GLUT1: Difference between revisions

'''Glucose transporter 1''' (or '''GLUT1'''), 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]].<ref name="pmid3839598">{{cite journal | vauthors = Mueckler M, Caruso C, Baldwin SA, Panico M, Blench I, Morris HR, Allard WJ, Lienhard GE, Lodish HF | title = Sequence and structure of a human glucose transporter | journal = Science | volume = 229 | issue = 4717 | pages = 941–5 | date = September 1985 | pmid = 3839598 | doi = 10.1126/science.3839598 | bibcode = 1985Sci...229..941M }}</ref> GLUT1 [[facilitated diffusion|facilitates]] the transport of [[glucose]] across the [[cell membrane|plasma membranes]] of mammalian cells.<ref name="pmid8839927">{{cite journal | vauthors = Olson AL, Pessin JE | title = Structure, function, and regulation of the mammalian facilitative glucose transporter gene family | journal = Annual Review of Nutrition | volume = 16 | issue = | pages = 235–56 | year = 1996 | pmid = 8839927 | doi = 10.1146/annurev.nu.16.070196.001315 }}</ref> This gene encodes a majorfacilitative [[glucose transporter]] that is highly expressed in theerythrocytes mammalianand endothelial cells, including cells of the [[blood-brainblood–brain barrier]]. The encoded protein is found primarily in the [[cell membrane]] and on the cell surface, where it can also function as a [[Cell surface receptor|receptor]] for [[Human T-lymphotropic virus|human T-cell leukemia virus (HTLV)]] [[Human T-lymphotropic virus 1|I]] and [[Human T-lymphotropic virus 2|II]].<ref name="entrez">{{citation-attribution|1={{cite web|url=httphttps://www.ncbi.nlm.nih.gov/gene/54968|title=Entrez Gene: Transmembrane protein 70|access-date=2018-08-14}}{{PD-notice}}</ref> GLUT1 accounts for 2 percent of the protein in the plasma membrane of erythrocytes.

[[Mutation]]s in this gene can cause [[Glut1 deficiency|GLUT1 deficiency syndrome 1, GLUT1 deficiency syndrome 2]], [[idiopathic generalized epilepsy]] 12, [[dystonia]] 9, and [[Hereditary stomatocytosis#Variants|stomatin-deficient cryohydrocytosis]].<ref name=":0">{{Cite web|url=https://www.uniprot.org/uniprot/P11166|title=SLC2A1 -– Solute carrier family 2, facilitated glucose transporter member 1 -– Homo sapiens (Human) -– SLC2A1 gene & protein|website=www.uniprot.org|language=en|access-date=2018-08-27}}{{CC-notice|cc=by4}}</ref><ref name=":3">{{cite journal | vauthors = | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158-D169D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }}</ref>

GLUT1 was the first [[glucose transporter]] to be characterized. GLUT 1 is highly conserved.<ref name="pmid3839598"/> GLUT 1 of humans and mice have 98% identity at the amino acid level. GLUT 1 is encoded by the SLC2 gene and is one of a family of 14 genes encoding GLUT proteins.<ref>{{cite journal | vauthors = Mueckler M, Thorens B | title = The SLC2 (GLUT) family of membrane transporters | journal = Molecular Aspects of Medicine | volume = 34 | issue = 2-32–3 | pages = 121–38 | year = 2013 | pmid = 23506862 | pmc = 4104978 | doi = 10.1016/j.mam.2012.07.001 }}</ref>

The ''SLC2A1'' gene is located on the p arm of [[chromosome 1]] in position 34.2 and has 10 [[exon]]s spanning 33,802 base pairs.<ref name = "entrez"/> The gene produces a 54.1 kDa protein composed of 492 [[amino acids]].<ref name=COPaKB>{{cite journal | vauthors = Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB">{{cite web | url = https://amino.heartproteome.org/web/protein/P11166 | website = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = SLC2A1 -– Solute carrier family 2, facilitated glucose transporter member 1 }}</ref><ref>{{cite journal | vauthors = Wang D, Kranz-Eble P, De Vivo DC | title = Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome | journal = Human Mutation | volume = 16 | issue = 3 | pages = 224–31 | date = September 2000 | pmid = 10980529 | doi = 10.1002/1098-1004(200009)16:333<224::AID-HUMU5>3.0.CO;2-P | s2cid = 3169748 | doi-broken-dateaccess = 2018-08-29free }}</ref><ref name=":1">Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {138140}: {08/21/2017}: . World Wide Web URL: https://omim.org/</ref> It is a [[Integral membrane protein#Integral polytopic protein|multi-pass protein]] located in the cell membrane.<ref name=":0" /><ref name=":3" /> This protein lacks a [[Signal peptide|signal sequence]]; its [[C-terminus]], [[N-terminus]], and the very [[Hydrophile|hydrophilic]] [[protein domain|domain]] in the protein's center are all predicted to lie on the [[cytoplasm]]ic side of the cell membrane.<ref name=":1" /><ref name="pmid3839598"/>

