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SLC13A5

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SLC13A5
Identifiers
AliasesSLC13A5, EIEE25, NACT, mIndy, solute carrier family 13 member 5, INDY, DEE25
External IDsOMIM: 608305; MGI: 3037150; HomoloGene: 21941; GeneCards: SLC13A5; OMA:SLC13A5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

284111

237831

Ensembl

ENSG00000141485

ENSMUSG00000020805

UniProt

Q86YT5

Q67BT3

RefSeq (mRNA)

NM_001143838
NM_001284509
NM_001284510
NM_177550

NM_001004148
NM_001372402
NM_001372403

RefSeq (protein)

NP_001137310
NP_001271438
NP_001271439
NP_808218

NP_001004148
NP_001359331
NP_001359332

Location (UCSC)Chr 17: 6.68 – 6.71 MbChr 11: 72.13 – 72.16 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
NaCT
Identifiers
SymbolSLC13A5
PDB7JSJ
UniProtQ86YT5
Search for
StructuresSwiss-model
DomainsInterPro

Solute carrier family 13 (sodium-dependent citrate transporter), member 5 also known as the Na+/citrate cotransporter or mIndy is a protein that in humans is encoded by the SLC13A5 gene.[5] It is the mammalian homolog of the fly Indy gene.

Function

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SLC13A5 is a tricarboxylate plasma transporter with a preference for citrate.[5]

Clinical significance

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In 2014, by means of exome sequencing it was determined that a genetic mutation of the gene is the cause of a rare SLC13A5 Epilepsy.[6] Mutations in SLC13A5 cause autosomal recessive epileptic encephalopathy with seizure onset in the first days of life.[6] Those afflicted suffer from seizures, global developmental delay, movement disorder and hypotonia.

Reduced expression of homologous genes is associated with longer lifespan in Drosophila melanogaster and Caenorhabditis elegans,[7][8] and obesity protection in laboratory mice.[9] Increased expression is associated with type 2 diabetes and non-alcoholic fatty liver disease. A sugary diet upregulates the expression of the gene, and so does Interleukin 6 signaling.[10]

Small molecule inhibitors

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There are four small-molecule inhibitors to SLC13A5 that have been reported from Pfizer[11][12] and a derivative from China Pharmaceutical University,[13] Boehringer Ingelheim and the group of Elisabeth P. Carpenter from the Centre for Medicines Discovery,[14] and Eternygen.[15] The Pfizer molecule is an orthosteric inhibitor that locks the protein in an inward-facing state of the reaction cycle,[16] while the mechanism of action for other inhibitors remains unknown.

References

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  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000141485 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000020805 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: Solute carrier family 13 (sodium-dependent citrate transporter), member 5".
  6. 1 2 Thevenon J, Milh M, Feillet F, St-Onge J, Duffourd Y, Jugé C, et al. (July 2014). "Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life". American Journal of Human Genetics. 95 (1): 113–120. doi:10.1016/j.ajhg.2014.06.006. PMC 4085634. PMID 24995870.
  7. ↑ Rogina B, Reenan RA, Nilsen SP, Helfand SL (December 2000). "Extended life-span conferred by cotransporter gene mutations in Drosophila". Science. 290 (5499): 2137–2140. Bibcode:2000Sci...290.2137R. doi:10.1126/science.290.5499.2137. PMID 11118146.
  8. ↑ Fei YJ, Liu JC, Inoue K, Zhuang L, Miyake K, Miyauchi S, et al. (April 2004). "Relevance of NAC-2, an Na+-coupled citrate transporter, to life span, body size and fat content in Caenorhabditis elegans". The Biochemical Journal. 379 (Pt 1): 191–198. doi:10.1042/bj20031807. PMC 1224044. PMID 14678010.
  9. ↑ Birkenfeld AL, Lee HY, Guebre-Egziabher F, Alves TC, Jurczak MJ, Jornayvaz FR, et al. (August 2011). "Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice". Cell Metabolism. 14 (2): 184–195. doi:10.1016/j.cmet.2011.06.009. PMC 3163140. PMID 21803289.
  10. ↑ von Loeffelholz C, Lieske S, Neuschäfer-Rube F, Willmes DM, Raschzok N, Sauer IM, et al. (August 2017). "The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism". Hepatology. 66 (2): 616–630. doi:10.1002/hep.29089. PMC 5519435. PMID 28133767.
  11. ↑ Huard K, Brown J, Jones JC, Cabral S, Futatsugi K, Gorgoglione M, et al. (December 2015). "Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5)". Scientific Reports. 5 (1) 17391. doi:10.1038/srep17391. PMC 4664966. PMID 26620127.
  12. ↑ Huard K, Gosset JR, Montgomery JI, Gilbert A, Hayward MM, Magee TV, et al. (February 2016). "Optimization of a Dicarboxylic Series for in Vivo Inhibition of Citrate Transport by the Solute Carrier 13 (SLC13) Family". Journal of Medicinal Chemistry. 59 (3): 1165–1175. doi:10.1021/acs.jmedchem.5b01752. PMID 26734723.
  13. ↑ Zhang L, Hu W, Guo H, Sun Q, Xu X, Li Z, et al. (April 2024). "Discovery of Highly Potent Solute Carrier 13 Member 5 (SLC13A5) Inhibitors for the Treatment of Hyperlipidemia". Journal of Medicinal Chemistry. 67 (8): 6687–6704. doi:10.1021/acs.jmedchem.4c00260. PMID 38574002.
  14. ↑ Quigley A, Kley JT, Pautsch A, Kauschke SG, Chu-Antypas A, Tessitore A, et al. (April 2026). "Discovery and Characterization of a Nonacidic Small-Molecule Inhibitor of the Sodium-Coupled Dicarboxylate Transporter NaCT". Journal of Medicinal Chemistry. doi:10.1021/acs.jmedchem.5c02711. PMID 42049193.
  15. ↑ Zahn G, Willmes DM, El-Agroudy NN, Yarnold C, Jarjes-Pike R, Schaertl S, et al. (August 2022). "A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity". Metabolites. 12 (8): 732. doi:10.3390/metabo12080732. PMC 9413491. PMID 36005604.
  16. ↑ Sauer DB, Song J, Wang B, Hilton JK, Karpowich NK, Mindell JA, et al. (March 2021). "Structure and inhibition mechanism of the human citrate transporter NaCT". Nature. 591 (7848): 157–161. doi:10.1038/s41586-021-03230-x. PMC 7933130. PMID 33597751.

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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