Glucose transporter 1 (orGLUT1), also known assolute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is auniporterprotein that in humans is encoded by theSLC2A1gene.[5] GLUT1facilitates the transport ofglucose across theplasma membranes of mammalian cells.[6] This gene encodes a facilitativeglucose transporter that is highly expressed in erythrocytes and endothelial cells, including cells of theblood–brain barrier. The encoded protein is found primarily in thecell membrane and on the cell surface, where it can also function as areceptor forhuman T-cell leukemia virus (HTLV)I andII.[7] GLUT1 accounts for 2 percent of the protein in the plasma membrane of erythrocytes. During early development, GLUT1 expression is compartmentalized across different tissues, ensuring that metabolic requirements are met in a tissue-specific manner. This tissue-specific glucose metabolism is essential for regulating the differentiation of specific lineages, such as the epiblast to mesoderm transition during gastrulation. GLUT1's role in glucose uptake supports localized metabolic needs that interact with developmental signalling pathways to shape the emerging body plan.[8]
Mutations in this gene can causeGLUT1 deficiency syndrome 1, GLUT1 deficiency syndrome 2,idiopathic generalized epilepsy 12,dystonia 9, andstomatin-deficient cryohydrocytosis.[9][10] Disruption in GLUT1-mediated glucose transport can lead to defects in cell differentiation and morphogenesis.
GLUT1 was the firstglucose transporter to be characterized. GLUT1 is highly conserved.[5] GLUT1 of humans and mice have 98% identity at the amino acid level. GLUT1 is encoded by the SLC2 gene and is one of a family of 14 genes encoding GLUT proteins.[11]
TheSLC2A1 gene is located on the p arm ofchromosome 1 in position 34.2 and has 10exons spanning 33,802 base pairs.[7] The gene produces a 54.1 kDa protein composed of 492amino acids.[12][13][14][15] It is amulti-pass protein located in the cell membrane.[9][10] This protein lacks asignal sequence; itsC-terminus,N-terminus, and the veryhydrophilicdomain in the protein's center are all predicted to lie on thecytoplasmic side of the cell membrane.[15][5]
GLUT1 behaves as aMichaelis–Menten enzyme and contains 12 membrane-spanningalpha helices, each containing 20 amino acid residues. A helical wheel analysis shows that the membrane-spanning alpha-helices areamphipathic, 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]
Energy-yielding metabolism inerythrocytes depends on a constant supply of glucose from theblood plasma, where the glucose concentration is maintained at about 5mM. Glucose enters the erythrocyte byfacilitated 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 IIIintegral protein with 12 hydrophobic segments, each of which is believed to form a membrane-spanninghelix. 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 transmembranechannel lined with hydrophilic residues that can hydrogen-bond with glucose as it moves through the channel.[16]
GLUT1 is responsible for the low level of basal glucose uptake required to sustain respiration in most mammalian cells. Expression levels of GLUT1 in cell membranes are increased by reduced glucose levels and decreased by increased glucose levels.[8]
GLUT1 also participates incell signaling processes, particularly duringembryogenesis, such asgastrulation. Specifically, by determining the baseline level of metabolic flux throughglycolysis, it supports the cellular response to morphogens such asfibroblast growth factors (FGFs) and the downstreamERK pathways.[8]
GLUT1 is also a major receptor for uptake ofvitamin C as well asglucose, 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.[17]
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 inerythrocytes and also in theendothelial cells of barrier tissues such as theblood–brain barrier.[18]
Mutations in the GLUT1 gene are responsible for GLUT1 deficiency orDe Vivo disease, which is a rareautosomal dominant disorder.[19] This disease is characterized by a lowcerebrospinal fluid glucose concentration (hypoglycorrhachia), a type ofneuroglycopenia, which results from impaired glucose transport across the blood–brain barrier.