GLUT1 behaves as a [[Michaelis-MentenMichaelis–Menten]] enzyme and contains 12 membrane-spanning [[alpha helices]], each containing 20 amino acid residues. A helical wheel analysis shows that the membrane -spanning alpha -helices are [[amphipathic]], with one side being polar and the other side hydrophobic. Six of these membrane -spanning helices are believed to bind together in the membrane to create a polar channel in the center through which glucose can traverse, with the hydrophobic regions on the outside of the channel adjacent to the fatty acid tails of the membrane.{{citation needed|date=November 2015}}

Energy-yielding metabolism in [[erythrocytes]] depends on a constant supply of glucose from the [[blood plasma]], where the glucose concentration is maintained at about 5mM. Glucose enters the erythrocyte by [[facilitated diffusion]] via a specific glucose transporter, at a rate of about 50,000 times greater than uncatalyzed transmembrane diffusion. The glucose transporter of erythrocytes (called GLUT1 to distinguish it from related glucose transporters in other tissues) is a type III [[integral protein]] with 12 hydrophobic segments, each of which is believed to form a membrane-spanning [[Alpha helix|helix]]. The detailed structure of GLUT1 is not known yet, but one plausible model suggests that the side-by-side assembly of several helices produces a transmembrane [[Ion channel|channel]] lined with hydrophilic residues that can hydrogen-bond with glucose as it moves through the channel.<ref name=Lehninger2008>{{cite book |vauthors=Nelson DL, Cox MM | year = 2008 | title = Lehninger, Principles of Biochemistry | url = http://bcs.whfreeman.com/lehninger5e/ |publisher = W. H. Freeman and Company | isbn = 978-0-7167-7108-1 }}{{page needed|dateurl-access=Novemberregistration 2015|url=https://archive.org/details/lehningerprincip00lehn_1}}</ref>

GLUT1 is also a major receptor for uptake of [[Vitamin C]] as well as [[glucose]], especially in non vitamin C producing mammals as part of an adaptation to compensate by participating in a Vitamin C recycling process. In mammals that do produce Vitamin C, [[GLUT4]] is often expressed instead of GLUT1.<ref name="Amélie2008">{{cite journal | vauthors = Montel-Hagen A, Kinet S, Manel N, Mongellaz C, Prohaska R, Battini JL, Delaunay J, Sitbon M, Taylor N | title = Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C | journal = Cell | volume = 132 | issue = 6 | pages = 1039–48 | date = March 2008 | pmid = 18358815 | doi = 10.1016/j.cell.2008.01.042 | laysummarys2cid = 18128118 | doi-access = free }}*{{lay source |template = cite web|url = https://www.sciencedaily.com/releases/2008/03/080320120726.htm |title laydate= How Humans Make Up For An 'Inborn' Vitamin C Deficiency|date = March 21, 2008 | laysourcewebsite = ScienceDaily }}</ref>

GLUT1 expression occurs in almost all tissues, with the degree of expression typically correlating with the rate of cellular glucose metabolism. 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]].<ref>{{cite journal | vauthors = Uldry M, Thorens B | title = The SLC2 family of facilitated hexose and polyol transporters | journal = Pflügers Archiv | volume = 447 | issue = 5 | pages = 480–9 | date = February 2004 | pmid = 12750891 | doi = 10.1007/s00424-003-1085-0 | s2cid = 25539725 | url = http://doc.rero.ch/record/316469/files/424_2004_Article_1264.pdf }}</ref>

Mutations in the GLUT1 gene are responsible for GLUT1 deficiency or [[De Vivo disease]], which is a rare [[Dominance (genetics)|autosomal dominant]] disorder.<ref>{{cite journal | vauthors = Seidner G, Alvarez MG, Yeh JI, O'Driscoll KR, Klepper J, Stump TS, Wang D, Spinner NB, Birnbaum MJ, De Vivo DC | title = GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brainblood–brain barrier hexose carrier | journal = Nature Genetics | volume = 18 | issue = 2 | pages = 188–91 | date = February 1998 | pmid = 9462754 | doi = 10.1038/ng0298-188 | s2cid = 7378231 }}</ref> This disease is characterized by a low [[cerebrospinal fluid]] glucose concentration (hypoglycorrhachia), a type of [[neuroglycopenia]], which results from impaired glucose transport across the blood–brain barrier.

