GLUT1

Classification

GLUT proteins, encoded by the SLC2 genes, are part of the Major Facilitator Superfamily (MFS) of substrate transporters. Structural elements characteristic of GLUT proteins are twelve transmembrane domains, one N-linked glycosylation site, and lengths of about five-hundred amino acids.^[1] GLUT proteins transport a variety of monosaccharides that enable cellular respiration and are thus abundant in the body. According to the CATH[1] classification database, the MFS superfamily has 23,982 unique species and 134 domains.

Function

The GLUT1 is an insulin-independent glucose transporter expressed by all cells in the body to maintain adequate baseline glucose uptake. Some examples of tissues that express GLUT1 at high rates include: the placenta and fetal tissues, epithelial cells of the retina and mammary gland, and the brain.^[2]

Brain

The GLUT1 transporter works synergistically with other solute carriers in the brain. Astrocytes and endothelial cells of brain capillaries primarily express GLUT1; neurons primarily express Glut3. GLUT1 has a relatively high Km and is upregulated in times of hypoglycemia in the brain to ensure adequate glucose uptake. Glut3 has a low Km to ensure a steady supply of glucose for neurons even when extracellular glucose concentrations are low.^[3]

Pregnancy

The GLUT1 transporter is highly expressed in both the placenta and the developing embryo/fetus.^[4] During pregnancy, there is no significant fetal gluconeogenesis in humans.^[5] High GLUT1 expression in the fetoplacental tissues ensures that the fetus receives a steady supply of glucose.

Retina

GLUT1 is the most abundant glucose transporter in the retina. Retinal pigmented epithelium and retinal capillary endothelium, the tissues that comprise the retina-brain barrier, express GLUT1.^[6] The retina has a consistently high energy requirement due to abundance of energy-consuming enzymes such as Sodium-Potassium ATPase. Studies on mice have shown that GLUT1 knockout leads to photoreceptor cell death - a greater effect was noted in cone cells versus rod cells.^[7]

Disease

Cancer

Oncogenes such as Ras and Src have been linked to upregulation of GLUT1 in rat tumors. Many studies have shown that GLUT1 is upregulated in malignancies of the breast.^[8] Upregulation of the GLUT1 transporter has been shown to increase cell proliferation in some types of breast cancer.^[9]

Relevance

Structural highlights

The GLUT1 transporter has one known site at Asn 45 and varied molecular weights of the GLUT1 transporter suggest glycosylation is dependent on cell type. This glycosylation site is thought to be important for glucose binding to the extracellular portion of the transporter. Mutations in the GLUT1 transporter from Asn 45 to an Asp, Tyr, or Gln residue have been shown to increase the Km of the enzyme.^[10]

has a and is proposed to be comprised of . In the structure 4pyp, these residues are Gly27, Thr30, Ile164, Val165, Ile168, and Phe291. This hydrophobic pocket has been proposed to facilitate substrate binding and unbinding between the "occluded" and "inward-open" conformations.^[11]

The GLUT1 transporter also has three proposed ATP-binding sites. The lone is proposed to be comprised of the residues Gly111, Phe112, Ser113, Lys114, Leu115, Gly116, Lys117, and Ser118. This is a domain consistent with Walker Motif A (G-X-X-G/X-X-G-K-T/X). The is one of two in the cytoplasmic portion of the protein. The residues comprising this ATP-binding site are Lys225, Ser226, Val227, Leu228, and Lys229. The , also localized to the cytoplasm, is comprised of the amino acids Gly332, Arg 333, Arg334, Thr335, Leu336, His337, and Leu338. This sequence is consistent with Walker Motif B (G-X-X-X-L-X-X).^[12] Some studies on GLUT1 show that ATP binding to the cytosolic domains causes C-terminus binding to the C-terminal side of the intracellular loop of the protein, preventing substrate import. ATP binding is not known to have any effects when binding extracellularly.^[13]

