Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEP3QGN)

• DOT Name: Excitatory amino acid transporter 2 (SLC1A2)
• Synonyms: Glutamate/aspartate transporter II; Sodium-dependent glutamate/aspartate transporter 2; Solute carrier family 1 member 2
• Gene Name: SLC1A2
• Related Disease:
  Developmental and epileptic encephalopathy, 41
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: EAA2_HUMAN
• PDB ID: 7VR7; 7VR8; 7XR4; 7XR6
• Pfam ID: PF00375
• Sequence:
  MASTEGANNMPKQVEVRMHDSHLGSEEPKHRHLGLRLCDKLGKNLLLTLTVFGVILGAVC
  GGLLRLASPIHPDVVMLIAFPGDILMRMLKMLILPLIISSLITGLSGLDAKASGRLGTRA
  MVYYMSTTIIAAVLGVILVLAIHPGNPKLKKQLGPGKKNDEVSSLDAFLDLIRNLFPENL
  VQACFQQIQTVTKKVLVAPPPDEEANATSAVVSLLNETVTEVPEETKMVIKKGLEFKDGM
  NVLGLIGFFIAFGIAMGKMGDQAKLMVDFFNILNEIVMKLVIMIMWYSPLGIACLICGKI
  IAIKDLEVVARQLGMYMVTVIIGLIIHGGIFLPLIYFVVTRKNPFSFFAGIFQAWITALG
  TASSAGTLPVTFRCLEENLGIDKRVTRFVLPVGATINMDGTALYEAVAAIFIAQMNGVVL
  DGGQIVTVSLTATLASVGAASIPSAGLVTMLLILTAVGLPTEDISLLVAVDWLLDRMRTS
  VNVVGDSFGAGIVYHLSKSELDTIDSQHRVHEDIEMTKTQSIYDDMKNHRESNSNQCVYA
  AHNSVIVDECKVTLAANGKSADCSVEEEPWKREK
• Function: Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate. Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion. Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport. Essential for the rapid removal of released glutamate from the synaptic cleft, and for terminating the postsynaptic action of glutamate.
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Glutamatergic sy.pse (hsa04724)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
• Reactome Pathway:
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)
  Transport of inorganic cations/anions and amino acids/oligopeptides (R-HSA-425393)
  Astrocytic Glutamate-Glutamine Uptake And Metabolism (R-HSA-210455)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 41	DISFFS50	Definitive	Autosomal dominant	[1]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Excitatory amino acid transporter 2 (SLC1A2) decreases the response to substance of Cisplatin.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Excitatory amino acid transporter 2 (SLC1A2).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[12]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[13]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[12]
Vitamin A	DMJ2AH4	Approved	Vitamin A increases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[12]
Thiamphenicol	DMDRKH2	Approved	Thiamphenicol increases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[19]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[20]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[21]
(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE	DMTPQ84	Investigative	(11-BETA)-11,21-DIHYDROXY-PREGN-4-ENE-3,20-DIONE increases the expression of Excitatory amino acid transporter 2 (SLC1A2).	[12]

References

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• [2] De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies. Am J Hum Genet. 2016 Aug 4;99(2):287-98. doi: 10.1016/j.ajhg.2016.06.003. Epub 2016 Jul 28.
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• [11] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [12] Translational control of glial glutamate transporter EAAT2 expression. J Biol Chem. 2007 Jan 19;282(3):1727-37. doi: 10.1074/jbc.M609822200. Epub 2006 Nov 30.
• [13] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [14] Human nasal olfactory epithelium as a dynamic marker for CNS therapy development. Exp Neurol. 2011 Dec;232(2):203-11. doi: 10.1016/j.expneurol.2011.09.002. Epub 2011 Sep 16.
• [15] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] Bisphenol A exposure disrupts aspartate transport in HepG2 cells. J Biochem Mol Toxicol. 2020 Aug;34(8):e22516. doi: 10.1002/jbt.22516. Epub 2020 May 3.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [20] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [21] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.
• [22] CD44-SLC1A2 gene fusions in gastric cancer. Sci Transl Med. 2011 Apr 6;3(77):77ra30. doi: 10.1126/scitranslmed.3001423.