Many mutations in the ''SLC2A1'' gene, including LYS456TER, TYR449TER, LYS256VAL, ARG126HIS, ARG126LEU and GLY91ASP, have been shown to cause GLUT1 deficiency syndrome 1 (GLUT1DS1), a [[Neurological disorder|neurologic disorder]] showing wide [[Phenotype|phenotypic]] variability. This disease can be inherited in either an [[Genetic disorder#Autosomal recessive|autosomal recessive]] or [[Genetic disorder#Autosomal dominant|autosomal dominant]] manner.<ref name=":1" /> The most severe 'classic' phenotype comprises infantile-onset [[Epileptic seizure|epileptic]] [[encephalopathy]] associated with [[Global developmental delay|delayed development]], acquired [[microcephaly]], [[Motor coordination|motor incoordination]], and [[spasticity]]. Onset of [[Seizure (disambiguation)|seizuresseizure]]s, usually characterized by [[apnea|apneic episodes]], [[staring]] spells, and episodic [[eye movements]], occurs within the first 4 months of life. Other [[Paroxysmal attack|paroxysmal]] findings include intermittent [[ataxia]], [[Confusion#Medical term|confusion]], [[lethargy]], [[sleep disorder|sleep disturbance]], and [[headache]]. Varying degrees of [[Cognitive deficit|cognitive impairment]] can occur, ranging from [[Learning disability|learning disabilities]] to severe [[Intellectual disability|mental retardation]].<ref name=":0" /><ref name=":3" />

GLUT1 is also a receptor used by the [[Human T-lymphotropic virus|HTLV]] virus to gain entry into target cells.<ref>{{cite journal | vauthors = Manel N, Kim FJ, Kinet S, Taylor N, Sitbon M, Battini JL | title = The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV | journal = Cell | volume = 115 | issue = 4 | pages = 449–59 | date = November 2003 | pmid = 14622599 | doi = 10.1016/S0092-8674(03)00881-X | urls2cid = http://linkinghub.elsevier.com/retrieve/pii/S009286740300881X14399680 | doi-access = free }}</ref>

GLUT1 has been shown to [[Protein-protein interaction|interact]] with [[GIPC1]].<ref name="pmid10198040">{{cite journal | vauthors = Bunn RC, Jensen MA, Reed BC | title = Protein interactions with the glucose transporter binding protein GLUT1CBP that provide a link between GLUT1 and the cytoskeleton | journal = Molecular Biology of the Cell | volume = 10 | issue = 4 | pages = 819–32 | date = April 1999 | pmid = 10198040 | pmc = 25204 | doi = 10.1091/mbc.10.4.819 }}</ref> It is found in a [[protein complex|complex]] with Adducin ([[ADD2]]) and Dematin ([[DMTNEPB49]]) and interacts (via C-terminus cytoplasmic region) with DMTNDematin [[Protein isoform|isoform]] 2.<ref>{{cite journal | vauthors = Khan AA, Hanada T, Mohseni M, Jeong JJ, Zeng L, Gaetani M, Li D, Reed BC, Speicher DW, Chishti AH | title = Dematin and adducin provide a novel link between the spectrin cytoskeleton and human erythrocyte membrane by directly interacting with glucose transporter-1 | journal = The Journal of Biological Chemistry | volume = 283 | issue = 21 | pages = 14600–9 | date = May 2008 | pmid = 18347014 | pmc = 2386908 | doi = 10.1074/jbc.M707818200 | doi-access = free }}</ref> It also interacts with [[SNX27]]; the interaction is required when [[endocytosis|endocytosed]] to prevent degradation in [[lysosome]]s and promote recycling to the plasma membrane.<ref>{{cite journal | vauthors = Steinberg F, Gallon M, Winfield M, Thomas EC, Bell AJ, Heesom KJ, Tavaré JM, Cullen PJ | title = A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport | journal = Nature Cell Biology | volume = 15 | issue = 5 | pages = 461–71 | date = May 2013 | pmid = 23563491 | pmc = 4052425 | doi = 10.1038/ncb2721 }}</ref> This protein interacts with [[STOM]].<ref>{{cite journal | vauthors = Rungaldier S, Oberwagner W, Salzer U, Csaszar E, Prohaska R | title = Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1828 | issue = 3 | pages = 956–66 | date = March 2013 | pmid = 23219802 | pmc = 3790964 | doi = 10.1016/j.bbamem.2012.11.030 }}</ref> It interacts with [[SGTA]] (via Gln-rich region) and has binary interactions with [[CREB|CREB3-2]].<ref name=":0" /><ref name=":3" />

