 and GLUT4 as well as the hexokinase IV are the basic suppliers of glucose for the organism, which work efficiently even when the blood sugar level is low because they have a low Km (and therefore a high affinity). It is important that the amount of glucose that is metabolized in the cell depends exclusively on the amount of hexokinase in the cell and not on the blood sugar level.

GLUT2 and glucokinase, on the other hand, are dependent in their activity on the blood sugar concentration , as they have a low affinity (high Km). This means that glucose is only absorbed if there is hyperglycaemia . They thus serve as a kind of glucose sensor. If there is a glucose deficiency, then the supply of the organs and muscles is ensured first (the supply of the erythrocytes and the CNS with glucose is of particular importance, since they depend on a minimum glucose concentration) before glucose is stored in the liver cells or fat cells .

The glucokinase in the pancreas ensures that, depending on the blood sugar concentration, sufficient insulin is produced and secreted. If the hexokinase were localized in these cells, the β-cells would be completely non-adapted and would constantly secrete insulin.

Most cells are unable to synthesize free glucose on their own because they lack glucose-6-phosphatase . They are therefore dependent on a blood supply. Only hepatocytes and, to a limited extent, intestinal and kidney cells are able to carry out gluconeogenesis .

Medical importance

Defects in GLUTs can cause several rare hereditary diseases.

literature

  • Rainer Klinke, Hans-Christian Pape, Stefan Silbernagl (Hrsg.): Textbook of Physiology . 5th edition. Thieme, Stuttgart 2005, ISBN 3-13-796003-7 .
  • Georg Löffler, Petro E. Petrides, Peter C. Heinrich (Eds.): Biochemistry and Pathobiochemistry . 8th edition. Springer, Berlin 2006, ISBN 978-3-540-32680-9 .

Individual evidence

  1. ↑ Xuejun C. Zhang, Lei Han: Uniporter substrate binding and transport: reformulating mechanistic questions. In: Biophysics Reports. 2, 2016, p. 45, doi : 10.1007 / s41048-016-0030-7 .
  2. ^ A b c d Joachim Rassow , Karin Hauser, Roland Netzker and Rainer Deutzmann: Biochemistry . 2nd edition, Thieme, Stuttgart 2008, ISBN 978-3-13-125352-1 . P. 353.
  3. ↑ Löffler / Petrides "Biochemie und Pathobiochemie" 9th edition, p. 445.
  4. ↑ KT Coppieters, A. Wiberg, N. Amirian, TW Kay, MG von Herrath: Persistent glucose transporter expression on pancreatic beta cells from longstanding type 1 diabetic individuals. In: Diabetes / metabolism research and reviews. Volume 27, Number 8, November 2011, ISSN  1520-7560 , pp. 746-754, doi : 10.1002 / dmrr.1246 , PMID 22069254 .
  5. ^ Solute Carrier Family 2 (Facilitated Glucose Transporter), Member 1; SLC2A1.  In: Online Mendelian Inheritance in Man . (English)
  6. ^ Solute Carrier Family 2 (Facilitated Glucose Transporter), Member 2; SLC2A2.  In: Online Mendelian Inheritance in Man . (English)
  7. ^ Simpson IA, Dwyer D, Malide D, Moley KH, Travis A, Vannucci SJ: The facilitative glucose transporter GLUT3: 20 years of distinction . In: Am. J. Physiol. Endocrinol. Metab. . 295, No. 2, August 2008, pp. E242-53. doi : 10.1152 / ajpendo.90388.2008 . PMID 18577699 . PMC 2519757 (free full text).
  8. ↑ Prof. Georg Löffler, Dr. Petro E. Petrides, Prof. Peter C. Heinrich: Biochemistry & Pathobiochemistry . Springer Medizin Verlag, Heidelberg 2006, ISBN 978-3-540-32680-9 . P. 376.
  9. ^ Solute Carrier Family 2 (Facilitated Glucose Transporter), Member 9; SLC2A9.  In: Online Mendelian Inheritance in Man . (English)
  10. ^ Solute Carrier Family 2 (Facilitated Glucose Transporter), Member 10; SLC2A10.  In: Online Mendelian Inheritance in Man . (English)
  11. ↑ OrphaNet: Bickel-Fanconi glycogenosis
  12. ↑ UniProt P11168
  13. ↑ Hypouricemia, renal, 2; RHUC2.  In: Online Mendelian Inheritance in Man . (English)
  14. ↑ Orphanet: Arterial tortuosity

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