GLUT1
Uniporter protein From Wikipedia, the free encyclopedia
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.[5] GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells.[6] This gene encodes a facilitative glucose transporter that is highly expressed in erythrocytes and endothelial cells, including cells of the blood–brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II.[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 cause GLUT1 deficiency syndrome 1, GLUT1 deficiency syndrome 2, idiopathic generalized epilepsy 12, dystonia 9, and stomatin-deficient cryohydrocytosis.[9][10] Disruption in GLUT1-mediated glucose transport can lead to defects in cell differentiation and morphogenesis.
Discovery
GLUT1 was the first glucose 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]
Structure
The SLC2A1 gene is located on the p arm of chromosome 1 in position 34.2 and has 10 exons spanning 33,802 base pairs.[7] The gene produces a 54.1 kDa protein composed of 492 amino acids.[12][13][14][15] It is a multi-pass protein located in the cell membrane.[9][10] This protein lacks a signal sequence; its C-terminus, N-terminus, and the very hydrophilic domain in the protein's center are all predicted to lie on the cytoplasmic side of the cell membrane.[15][5]
GLUT1 behaves as a Michaelis–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]
Function
Summarize
Perspective
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 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 channel 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 all cells. Expression levels of GLUT1 in cell membranes are increased by reduced glucose levels and decreased by increased glucose levels.[8]
GLUT1's function extends beyond its role in basic glucose transport, as it has been shown to interact with molecular signalling pathways during early embryogenesis. Specifically, it is involved in processes like mesodermal formation, neural tube development, and cell-fate transitions. It is also a key player in directing embryonic development, influencing cell fate transitions, and guiding tissue-specific differentiation during critical stages of embryogenesis. GLUT1-mediated glucose uptake plays a critical role in early embryogenesis, where glucose metabolism undergoes a conserved shift at the time of implantation. It helps fine-tune cell fate decisions and developmental transitions during this stage.[8]
Recent studies have shown that glucose metabolism actively directs cell fate. For example, the hexosamine biosynthetic pathway, which depends on glucose metabolism, produces UDP-GlcNAc,[clarification needed] a molecule crucial for cell differentiation and morphogenetic processes. This highlights how GLUT1-mediated glucose transport can influence signalling pathways such as ERK,[clarification needed] which are critical for the differentiation of epiblast cells into mesodermal tissue, guiding embryonic cell fate transitions. Influences cellular responses to key morphogens, such as FGF8 and FGF4, essential for proper development.[8]
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.[17]
Role of metabolism in Gastrulation
Gastrulation is a critical phase of embryogenesis where the primary body plan is established through the movement and differentiation of cells. Glucose uptake and utilization are compartmentalized across different embryonic tissues, with distinct waves of glucose activity in the epiblast and mesoderm during gastrulation.[8]
Spatiotemporal Waves of Glucose Uptake: Two waves of glucose uptake have been identified during mouse gastrulation. The first wave occurs in transitionary epiblast cells, located in the posterior region of the embryo. These cells exhibit an initial surge in glucose uptake, which expands as the primitive streak elongates. The second wave occurs in mesodermal cells, as they exit the primitive streak and migrate laterally to form mesenchymal tissue. This second wave of glucose activity coincides with increased metabolic demands during mesodermal migration and mesenchymal cell behavior. These waves of glucose uptake are linked with ERK signaling, an important pathway regulating cellular behavior during development. The coupling of glucose metabolism with ERK activity suggests that metabolic signals not only provide energy but also act as regulators of developmental processes. This interaction is especially significant for mesoderm migration, as inhibition of glycolysis or ERK signaling disrupts proper mesodermal development.[8]
Another critical aspect of glucose metabolism during gastrulation is the hexosamine biosynthetic pathway, which plays a key role in preparing epiblast cells for entry into the primitive streak. The pathway is important for regulating cell-fate transitions in the epiblast, supporting the initiation of mesodermal formation. Inhibition of the hexosamine biosynthetic pathway results in delayed primitive streak development, highlighting its importance in early embryonic development.[8]
Glucose metabolism shifts significantly after implantation, with increased glucose uptake supporting cellular processes such as proliferation and differentiation. However, high glucose uptake does not always correlate with increased glycolytic activity, as glucose can also be directed into parallel metabolic pathways.[8]
Given the high level of glucose activity in epiblast cells before primitive streak entry, it was hypothesized that metabolic regulation could play a role in the epithelial-to-mesenchymal transition during mouse gastrulation. Transitionary epiblast cells showed weakened E-cadherin expression but exhibited GLUT1 and GLUT3 activity, indicating enhanced glucose uptake during early-stage epithelial-to-mesenchymal transition.[8]
Together, these findings demonstrate that hexosamine biosynthetic pathway is crucial for regulating epithelial-to-mesenchymal transition in the posterior epiblast during mouse gastrulation, facilitating both the mesodermal fate acquisition and the ingression of epiblast cells into the primitive streak. The anterior epiblast cells, in contrast, are influenced by the anterior visceral endoderm, which prevents posteriorization and inhibits epithelial-to-mesenchymal transition, allowing glucose metabolism to shift towards ectoderm fate at later stages.[8]
Tissue distribution
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.[18]
Clinical significance
Summarize
Perspective
Mutations in the GLUT1 gene are responsible for GLUT1 deficiency or De Vivo disease, which is a rare autosomal dominant disorder.[19] 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.