GLUT1 has two significant types in the brain: 45k45-kDa and 55k55-kDa. GLUT1 45k45-kDa is present onin astroglia ofand neurons and. GLUT1 55k55-kDa is present onin capillariesthe inendothelial cells of the brain vasculature and is responsible for glucose transport across bloodthe brainblood–brain barrier and; its deficiency causes a low level of glucose in CSF (less than 60&nbsp;mg/dl) which may manifest aselicit convulsionseizures in deficient individuals.{{citation needed|date=November 2015}}

Recently it has been described a GLUT1 inhibitor, DERL3, thathas been described and is often methylated in colorectal cancer. In this cancer, DERL3 methylations seemsseem to mediate the Warburg Effecteffect.<ref>{{cite journal | vauthors = Lopez-Serra P, Marcilla M, Villanueva A, Ramos-Fernandez A, Palau A, Leal L, Wahi JE, Setien-Baranda F, Szczesna K, Moutinho C, Martinez-Cardus A, Heyn H, Sandoval J, Puertas S, Vidal A, Sanjuan X, Martinez-Balibrea E, Viñals F, Perales JC, Bramsem JB, Ørntoft TF, Andersen CL, Tabernero J, McDermott U, Boxer MB, Vander Heiden MG, Albar JP, Esteller M | title = A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect | journal = Nature Communications | volume = 5 | issue = | pages = 3608 | date = April 2014 | issue = 1 | pmid = 24699711 | pmc = 3988805 | doi = 10.1038/ncomms4608 | bibcode = 2014NatCo...5E3608L5.3608L }}</ref>

Fasentin is a small molecule inhibitor of the intracellular domain of GLUT1 preventing glucose uptake.<ref name="pmid19001437">{{cite journal | vauthors = Wood TE, Dalili S, Simpson CD, Hurren R, Mao X, Saiz FS, Gronda M, Eberhard Y, Minden MD, Bilan PJ, Klip A, Batey RA, Schimmer AD | title = A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death | journal = Molecular Cancer Therapeutics | volume = 7 | issue = 11 | pages = 3546–55 | date = November 2008 | pmid = 19001437 | doi = 10.1158/1535-7163.MCT-08-0569 | s2cid = 7706108 | url = http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19001437 | doi-access = free }}</ref>

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* {{cite journal |last1 vauthors = Lankford |first1=J, |last2=Butler |first2=IJ, |last3=Koenig |first3=MK | title = Glucose transporter type I deficiency causing mitochondrial dysfunction. | journal = Journal of childChild neurologyNeurology |date=June 2012volume |volume= 27 | issue = 6 | pages = 796–8 | date = June 2012 | pmid = 22156785 | doi = 10.1177/0883073811426503 |pmid s2cid =22156785 206549634 }}

* {{cite journal | vauthors = Hruz PW, Mueckler MM | title = Structural analysis of the GLUT1 facilitative glucose transporter (review) | journal = Molecular Membrane Biology | volume = 18 | issue = 3 | pages = 183–93 | year = 2001 | pmid = 11681785 | doi = 10.1080/09687680110072140 | s2cid = 218897534 | doi-access = free }}

* {{cite journal | vauthors = Baumann MU, Deborde S, Illsley NP | title = Placental glucose transfer and fetal growth | journal = Endocrine | volume = 19 | issue = 1 | pages = 13–22 | date = October 2002 | pmid = 12583599 | doi = 10.1385/ENDO:19:1:13 | s2cid = 26301249 }}

* {{cite journal | vauthors = Mobasheri A, Richardson S, Mobasheri R, Shakibaei M, Hoyland JA | title = Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes | journal = Histology and Histopathology | volume = 20 | issue = 4 | pages = 1327–38 | date = October 2005 | pmid = 16136514 | doi = 10.14670/HH-20.1327 | url = http://www.hh.um.es/Abstracts/Vol_20/20_4/20_4_1327.htm }}