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Sodium/glucose cotransporter 1

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the SLC5A1 gene[4][5] which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and the epithelial cells of the kidney tubules of the nephron for the purpose of glucose uptake into cells.[6] Recently, it has been seen to have functions that can be considered as promising therapeutic target to treat diabetes and obesity.[7] Through the use of the sodium glucose cotransporter 1 protein, cells are able to obtain glucose which is further utilized to make and store energy for the cell.

SLC5A1
Identifiers
AliasesSLC5A1, D22S675, NAGT, SGLT1, solute carrier family 5 member 1
External IDsOMIM: 182380; MGI: 107678; HomoloGene: 55456; GeneCards: SLC5A1; OMA:SLC5A1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6523

20537

Ensembl

n/a

ENSMUSG00000011034

UniProt

P13866

Q8C3K6

RefSeq (mRNA)

NM_000343
NM_001256314

NM_019810

RefSeq (protein)

NP_000334
NP_001243243

NP_062784

Location (UCSC)n/aChr 5: 33.26 – 33.32 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

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The sodium glucose cotransporter 1 is classified as an integral membrane protein that is made up of 14 alpha-helices constructed from the folding of 482-718 amino acid residues with both the N and C-terminal residing upon the extracellular side of the plasma membrane.[8] It is hypothesized that the protein contains protein kinase A and protein kinase C phosphorylation sites, which serve to regulate the proteins conformational shape through phosphorylation of amino acids with ATP.[8][9]

Function

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Glucose transporters are integral membrane proteins that mediate the transport of glucose and structurally related substances across cellular membranes. Two families of glucose transporter have been identified: the facilitated diffusion glucose transporter family (GLUT family), also known as uniporters, and the sodium-dependent glucose transporter family (SGLT family), also known as cotransporters or symporters.[10] The SLC5A1 gene encodes the sodium glucose cotransporter protein that is involved in the facilitated transport of glucose and galactose into eukaryotic and prokaryotic cells.[5] The role of the sodium-glucose cotransporter 1 is to absorb D-glucose and D-galactose from the brush-border membrane of the small intestines,[11][12] while also exchanging sodium ions and glucose from the tubule of the nephron.[13] The SGLT1 protein is able to uptake glucose through cellular membranes through coupling the energy generated from cotransporting 2 sodium ions with glucose through a symport mechanism.[14] This protein does not use ATP as energy source.[14]

Transport mechanism

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The sodium glucose cotransporter is original arranged with an outward-facing conformation with open receptors in preparation for 2 sodium ions and glucose to simultaneously bind.[6] Once bound, the protein receptor will change conformation to an occluded conformation, which prevents the dissociation of the sodium ions and glucose.[6] The protein will then change conformations once more to an inward-facing conformation in which allows sodium and glucose to dissociate.[6] The protein then returns to the outward-facing conformation state, ready to bind more sodium ions and glucose.[6]

History

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Cloning

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Co-transport proteins of mammalian cell membranes had eluded efforts of purification with classical biochemical methods until the late 1980s. These proteins had proven difficult to isolate because they contain hydrophilic and hydrophobic sequences and exist in membranes only in very low abundance (<0.2% of membrane proteins). The rabbit form of SGLT1 was the first mammalian co-transport protein ever to be cloned and sequenced, and this was reported in 1987.[15] To circumvent the difficulties with traditional isolation methods, a novel expression cloning technique was used. Size-fractionation of large amounts of rabbit intestinal mRNA with preparative gel electrophoresis were then sequentially injected into Xenopus oocytes to ultimately find the RNA species that induced the expression of sodium-glucose cotransport.[15]

Clinical significance

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SLC5A1 is medically relevant because of its role in the absorption of glucose and sodium, however, mutations in the gene can cause medical implications. A missense mutation[4] in the SLC5A1 gene of exon 1 can cause problems creating the SGLT1 protein, leading to a very rare glucose-galactose malabsorption disease.[4] This is because the mutation destroys the transport function.[4] Glucose-galactose malabsorption occurs when the lining of the intestinal cells cannot take in glucose and galactose which prevents the use of those molecules in catabolism and anabolism. The disease has symptoms that consist of watery and/or acidic diarrhea which is the result of water retention in the intestinal lumen and osmotic loss created by non-absorbed glucose, galactose and sodium.[16] Patients must stick to a diet devoid of these two sugars, or life-threatening diarrhea will occur.[17]

In humans without this genetic disorder, SLGT1 is key to the operation of oral rehydration therapy. By adding sodium and glucose to water, the co-transporter is allowed to transport all three, helping to speed up water absorption.[18]

Tissue distribution

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The SLC5A1 cotransporter is mainly expressed in the lumen of the small intestine, kidney, parotid glands, submandibular glands and in the heart.[19]

See also

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Interactions

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SLC5A1 has been shown to interact with PAWR.[20]