References

1. ↑ Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med. 2013 Apr-Jun;34(2-3):121-38. doi: 10.1016/j.mam.2012.07.001. PMID:23506862 doi:http://dx.doi.org/10.1016/j.mam.2012.07.001
2. ↑ Pragallapati S, Manyam R. Glucose transporter 1 in health and disease. J Oral Maxillofac Pathol. 2019 Sep-Dec;23(3):443-449. doi:, 10.4103/jomfp.JOMFP_22_18. PMID:31942129 doi:http://dx.doi.org/10.4103/jomfp.JOMFP_22_18
3. ↑ Koepsell H. Glucose transporters in brain in health and disease. Pflugers Arch. 2020 Sep;472(9):1299-1343. doi: 10.1007/s00424-020-02441-x. Epub, 2020 Aug 13. PMID:32789766 doi:http://dx.doi.org/10.1007/s00424-020-02441-x
4. ↑ Illsley NP, Baumann MU. Human placental glucose transport in fetoplacental growth and metabolism. Biochim Biophys Acta Mol Basis Dis. 2020 Feb 1;1866(2):165359. doi:, 10.1016/j.bbadis.2018.12.010. Epub 2018 Dec 26. PMID:30593896 doi:http://dx.doi.org/10.1016/j.bbadis.2018.12.010
5. ↑ Borges MH, Pullockaran J, Catalano PM, Baumann MU, Zamudio S, Illsley NP. Human placental GLUT1 glucose transporter expression and the fetal insulin-like growth factor axis in pregnancies complicated by diabetes. Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2411-2419. doi:, 10.1016/j.bbadis.2019.06.002. Epub 2019 Jun 5. PMID:31175930 doi:http://dx.doi.org/10.1016/j.bbadis.2019.06.002
6. ↑ Liu H, Prokosch V. Energy Metabolism in the Inner Retina in Health and Glaucoma. Int J Mol Sci. 2021 Apr 1;22(7). pii: ijms22073689. doi: 10.3390/ijms22073689. PMID:33916246 doi:http://dx.doi.org/10.3390/ijms22073689
7. ↑ Swarup A, Samuels IS, Bell BA, Han JYS, Du J, Massenzio E, Abel ED, Boesze-Battaglia K, Peachey NS, Philp NJ. Modulating GLUT1 expression in retinal pigment epithelium decreases glucose levels in the retina: impact on photoreceptors and Muller glial cells. Am J Physiol Cell Physiol. 2019 Jan 1;316(1):C121-C133. doi:, 10.1152/ajpcell.00410.2018. Epub 2018 Nov 21. PMID:30462537 doi:http://dx.doi.org/10.1152/ajpcell.00410.2018
8. ↑ Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol. 2005 Mar;202(3):654-62. doi: 10.1002/jcp.20166. PMID:15389572 doi:http://dx.doi.org/10.1002/jcp.20166
9. ↑ Oh S, Kim H, Nam K, Shin I. Glut1 promotes cell proliferation, migration and invasion by regulating epidermal growth factor receptor and integrin signaling in triple-negative breast cancer cells. BMB Rep. 2017 Mar;50(3):132-137. doi: 10.5483/bmbrep.2017.50.3.189. PMID:27931517 doi:http://dx.doi.org/10.5483/bmbrep.2017.50.3.189
10. ↑ Asano T, Katagiri H, Takata K, Lin JL, Ishihara H, Inukai K, Tsukuda K, Kikuchi M, Hirano H, Yazaki Y, et al.. The role of N-glycosylation of GLUT1 for glucose transport activity. J Biol Chem. 1991 Dec 25;266(36):24632-6. PMID:1761560
11. ↑ Ung PM, Song W, Cheng L, Zhao X, Hu H, Chen L, Schlessinger A. Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening. ACS Chem Biol. 2016 Jul 15;11(7):1908-16. doi: 10.1021/acschembio.6b00304. Epub, 2016 May 11. PMID:27128978 doi:http://dx.doi.org/10.1021/acschembio.6b00304
12. ↑ Liu Q, Vera JC, Peng H, Golde DW. The predicted ATP-binding domains in the hexose transporter GLUT1 critically affect transporter activity. Biochemistry. 2001 Jul 3;40(26):7874-81. doi: 10.1021/bi002850x. PMID:11425315 doi:http://dx.doi.org/10.1021/bi002850x
13. ↑ Sage JM, Cura AJ, Lloyd KP, Carruthers A. Caffeine inhibits glucose transport by binding at the GLUT1 nucleotide-binding site. Am J Physiol Cell Physiol. 2015 May 15;308(10):C827-34. doi:, 10.1152/ajpcell.00001.2015. Epub 2015 Feb 25. PMID:25715702 doi:http://dx.doi.org/10.1152/ajpcell.00001.2015