Many mutations in theSLC2A1 gene, including LYS456TER, TYR449TER, LYS256VAL, ARG126HIS, ARG126LEU and GLY91ASP, have been shown to cause GLUT1 deficiency syndrome 1 (GLUT1DS1), aneurologic disorder showing widephenotypic variability. This disease can be inherited in either anautosomal recessive orautosomal dominant manner.[15] The most severe 'classic' phenotype comprises infantile-onsetepilepticencephalopathy associated withdelayed development, acquiredmicrocephaly,motor incoordination, andspasticity. Onset ofseizures, usually characterized byapneic episodes,staring spells, and episodiceye movements, occurs within the first 4 months of life. Otherparoxysmal findings include intermittentataxia,confusion,lethargy,sleep disturbance, andheadache. Varying degrees ofcognitive impairment can occur, ranging fromlearning disabilities to severemental retardation.[9][10]
Other mutations, like GLY314SER, ALA275THR, ASN34ILE, SER95ILE, ARG93TRP, ARG91TRP, a 3-bpinsertion (TYR292) and a 12-bpdeletion (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-induceddyskinesia. The dyskinesia involves transient abnormal involuntarymovements, such asdystonia andchoreoathetosis, induced by exercise or exertion, and affecting the exercised limbs. Some patients may also haveepilepsy, most commonlychildhood absence epilepsy. Mild mental retardation may also occur. In some patients involuntary exertion-induced dystonic, choreoathetotic, andballistic movements may be associated withmacrocytichemolytic anemia.[9][10] Inheritance of this disease is autosomal dominant.[15]
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 detectablebrainlesions and/ormetabolic abnormalities. Generalized seizures arise diffusely and simultaneously from bothhemispheres of the brain. Seizure types includejuvenile myoclonic seizures,absence seizures, andgeneralized tonic-clonic seizures. In some EIG12 patients seizures may remit with age.[9][10] Inheritance of this disease is autosomal dominant.[15]
Another mutation, ARG212CYS, has been shown to cause Dystonia 9 (DYT9), an autosomal dominant neurologic disorder characterized by childhood onset of paroxysmal choreoathetosis and progressive spasticparaplegia. Most patients show some degree of cognitive impairment. Other variable features may include seizures,migraine headaches, and ataxia.[9][10]
Certain mutations, like GLY286ASP and a 3-bp deletion in ILE435/436, causestomatin-deficient cryohydrocytosis with neurologic defects, a rare form of stomatocytosis characterized by episodichemolytic anemia, cold-induced red cellscation leak, erratichyperkalemia,neonatal hyperbilirubinemia,hepatosplenomegaly,cataracts, seizures, mental retardation, and movement disorder.[9][10] Inheritance of this disease is autosomal dominant.[15]
GLUT1 is also a receptor used by theHTLV virus to gain entry into target cells.[20]
Glut1 has also been demonstrated as a powerful histochemical marker forhemangioma of infancy[21]
GLUT1 has been shown tointeract withGIPC1.[22] It is found in acomplex with adducin (ADD2) and Dematin (EPB49) and interacts (via C-terminus cytoplasmic region) with Dematinisoform 2.[23] It also interacts withSNX27; the interaction is required whenendocytosed to prevent degradation inlysosomes and promote recycling to the plasma membrane.[24] This protein interacts withSTOM.[25] It interacts withSGTA (via Gln-rich region) and has binary interactions withCREB3-2.[9][10]
GLUT1 has two significant types in the brain: 45-kDa and 55-kDa. GLUT1 45-kDa is present in astroglia and neurons. GLUT1 55-kDa is present in the endothelial cells of the brain vasculature and is responsible for glucose transport across the blood–brain barrier; its deficiency causes a low level of glucose in CSF (less than 60 mg/dl) which may elicit seizures in deficient individuals.[citation needed]
Recently a GLUT1 inhibitor DERL3 has been described and is often methylated in colorectal cancer. In this cancer, DERL3 methylations seem to mediate the Warburg effect.[26]
Fasentin is a small molecule inhibitor of the intracellular domain of GLUT1 preventing glucose uptake.[27]
Recently, a new more selective GLUT1 inhibitor, Bay-876, has been described.[28]
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
This article incorporates text from this source, which is in thepublic domain:"Entrez Gene: Transmembrane protein 70". Retrieved2018-08-14.
This article incorporates text available under theCC BY 4.0 license.This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