References

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  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000011034 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ a b c d Turk E, Martín MG, Wright EM (May 1994). "Structure of the human Na+/glucose cotransporter gene SGLT1". The Journal of Biological Chemistry. 269 (21): 15204–9. doi:10.1016/S0021-9258(17)36592-4. PMID 8195156.
  5. ^ a b "Entrez Gene: SLC5A1 solute carrier family 5 (sodium/glucose cotransporter), member 1".
  6. ^ a b c d e Lodish H, Berk A, Kaiser CA, Krieger M, Bretscher A, Ploegh H, Amon A, Martin KC (April 2016). Molecular cell biology (Eighth ed.). New York. ISBN 9781464183393. OCLC 949909675.{{cite book}}: CS1 maint: location missing publisher (link)
  7. ^ Sinha, Jitendra Kumar; Durgvanshi, Shantanu; Verma, Manish; Ghosh, Shampa (June 2023). "Investigation of SLC6A9 and SLC5A1 as a promising therapeutic target for obesity and diabetes using in silico characterization, 3D structure prediction and molecular docking analysis". Alzheimer's & Dementia. 19 (S1). doi:10.1002/alz.064229. ISSN 1552-5260.
  8. ^ a b Wright EM, Hirsch JR, Loo DD, Zampighi GA (January 1997). "Regulation of Na+/glucose cotransporters". The Journal of Experimental Biology. 200 (Pt 2): 287–93. doi:10.1242/jeb.200.2.287. PMID 9050236.
  9. ^ Avendaño C, Menéndez JC (2008). "Drugs That Inhibit Signalling Pathways for Tumor Cell Growth and Proliferation". Medicinal Chemistry of Anticancer Drugs. Elsevier. pp. 251–305. doi:10.1016/b978-0-444-52824-7.00009-3. ISBN 9780444528247.
  10. ^ Wright EM, Loo DD, Panayotova-Heiermann M, Lostao MP, Hirayama BH, Mackenzie B, et al. (November 1994). "'Active' sugar transport in eukaryotes" (PDF). The Journal of Experimental Biology. 196: 197–212. doi:10.1242/jeb.196.1.197. PMID 7823022.
  11. ^ Wright EM, Turk E (February 2004). "The sodium/glucose cotransport family SLC5". Pflügers Archiv. 447 (5): 510–8. doi:10.1007/s00424-003-1063-6. PMID 12748858. S2CID 41985805.
  12. ^ Gorboulev, V.; Schurmann, A.; Vallon, V.; Kipp, H.; Jaschke, A.; Klessen, D.; Friedrich, A.; Scherneck, S.; Rieg, T.; Cunard, R.; Veyhl-Wichmann, M. (2012-01-01). "Na+-D-glucose Cotransporter SGLT1 is Pivotal for Intestinal Glucose Absorption and Glucose-Dependent Incretin Secretion". Diabetes. 61 (1): 187–196. doi:10.2337/db11-1029. ISSN 0012-1797. PMC 3237647. PMID 22124465.
  13. ^ Hamilton KL, Butt AG (December 2013). "Glucose transport into everted sacs of the small intestine of mice". Advances in Physiology Education. 37 (4): 415–26. doi:10.1152/advan.00017.2013. PMID 24292921. S2CID 8525585.
  14. ^ a b Poulsen, Søren Brandt; Fenton, Robert A.; Rieg, Timo (March 2017). "Sodium-glucose cotransport". Current Opinion in Nephrology and Hypertension. 24 (5): 463–469. doi:10.1097/MNH.0000000000000152. ISSN 1473-6543. PMC 5364028. PMID 26125647.
  15. ^ a b Hediger MA, Coady MJ, Ikeda TS, Wright EM (1987). "Expression cloning and cDNA sequencing of the Na+/glucose co-transporter". Nature. 330 (6146): 379–81. Bibcode:1987Natur.330..379H. doi:10.1038/330379a0. PMID 2446136. S2CID 4319002.
  16. ^ Wright EM, Turk E, Martin MG (2002). "Molecular basis for glucose-galactose malabsorption". Cell Biochemistry and Biophysics. 36 (2–3): 115–21. doi:10.1385/CBB:36:2-3:115. PMID 12139397. S2CID 25248625.
  17. ^ "Glucose galactose malabsorption". Genes and Disease [Internet]. National Center for Biotechnology Information (US). 1998.
  18. ^ Guyton, A.C.; Hall, J.E. (19 July 2010). Guyton and Hall Textbook of Medical Physiology: Enhanced E-book. Philadelphia: Elsevier Health Sciences. p. 330. ISBN 978-0-7216-0240-0.
  19. ^ Sabino-Silva R, Mori RC, David-Silva A, Okamoto MM, Freitas HS, Machado UF (November 2010). "The Na(+)/glucose cotransporters: from genes to therapy". Brazilian Journal of Medical and Biological Research. 43 (11): 1019–26. doi:10.1590/S0100-879X2010007500115. PMID 21049241.
  20. ^ Xie J, Guo Q (July 2004). "Par-4 inhibits choline uptake by interacting with CHT1 and reducing its incorporation on the plasma membrane". The Journal of Biological Chemistry. 279 (27): 28266–75. doi:10.1074/jbc.M401495200. PMID 15090548.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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