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 and endothelial cells, mammalianincluding 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> [[Mutation]]s in this gene can cause [[Glut1 deficiency|GLUT1 deficiencyaccounts syndrome 1, GLUT1 deficiency syndromefor 2]], [[idiopathicpercent generalizedof 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 &the protein|website=www.uniprot.org|language=en|access-date=2018-08-27}}{{CC-notice|cc=by4}}</ref><ref name=":3">{{citein journal|vauthors=|date=Januarythe 2017|title=UniProt:plasma themembrane universalof protein knowledgebase|url=https://doierythrocytes.org/10.1093/nar/gkw1099|journal=Nucleic Acids Research|volume=45|issue=D1|pages=D158-D169|doi=10.1093/nar/gkw1099|pmc=5210571|pmid=27899622}}</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 = OctOctober 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 | workwebsite = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = SLC2A1 -– Solute carrier family 2, facilitated glucose transporter member 1 }}</ref><ref>{{Citecite journal |last vauthors = Wang|first= D.|last2=, Kranz-Eble|first2= P.|last3=, De Vivo DC |first3=D. C.|date=2000-9|title = Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome |url=https://www.ncbi.nlm.nih.gov/pubmed/10980529| journal = Human Mutation | volume = 16 | issue = 3 | pages =224–231 224–31 | date = September 2000 | pmid = 10980529 | doi = 10.1002/1098-1004(200009)16:333<224::AID-HUMU5>3.0.CO;2-P |issn s2cid =1098-1004 3169748 |pmid doi-access =10980529 free }}</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_proteinIntegral membrane protein#Integral_polytopic_proteinIntegral 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|cytoplasmic]]ic side of the cell membrane.<ref name=":1" /><ref>{{Cite journal|lastname=Mueckler|first=M.|last2=Caruso|first2=C.|last3=Baldwin|first3=S. A.|last4=Panico|first4=M.|last5=Blench|first5=I.|last6=Morris|first6=H. R.|last7=Allard|first7=W. J.|last8=Lienhard|first8=G. E.|last9=Lodish|first9=H. F.|date=1985-09-06|title=Sequence and structure of a human glucose transporter|url=https:"pmid3839598"//www.ncbi.nlm.nih.gov/pubmed/3839598|journal=Science (New York, N.Y.)|volume=229|issue=4717|pages=941–945|issn=0036-8075|pmid=3839598}}</ref>

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_disorderGenetic disorder#Autosomal_recessiveAutosomal recessive|autosomal recessive]] or [[Genetic_disorderGenetic disorder#Autosomal_dominantAutosomal dominant|autosomal dominant]] manner.<ref name=":1" /> The most severe 'classic' phenotype comprises infantile-onset [[Epileptic_seizureEpileptic seizure|epileptic]] [[encephalopathy]] associated with [[Global_developmental_delayGlobal developmental delay|delayed development]], acquired [[microcephaly]], [[Motor_coordinationMotor 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_attackParoxysmal attack|paroxysmal]] findings include intermittent [[ataxia]], [[Confusion#Medical_termMedical term|confusion]], [[lethargy]], [[sleep disorder|sleep disturbance]], and [[headache]]. Varying degrees of [[Cognitive_deficitCognitive deficit|cognitive impairment]] can occur, ranging from [[Learning_disabilityLearning disability|learning disabilities]] to severe [[Intellectual_disabilityIntellectual disability|mental retardation]].<ref name=":0" /><ref name=":3" />

Other mutations, like GLY314SER, ALA275THR, ASN34ILE, SER95ILE, ARG93TRP, ARG91TRP, a 3-bp [[Insertion (genetics)|insertion]] (TYR292) and a 12-bp [[Deletion (genetics)|deletion]] (1022_1033del) in exon 6, have been shown to cause GLUT1 deficiency syndrome 2 (GLUT1DS2), a clinically variable disorder characterized primarily by onset in childhood of paroxysmal exercise-induced [[dyskinesia]]. The dyskinesia involves transient abnormal involuntary [[Movement_disordersMovement disorders|movements]], such as [[dystonia]] and [[choreoathetosis]], induced by exercise or exertion, and affecting the exercised limbs. Some patients may also have [[epilepsy]], most commonly [[childhood absence epilepsy]]. Mild mental retardation may also occur. In some patients involuntary exertion-induced dystonic, choreoathetotic, and [[ballistic movement|ballistic movements]]s may be associated with [[Macrocytic anemia|macrocytic]] [[hemolytic anemia]].<ref name=":0" /><ref name=":3" /> Inheritance of this disease is autosomal dominant.<ref name=":1" />

