Sodium/glucose cotransporter 1 explained

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the gene[1] [2] 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.[3] Recently, it has been seen to have functions that can be considered as promising therapeutic target to treat diabetes and obesity.[4] 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.

Structure

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.[5] 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.[6]

Function

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.[7] 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. 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,[8] [9] while also exchanging sodium ions and glucose from the tubule of the nephron.[10] 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.[11] This protein does not use ATP as energy source.

Transport mechanism

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. Once bound, the protein receptor will change conformation to an occluded conformation, which prevents the dissociation of the sodium ions and glucose. The protein will then change conformations once more to an inward-facing conformation in which allows sodium and glucose to dissociate. The protein then returns to the outward-facing conformation state, ready to bind more sodium ions and glucose.

History

Cloning

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. 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.[12]

Clinical significance

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[1] in the SLC5A1 gene of exon 1 can cause problems creating the SGLT1 protein, leading to a very rare glucose-galactose malabsorption disease.[1] This is because the mutation destroys the transport function.[1] 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.[13] Patients must stick to a diet devoid of these two sugars, or life-threatening diarrhea will occur.[14]

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.[15]

Tissue distribution

The SLC5A1 cotransporter is mainly expressed in the lumen of the small intestine, kidney, parotid glands, submandibular glands and in the heart.[16]

See also

Interactions

SLC5A1 has been shown to interact with PAWR.[17]

Further reading

Notes and References

  1. Turk E, Martín MG, Wright EM . Structure of the human Na+/glucose cotransporter gene SGLT1 . The Journal of Biological Chemistry . 269 . 21 . 15204–9 . May 1994 . 10.1016/S0021-9258(17)36592-4 . 8195156 . free .
  2. Web site: Entrez Gene: SLC5A1 solute carrier family 5 (sodium/glucose cotransporter), member 1.
  3. Book: Molecular cell biology. Harvey . Lodish . Arnold . Berk . Chris A. . Kaiser . Monty . Krieger . Anthony . Bretscher . Hidde . Ploegh . Angelika . Amon . Kelsey C. . Martin . vanc . 9781464183393 . Eighth . New York . 949909675 . April 2016.
  4. 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 . en . 19 . S1 . 10.1002/alz.064229 . 1552-5260. free .
  5. Wright EM, Hirsch JR, Loo DD, Zampighi GA . Regulation of Na+/glucose cotransporters . The Journal of Experimental Biology . 200 . Pt 2 . 287–93 . January 1997 . 10.1242/jeb.200.2.287 . 9050236 .
  6. Book: Avendaño C, Menéndez JC . Drugs That Inhibit Signalling Pathways for Tumor Cell Growth and Proliferation. 2008. 10.1016/b978-0-444-52824-7.00009-3 . Medicinal Chemistry of Anticancer Drugs . 251–305 . Elsevier . 9780444528247 .
  7. Wright EM, Loo DD, Panayotova-Heiermann M, Lostao MP, Hirayama BH, Mackenzie B, Boorer K, Zampighi G . 6 . 'Active' sugar transport in eukaryotes . The Journal of Experimental Biology . 196 . 197–212 . November 1994 . 10.1242/jeb.196.1.197 . 7823022 .
  8. Wright EM, Turk E. February 2004. The sodium/glucose cotransport family SLC5. Pflügers Archiv. 447. 5. 510–8. 10.1007/s00424-003-1063-6. 12748858. 41985805.
  9. 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. en. 61. 1. 187–196. 10.2337/db11-1029. 0012-1797. 3237647. 22124465.
  10. 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. 10.1152/advan.00017.2013. 24292921. 8525585 .
  11. Poulsen. Søren Brandt. Fenton. Robert A.. Rieg. Timo. March 2017. Sodium-glucose cotransport. Current Opinion in Nephrology and Hypertension. 24. 5. 463–469. 10.1097/MNH.0000000000000152. 1473-6543. 5364028. 26125647.
  12. Hediger MA, Coady MJ, Ikeda TS, Wright EM . Expression cloning and cDNA sequencing of the Na+/glucose co-transporter . Nature . 330 . 6146 . 379–81 . 1987 . 2446136 . 10.1038/330379a0 . 1987Natur.330..379H . 4319002 .
  13. Wright EM, Turk E, Martin MG . Molecular basis for glucose-galactose malabsorption . Cell Biochemistry and Biophysics . 36 . 2–3 . 115–21 . 2002 . 12139397 . 10.1385/CBB:36:2-3:115 . 25248625 .
  14. Book: https://www.ncbi.nlm.nih.gov/books/NBK22210/ . Genes and Disease [Internet] . Glucose galactose malabsorption . 1998 . National Center for Biotechnology Information (US) .
  15. Book: Guyton . A.C. . Hall . J.E. . [{{google books |plainurl = y |id = Po0zyO0BFzwC }} Guyton and Hall Textbook of Medical Physiology: Enhanced E-book ]. 19 July 2010. Elsevier Health Sciences. Philadelphia . 1-4377-2674-7 -->,978-0-7216-0240-0 . 330 .
  16. Sabino-Silva R, Mori RC, David-Silva A, Okamoto MM, Freitas HS, Machado UF . The Na(+)/glucose cotransporters: from genes to therapy . Brazilian Journal of Medical and Biological Research . 43 . 11 . 1019–26 . November 2010 . 21049241 . 10.1590/S0100-879X2010007500115 . free .
  17. Xie J, Guo Q . 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 . July 2004 . 15090548 . 10.1074/jbc.M401495200 . free .

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