| Structural highlights
Disease
GTR9_HUMAN Hereditary renal hypouricemia. The disease is caused by variants affecting the gene represented in this entry.
Function
GTR9_HUMAN High-capacity urate transporter, which may play a role in the urate reabsorption by proximal tubules (PubMed:18327257, PubMed:18701466, PubMed:22647630, PubMed:28083649, PubMed:36749388). May have a residual high-affinity, low-capacity glucose and fructose transporter activity (PubMed:18327257, PubMed:18701466, PubMed:18842065). Transports urate at rates 45- to 60-fold faster than glucose (PubMed:18842065). Does not transport galactose (PubMed:28083649). May mediate small uptake of adenine but not of other nucleobases (PubMed:22647630).[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Glucose transporter 9 (GLUT9) is a critical urate transporter involved in renal reabsorption, playing a pivotal role in regulating physiological urate levels and representing a potential therapeutic target for gout. Despite such clinical significance, the structural basis of urate recognition and transport by GLUT9 remains elusive. Here, we present the cryoelectron microscopy (cryo-EM) structures of GLUT9 in the inward-open conformation in both apo and urate-bound states. Urate binds in a cleft between the N-terminal and C-terminal domains, interacting via hydrogen bonds and hydrophobic interactions. Structural comparison with sugar-transporting GLUTs highlights unique amino acid compositions in the substrate recognition pocket of GLUT9. Functional and mutational studies directly measuring GLUT9-mediated urate uptake further demonstrate the cooperative roles of multiple residues in urate recognition. Our findings elucidate the structural basis of urate transport by GLUT9 and provide valuable insights for the development of uricosuric drugs targeting GLUT9.
Structural basis of urate transport by glucose transporter 9.,Matsushita D, Toyoda Y, Lee Y, Aoi M, Matsuo H, Takada T, Nishizawa T Cell Rep. 2025 Apr 4;44(4):115514. doi: 10.1016/j.celrep.2025.115514. PMID:40186864[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J, Wilson JF, Marinaki A, Riches PL, Shu X, Janicijevic B, Smolej-Narancic N, Gorgoni B, Morgan J, Campbell S, Biloglav Z, Barac-Lauc L, Pericic M, Klaric IM, Zgaga L, Skaric-Juric T, Wild SH, Richardson WA, Hohenstein P, Kimber CH, Tenesa A, Donnelly LA, Fairbanks LD, Aringer M, McKeigue PM, Ralston SH, Morris AD, Rudan P, Hastie ND, Campbell H, Wright AF. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet. 2008 Apr;40(4):437-42. PMID:18327257 doi:10.1038/ng.106
- ↑ Anzai N, Ichida K, Jutabha P, Kimura T, Babu E, Jin CJ, Srivastava S, Kitamura K, Hisatome I, Endou H, Sakurai H. Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem. 2008 Oct 3;283(40):26834-8. PMID:18701466 doi:10.1074/jbc.C800156200
- ↑ Caulfield MJ, Munroe PB, O'Neill D, Witkowska K, Charchar FJ, Doblado M, Evans S, Eyheramendy S, Onipinla A, Howard P, Shaw-Hawkins S, Dobson RJ, Wallace C, Newhouse SJ, Brown M, Connell JM, Dominiczak A, Farrall M, Lathrop GM, Samani NJ, Kumari M, Marmot M, Brunner E, Chambers J, Elliott P, Kooner J, Laan M, Org E, Veldre G, Viigimaa M, Cappuccio FP, Ji C, Iacone R, Strazzullo P, Moley KH, Cheeseman C. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008 Oct 7;5(10):e197. PMID:18842065 doi:10.1371/journal.pmed.0050197
- ↑ Witkowska K, Smith KM, Yao SY, Ng AM, O'Neill D, Karpinski E, Young JD, Cheeseman CI. Human SLC2A9a and SLC2A9b isoforms mediate electrogenic transport of urate with different characteristics in the presence of hexoses. Am J Physiol Renal Physiol. 2012 Aug 15;303(4):F527-39. PMID:22647630 doi:10.1152/ajprenal.00134.2012
- ↑ Ebert K, Ludwig M, Geillinger KE, Schoberth GC, Essenwanger J, Stolz J, Daniel H, Witt H. Reassessment of GLUT7 and GLUT9 as Putative Fructose and Glucose Transporters. J Membr Biol. 2017 Apr;250(2):171-182. PMID:28083649 doi:10.1007/s00232-016-9945-7
- ↑ Matsushita D, Toyoda Y, Lee Y, Aoi M, Matsuo H, Takada T, Nishizawa T. Structural basis of urate transport by glucose transporter 9. Cell Rep. 2025 Apr 4;44(4):115514. PMID:40186864 doi:10.1016/j.celrep.2025.115514
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