Some mutations, particularly ASN411SER, ARG458TRP, ARG223PRO and ARG232CYS, have been shown to cause idiopathic generalized epilepsy 12 (EIG12), a disorder characterized by recurring generalized seizures in the absence of detectable [[brain]] [[lesion]]s and/or [[Metabolic disorder|metabolic abnormalities]]. Generalized seizures arise diffusely and simultaneously from both [[Cerebral hemisphere|hemispheres of the brain]]. Seizure types include [[Juvenile_myoclonic_epilepsyJuvenile myoclonic epilepsy|juvenile myoclonic seizures]], [[absence seizure|absence seizures]]s, and [[Generalized tonic–clonic seizure|generalized tonic-clonic seizures]]. In some EIG12 patients seizures may remit with age.<ref name=":0" /><ref name=":3" /> Inheritance of this disease is autosomal dominant.<ref name=":1" />

Certain mutations, like GLY286ASP and a 3-bp deletion in ILE435/436, cause [[Stomatin]]-deficient cryohydrocytosis with neurologic defects (SDCHCN), a rare form of stomatocytosis characterized by episodic [[hemolytic anemia]], cold-induced red cells [[Ion#Anions_and_cationsAnions and cations|cation]] leak, erratic [[hyperkalemia]], [[Neonatal_jaundiceNeonatal jaundice|neonatal hyperbilirubinemia]], [[hepatosplenomegaly]], [[cataract]]s, seizures, mental retardation, and movement disorder.<ref name=":0" /><ref name=":3" /> Inheritance of this disease is autosomal dominant.<ref name=":1" />

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>{{Citecite journal |last vauthors = Khan|first=Anwar A.|last2=AA, Hanada|first2=Toshihiko|last3= T, Mohseni|first3=Morvarid|last4= M, Jeong|first4=Jong-Jin|last5= JJ, Zeng|first5=Lixiao|last6= L, Gaetani|first6=Massimiliano|last7= M, Li|first7=Donghai|last8= D, Reed|first8=Brent C.|last9=BC, Speicher DW, Chishti AH |first9=David W.|date=2008-05-23|title = Dematin and adducin provide a novel link between the spectrin cytoskeleton and human erythrocyte membrane by directly interacting with glucose transporter-1 |url=https://www.ncbi.nlm.nih.gov/pubmed/18347014| journal = The Journal of Biological Chemistry | volume = 283 | issue = 21 | pages =14600–14609 14600–9 | date = May 2008 | pmid = 18347014 | pmc = 2386908 | doi = 10.1074/jbc.M707818200 |issn=0021 doi-9258|pmcaccess =PMC2386908|pmid=18347014 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>{{Citecite journal |last vauthors = Steinberg|first=Florian|last2= F, Gallon|first2=Matthew|last3= M, Winfield|first3=Mark|last4= M, Thomas|first4=Elaine C.|last5=EC, Bell|first5=Amanda J.|last6=AJ, Heesom|first6=Kate J.|last7=KJ, Tavaré|first7=Jeremy M.|last8=JM, Cullen PJ |first8=Peter J.|date=2013-5|title = A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport |url=https://www.ncbi.nlm.nih.gov/pubmed/23563491| journal = Nature Cell Biology | volume = 15 | issue = 5 | pages =461–471 461–71 |doi date =10.1038/ncb2721 May 2013 |issn pmid =1476-4679 23563491 | pmc =PMC4052425 4052425 |pmid doi =23563491 10.1038/ncb2721 }}</ref> This protein interacts with [[STOM]].<ref>{{Citecite journal |last vauthors = Rungaldier|first=Stefanie|last2= S, Oberwagner|first2=Walter|last3= W, Salzer|first3=Ulrich|last4= U, Csaszar|first4=Edina|last5= E, Prohaska R |first5=Rainer|date=2013-3| title = Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains |url=https://www.ncbi.nlm.nih.gov/pubmed/23219802| journal = Biochimica Etet Biophysica Acta (BBA) - Biomembranes | volume = 1828 | issue = 3 | pages =956–966 956–66 | date = March 2013 | pmid = 23219802 | pmc = 3790964 | doi = 10.1016/j.bbamem.2012.11.030|issn=0006-3002|pmc=PMC3790964|pmid=23219802 }}</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 | 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 }}