Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPH1TA7)

• DOT Name: Na(+)/citrate cotransporter (SLC13A5)
• Synonyms: NaCT; Sodium-coupled citrate transporter; Sodium-dependent citrate transporter; Solute carrier family 13 member 5
• Gene Name: SLC13A5
• Related Disease:
  Developmental and epileptic encephalopathy, 25
  Amelocerebrohypohidrotic syndrome
  Pyridoxine-dependent epilepsy
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: S13A5_HUMAN
• PDB ID: 7JSJ; 7JSK
• Pfam ID: PF00939
• Sequence:
  MASALSYVSKFKSFVILFVTPLLLLPLVILMPAKFVRCAYVIILMAIYWCTEVIPLAVTS
  LMPVLLFPLFQILDSRQVCVQYMKDTNMLFLGGLIVAVAVERWNLHKRIALRTLLWVGAK
  PARLMLGFMGVTALLSMWISNTATTAMMVPIVEAILQQMEATSAATEAGLELVDKGKAKE
  LPGSQVIFEGPTLGQQEDQERKRLCKAMTLCICYAASIGGTATLTGTGPNVVLLGQMNEL
  FPDSKDLVNFASWFAFAFPNMLVMLLFAWLWLQFVYMRFNFKKSWGCGLESKKNEKAALK
  VLQEEYRKLGPLSFAEINVLICFFLLVILWFSRDPGFMPGWLTVAWVEGETKYVSDATVA
  IFVATLLFIVPSQKPKFNFRSQTEEERKTPFYPPPLLDWKVTQEKVPWGIVLLLGGGFAL
  AKGSEASGLSVWMGKQMEPLHAVPPAAITLILSLLVAVFTECTSNVATTTLFLPIFASMS
  RSIGLNPLYIMLPCTLSASFAFMLPVATPPNAIVFTYGHLKVADMVKTGVIMNIIGVFCV
  FLAVNTWGRAIFDLDHFPDWANVTHIET
• Function: High-affinity sodium/citrate cotransporter that mediates the entry of citrate into cells, which is a critical participant of biochemical pathways. May function in various metabolic processes in which citrate has a critical role such as energy production (Krebs cycle), fatty acid synthesis, cholesterol synthesis, glycolysis, and gluconeogenesis. Transports citrate into the cell in a Na(+)-dependent manner, recognizing the trivalent form of citrate (physiological pH) rather than the divalent form. Can recognize succinate as a substrate, but its affinity for succinate is several fold lower than for citrate. The stoichiometry is probably 4 Na(+) for each carboxylate, irrespective of whether the translocated substrate is divalent or trivalent, rendering the process electrogenic. Involved in the regulation of citrate levels in the brain.
• Tissue Specificity: Expressed most predominantly in the liver, with moderate expression detectable in the brain and testis.
• Reactome Pathway: Sodium-coupled sulphate, di- and tri-carboxylate transporters (R-HSA-433137)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 25	DISSGXC8	Strong	Autosomal recessive	[1]
Amelocerebrohypohidrotic syndrome	DIS0DATV	Supportive	Autosomal recessive	[2]
Pyridoxine-dependent epilepsy	DISVYADQ	Supportive	Autosomal recessive	[3]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Na(+)/citrate cotransporter (SLC13A5) decreases the response to substance of Doxorubicin.	[18]
Cisplatin	DMRHGI9	Approved	Na(+)/citrate cotransporter (SLC13A5) decreases the response to substance of Cisplatin.	[18]
Fluorouracil	DMUM7HZ	Approved	Na(+)/citrate cotransporter (SLC13A5) decreases the response to substance of Fluorouracil.	[18]
Sorafenib	DMS8IFC	Approved	Na(+)/citrate cotransporter (SLC13A5) decreases the response to substance of Sorafenib.	[18]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Citrate	DM37NYK	Preclinical	Na(+)/citrate cotransporter (SLC13A5) affects the uptake of Citrate.	[19]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Na(+)/citrate cotransporter (SLC13A5).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Na(+)/citrate cotransporter (SLC13A5).	[11]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[12]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Na(+)/citrate cotransporter (SLC13A5).	[13]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Na(+)/citrate cotransporter (SLC13A5).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Na(+)/citrate cotransporter (SLC13A5).	[17]

References

• [1] Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life. Am J Hum Genet. 2014 Jul 3;95(1):113-20. doi: 10.1016/j.ajhg.2014.06.006.
• [2] SLC13A5 is the second gene associated with Kohlschtter-T?nz syndrome. J Med Genet. 2017 Jan;54(1):54-62. doi: 10.1136/jmedgenet-2016-103988. Epub 2016 Sep 6.
• [3] Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B(6)-Dependent Epilepsy. Am J Hum Genet. 2016 Dec 1;99(6):1325-1337. doi: 10.1016/j.ajhg.2016.10.011.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [12] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [13] SLC13A5 is a novel transcriptional target of the pregnane X receptor and sensitizes drug-induced steatosis in human liver. Mol Pharmacol. 2015 Apr;87(4):674-82. doi: 10.1124/mol.114.097287. Epub 2015 Jan 27.
• [14] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [15] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [16] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Comparative proteomic analysis of SLC13A5 knockdown reveals elevated ketogenesis and enhanced cellular toxic response to chemotherapeutic agents in HepG2 cells. Toxicol Appl Pharmacol. 2020 Sep 1;402:115117. doi: 10.1016/j.taap.2020.115117. Epub 2020 Jul 4.
• [19] Analysis of naturally occurring mutations in the human uptake transporter NaCT important for bone and brain development and energy metabolism. Sci Rep. 2018 Jul 27;8(1):11330. doi: 10.1038/s41598-018-29547-8.