==Facilitated Glucose Transporter 3, Solute Carrier Family 2 (GLUT3/ SLC2A3) in Homo Sapiens==

<StructureSection load='5c65' size='340' side='right' caption='Human glucose transporter complex with cholesterol derivative (PDB code [[5c65]])'>

doi:10.1080/00365510802632163</ref>. GLUT3 is categorized as a Class I transporter due to its protein sequence and structural similarity to other glucose transporters grouped in Class I<ref name="three"/>. GLUT3 displays the highest affinity for glucose of all of the Class I glucose transporters and has a transport capacity five times greater than that of GLUT1 and GLUT4<ref name="five"> Simpson,I. A., Dwyer, D., Malide, D., Moley, K. H., Travis, A., & Vannucci, S. J. (2008). The facilitative glucose transporter GLUT3: 20 years of distinction. American Journal of Physiology - Endocrinology and Metabolism, 295(2), E242-E253. doi:10.1152/ajpendo.90388.2008</ref>. In humans, GLUT3 is found predominantly in brain tissue, highly and specifically expressed by neurons, and has some expression in peripheral tissues. For this reason GLUT3 is commonly known as the “neuronal glucose transporter”<ref name="five"/><ref name="six">Maher, F., Vannucci, S. J., & Simpson, I. A. (1994). Glucose transporter proteins in brain. FASEB Journal, 8(13), 1003-1011.</ref>. GLUT3 has a more restricted expression pathway, which represents specialized functions for the protein<ref name="seven">Xu, J., Lu, C., Wang, J., Zhang, R., Qian, X., & Zhu, H. (2015). Regulation of human trophoblast GLUT3 glucose transporter by mammalian target of rapamycin signaling. International Journal of Molecular Sciences, 16(6), 13815-13828. doi:10.3390/ijms160613815</ref>. GLUT3 has been found to play an important role in gestational development and maintaining the brain's structure. Defects in GLUT3 can cause fetal death as well as neurodegeneration, which can lead to diseases like Alzheimer’s<ref name="eight">Liu, Y., Liu, F., Iqbal, K., Grundke-Iqbal, I., & Gong, C. -. (2008). Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in alzheimer disease. FEBS Letters, 582(2), 359-364. doi:10.1016/j.febslet.2007.12.035</ref>.

==Structure==

GLUT3(<scene name='71/716527/5c65/1'>5c65</scene>) is a transport protein consisting of 481 amino acids and weighing 52,520 Daltons in its asymmetrical unit<ref name="nineteen">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/</ref>. This protein is an alpha-helical protein consisting of two chains, two different ligands and water<ref name="nineteen"/>. The structure was determined by X-Ray diffraction and was measured at a resolution of 2.65 Angstroms<ref name="twentytwo">http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c65</ref>. GLUT3 consists of 12 transmembrane segments (TMs) folded “into the N-terminal and C-terminal domains, each comprising ‘3+3’ inverted repeats”<ref name="nine"/> These TMs consist of four 3 repeated sections. [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F1.html Here] is a figure by Deng, D., et al. showing these repeated transmembrane segments<ref name="nine">Deng, D., Sun, P., Yan, C., Ke, M., Jiang, X., Xiong, L., . . . Yan, N. (2015). Molecular basis of ligand recognition and transport by glucose transporters. Nature, 526(7573), 391-396. doi:10.1038/nature14655</ref>. The protein consists of two different ligands, Y01 and 37X<ref name="eighteen">http://www.rcsb.org/pdb/explore.do?structureId=5C65</ref>. Octyl Glucose Neopentyl Glycol (<scene name='71/716528/37x/2'>37X</scene>) has a chemical formula of C₂₇H₅₂O₁₂ and a molecular weight of 569 Da. There are six 37X (501-506a) bound to chain A of 5c65. These ligands are kept in place by hydrogen bonds to arginine, proline, and serine and by van der Waals forces. Chain B has three 37X ligands attached to it (501-503b). These are attached through hydrogen bonds by arginine, proline, and serine as well as by van der Waals forces<ref name="twenty">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/bound/37X</ref>. To view 37X in 3D use [http://www.rcsb.org/pdb/explore/jmol”.do?structureId=5C65&residueNr=37X JSmol]. Cholesterol hemisuccinate (<scene name='71/716528/Y01/1'>Y01</scene>) has a chemical formula of C₃₁H₅₀O₄ and has a molecular weight of 487 Da. One Y01 is attached to chain a and another Y01 is attached to chain b<ref name="twentyone">http://www.ebi.ac.uk/pdbe/entry/pdb/5c65/bound/Y01</ref>. To view Y01 in 3D use [http://www.rcsb.org/pdb/explore/jmol.do?structureId=5C65&residueNr=Y01 JSmol]. GLUT3 was also identified and analyzed in a complex with alpha & beta d-glucose. This model was reported with a resolution of 1.5 Å and was in an open-occluded state<ref name="nine"/>. The alpha and beta d glucose were coordinated in a <scene name='71/716528/Binding_pocket/8'>binding pocket</scene> by amino acids N315, E378, Q159, W368, Q280, Q281, N286. These are located on TM8 and TM10a and TM10b<ref name="nine"/>. A figure of this glucose coordination by Deng, D., et al. is available [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F2.html here]. GLUT3 structure was also determined when bound to maltose in an outward-open and an outward-occluded conformation. This was measure to a resolution of 2.6 Å and 2.4 Å respectively. A figure of this maltose coordination by Deng, D., et al. is available [http://www.nature.com/nature/journal/v526/n7573/fig_tab/nature14655_F3.html here]. To get a better view of the structure of the protein use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5C65 FirstGlance].

This is 5c65 shown with <scene name="/12/3456/Sample/1">colored groups</scene>. This is 5c65 shown as a <scene name="/12/3456/Sample/2">transparent representation</scene> of the protein.