GLUT1 deficiency syndrome 1
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 neurologic disorder showing wide phenotypic variability. This disease can be inherited in either an autosomal recessive or autosomal dominant manner.[15] The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life. Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe mental retardation.[9][10]
GLUT1 deficiency syndrome 2
Other mutations, like GLY314SER, ALA275THR, ASN34ILE, SER95ILE, ARG93TRP, ARG91TRP, a 3-bp insertion (TYR292) and a 12-bp 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 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 movements may be associated with macrocytic hemolytic anemia.[9][10] Inheritance of this disease is autosomal dominant.[15]
Idiopathic generalized epilepsy 12
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 lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. In some EIG12 patients seizures may remit with age.[9][10] Inheritance of this disease is autosomal dominant.[15]
Dystonia 9
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 spastic paraplegia. Most patients show some degree of cognitive impairment. Other variable features may include seizures, migraine headaches, and ataxia.[9][10]
Stomatin-deficient cryohydrocytosis
Certain mutations, like GLY286ASP and a 3-bp deletion in ILE435/436, cause stomatin-deficient cryohydrocytosis with neurologic defects, a rare form of stomatocytosis characterized by episodic hemolytic anemia, cold-induced red cells cation leak, erratic hyperkalemia, neonatal hyperbilirubinemia, hepatosplenomegaly, cataracts, seizures, mental retardation, and movement disorder.[9][10] Inheritance of this disease is autosomal dominant.[15]
Role as a receptor for HTLV
GLUT1 is also a receptor used by the HTLV virus to gain entry into target cells.[20]
Role as a histochemical marker for hemangioma
Glut1 has also been demonstrated as a powerful histochemical marker for hemangioma of infancy[21]
Interactions
GLUT1 has been shown to interact with GIPC1.[22] It is found in a complex with adducin (ADD2) and Dematin (EPB49) and interacts (via C-terminus cytoplasmic region) with Dematin isoform 2.[23] It also interacts with SNX27; the interaction is required when endocytosed to prevent degradation in lysosomes and promote recycling to the plasma membrane.[24] This protein interacts with STOM.[25] It interacts with SGTA (via Gln-rich region) and has binary interactions with CREB3-2.[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]
Inhibitors
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]
Recent experiments have shown that inhibition of glucose metabolism, particularly glycolysis, impairs mesodermal migration. This finding suggests that glycolysis is crucial for mesodermal cell motility and proper developmental progression. Inhibitors such as 2-deoxy-D-glucose (2-DG) and 3-bromopyruvate (BrPA), which block glycolytic enzymes, reduce the distance over which mesodermal cells migrate, supporting the hypothesis that glycolysis regulates mesodermal movement during early development.[8]
In functional assays, mesoderm explants treated with inhibitors of glycolysis or ERK signaling exhibited reduced migration without a corresponding increase in proliferation, further demonstrating that glycolysis drives mesodermal migration, not just cell division. These findings suggest that glycolytic activity, rather than cell proliferation, is the primary driver of mesoderm expansion during gastrulation.[8]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
Glycolysis and Gluconeogenesis edit
- The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".
References
Further reading
External links
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