Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRDOV1Y)

• DOT Name: Na(+)/dicarboxylate cotransporter 3 (SLC13A3)
• Synonyms: NaDC-3; hNaDC3; Na(+)-coupled carboxylate transporter 3; NaC3; Sodium-dependent high-affinity dicarboxylate transporter 2; Solute carrier family 13 member 3; SLC13A3
• Gene Name: SLC13A3
• Related Disease: Leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate
• UniProt ID: S13A3_HUMAN
• Pfam ID: PF00939
• Sequence:
  MAALAAAAKKVWSARRLLVLLFTPLALLPVVFALPPKEGRCLFVILLMAVYWCTEALPLS
  VTALLPIVLFPFMGILPSNKVCPQYFLDTNFLFLSGLIMASAIEEWNLHRRIALKILMLV
  GVQPARLILGMMVTTSFLSMWLSNTASTAMMLPIANAILKSLFGQKEVRKDPSQESEENT
  AAVRRNGLHTVPTEMQFLASTEAKDHPGETEVPLDLPADSRKEDEYRRNIWKGFLISIPY
  SASIGGTATLTGTAPNLILLGQLKSFFPQCDVVNFGSWFIFAFPLMLLFLLAGWLWISFL
  YGGLSFRGWRKNKSEIRTNAEDRARAVIREEYQNLGPIKFAEQAVFILFCMFAILLFTRD
  PKFIPGWASLFNPGFLSDAVTGVAIVTILFFFPSQRPSLKWWFDFKAPNTETEPLLTWKK
  AQETVPWNIILLLGGGFAMAKGCEESGLSVWIGGQLHPLENVPPALAVLLITVVIAFFTE
  FASNTATIIIFLPVLAELAIRLRVHPLYLMIPGTVGCSFAFMLPVSTPPNSIAFASGHLL
  VKDMVRTGLLMNLMGVLLLSLAMNTWAQTIFQLGTFPDWADMYSVNVTALPPTLANDTFR
  TL
• Function: High-affinity sodium-dicarboxylate cotransporter that accepts a range of substrates with 4-6 carbon atoms, such as the citric acid cycle intermediates succinate and alpha-ketoglutarate (2-oxoglutarate), as well as other compounds including N-acetyl-L-aspartate. Transports the dicarboxylate into the cell with a probable stoichiometry of 3 Na(+) for 1 divalent dicarboxylate, rendering the process electrogenic. Can transport citrate in a Na(+)-dependent manner, recognizing the divalent form of citrate rather than the trivalent form which is normally found in blood.
• Tissue Specificity: Expression is highest in kidney . Detected in placenta, brain, liver and pancreas.
• Reactome Pathway: Sodium-coupled sulphate, di- and tri-carboxylate transporters (R-HSA-433137)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate	DISZU2KW	Limited	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[6]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[3]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[5]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[8]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[12]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Succinic acid	DMDWICP	Approved	Succinic acid affects the binding of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[9]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Na(+)/dicarboxylate cotransporter 3 (SLC13A3).	[11]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] 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.
• [9] The renal Na(+)-dependent dicarboxylate transporter, NaDC-3, translocates dimethyl- and disulfhydryl-compounds and contributes to renal heavy metal detoxification. J Am Soc Nephrol. 2002 Nov;13(11):2628-38. doi: 10.1097/01.asn.0000033463.58641.f9.
• [10] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.