==Mechanism ==

Multiple mechanistic theories have been proposed for facilitated glucose transporters. The simple carrier model was the earliest theory proposed by Widdas and contains four steps. First, the empty carrier opens to the cis side of the membrane for glucose to bind<ref name="three"/>. Then the substrate binding carrier translocates to the trans side of the membrane where it then releases glucose on that side. Last the empty carrier switches to the cis side. Multiple mechanistic theories, including the simple carrier model were proposed but all attempted to explain two key components of GLUT transporters, the asymmetry of the transport affinities and the trans-acceleration that occurs in the presence of hexose on the trans side. Trans acceleration or accelerated transport occurs when unidirectional uptake of sugar is stimulated by the presence of intracellular sugar<ref name="twelve">Naftalin RJ, Holman GD. Transport of sugars in human red cells. In: Ellory JC, Lew V, editors. \ Membrane Transport in Red Cells. New York, NY, USA: Academic Press; 1977.</ref>. After considerable research, two popular models remain for class 1 glut transporters. The two-site/fixed site transporter theory explains the asymmetry by having both substrate binding sites simultaneously available<ref name="thirteen">Carruthers, A., DeZutter, J., Ganguly, A., & Devaskar, S. U. (2009). Will the original glucose transporter isoform please stand up! American Journal of Physiology - Endocrinology and Metabolism, 297(4), E836-E848. doi:10.1152/ajpendo.00496.2009 </ref>. After glucose is bound, hexoses exchange between sites and speed the binding process. Although this method explains the asymmetry and the kinetics of class 1 glut transporters it is not known if all class 1 glut transporters undergo a trans-acceleration model<ref name="thirteen"/>. The alternating access model explains the mechanism for class 1 glut transporters that are symmetrical and follows three steps<ref name="fourteen">Jardetzky, O. (1966). Simple allosteric model for membrane pumps [27]. Nature, 211(5052), 969-970. doi:10.1038/211969a0</ref>. The transporter has a cavity for small substrates, and contains a substrate binding site. The transporter also has two different configurational openings to one cell membrane or the other. This mechanism differs from the two-site/fixed site transporter theory by assuming there is only one binding site available at a time, leading to four different conformation states. An empty outward open state, an occluded transporter state, a inward open state and finally another occluded state<ref name="fifteen">Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S. Structure and mechanism of the lactose permease of Escherichia coli. Science. 2003;301:610–615.</ref>. Trans-acceleration is only observed in a minority of class 1 glut transporters<ref name="sixteen">Caulfield MJ, Munroe PB, O’Neill D, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008;5:1509–1523.</ref>. GLUT3 has been proven to be dependent on trans-acceleration. This method was discovered when hexose was found to be moving against its concentration gradient<ref name="three"/>. This movement is argued to support both the two-site transporter theory and the alternating access model. Geminate exchange, named by Naftalin et al, explains this movement with the idea that hexose could exchange freely between two binding sites within the carrier<ref name="twelve"/>. While other scientists argue that hexose could move from outward to inward without glucose binding<ref name="seventeen">Vollers, S. S., & Carruthers, A. (2012). Sequence determinants of GLUT1-mediated accelerated-exchange transport: Analysis by homology-scanning mutagenesis. Journal of Biological Chemistry, 287(51), 42533-42544.doi:10.1074/jbc.M112.369587</ref>.

== Disease in Humans ==

Higher glucose concentration, as seen in diabetics, influences GLUT expression in leukocytes. Patients with type 2 diabetes have decreased GLUT3 in granulocytes, lymphocytes, and monocytes. In addition, the level of transcripts that encode GLUT3 are reduced in diabetic patients. Decreased expression of GLUT3 and other GLUT isoforms could possibly impair immune function and increase susceptibility to infection in type 2 diabetes<ref name="four"/>.

Alzheimer’s disease shows levels of impaired glucose uptake and metabolism, which leads to neurodegeneration via down-regulation of many other factors in the brain. GLUT3 is responsible for transporting glucose from extracellular space to neuronal tissue, specifically dendrites and axons. Decreased levels of GLUT3 in Alzheimer brain shows a positive correlation to decreased levels of N-acetylglucosamine, which is a derivative of glucose. The impaired presence of GLUT3 leads to hyperphosphorylation of the Tau protein, which normally stabilizes neuronal microtubules. Lastly there is a reduction in the transcription for factor hypoxia-inducible factor 1, which plays a role in glucose metabolism in the brain. The comparison between a normal healthy brain and an Alzheimer brain revealed that there was a 25-30% decrease in GLUT3 levels in the Alzheimer brain<ref name="eight"/>.

Huntington’s disease leads to decreased expression of GLUT3 in the plasma membrane. Increasing the expression of GLUT3 in a Huntington’s disease brain can delay the onset of the disease<ref name="ten">Vittori, A., Breda, C., Repici, M., Orth, M., Roos, R. A. C., Outeiro, T. F., . . . the REGISTRY investigators of the European Huntington's Disease Network. (2014). Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in huntington's disease. Human Molecular Genetics, 23(12), 3129-3137. doi:10.1093/hmg/ddu022</ref>. Rab11 is a protein that is involved with the regulation of transporter trafficking. It helps in the regulation of glucose transporters particularly the GLUT3 transporter. Its regulation is impaired by Huntington’s disease, which leads to the decreased cell surface expression of GLUT3 in the brain. The exact mechanism of Huntington’s disease is still unknown to this day<ref name="eleven">McClory, H., Williams, D., & Sapp, E. (2014). Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington’s disease mice. Acta Neuropathol Commun, 2, 1-9.</ref>.

== 3D structure of sugar transporters ==

See [[ABC transporter]]