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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.
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 ==
== Disease in Humans ==
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===Huntington’s Disease===
===Huntington’s Disease===
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>.
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>.
==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>.
</StructureSection>
</StructureSection>


== References ==
== References ==
<references/>
<references/>

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