Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTILR60R)

• DOT Name: Excitatory amino acid transporter 1 (SLC1A3)
• Synonyms: Sodium-dependent glutamate/aspartate transporter 1; GLAST-1; Solute carrier family 1 member 3
• Gene Name: SLC1A3
• Related Disease: Episodic ataxia type 6
• UniProt ID: EAA1_HUMAN
• PDB ID: 5LLM; 5LLU; 5LM4; 5MJU; 7NPW
• Pfam ID: PF00375
• Sequence:
  MTKSNGEEPKMGGRMERFQQGVRKRTLLAKKKVQNITKEDVKSYLFRNAFVLLTVTAVIV
  GTILGFTLRPYRMSYREVKYFSFPGELLMRMLQMLVLPLIISSLVTGMAALDSKASGKMG
  MRAVVYYMTTTIIAVVIGIIIVIIIHPGKGTKENMHREGKIVRVTAADAFLDLIRNMFPP
  NLVEACFKQFKTNYEKRSFKVPIQANETLVGAVINNVSEAMETLTRITEELVPVPGSVNG
  VNALGLVVFSMCFGFVIGNMKEQGQALREFFDSLNEAIMRLVAVIMWYAPVGILFLIAGK
  IVEMEDMGVIGGQLAMYTVTVIVGLLIHAVIVLPLLYFLVTRKNPWVFIGGLLQALITAL
  GTSSSSATLPITFKCLEENNGVDKRVTRFVLPVGATINMDGTALYEALAAIFIAQVNNFE
  LNFGQIITISITATAASIGAAGIPQAGLVTMVIVLTSVGLPTDDITLIIAVDWFLDRLRT
  TTNVLGDSLGAGIVEHLSRHELKNRDVEMGNSVIEENEMKKPYQLIAQDNETEKPIDSET
  KM
• 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. Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate.
• Tissue Specificity: Detected in brain . Detected at very much lower levels in heart, lung, placenta and skeletal muscle . Highly expressed in cerebellum, but also found in frontal cortex, hippocampus and basal ganglia .
• KEGG Pathway:
  Sy.ptic vesicle cycle (hsa04721)
  Glutamatergic sy.pse (hsa04724)
  Huntington disease (hsa05016)
• Reactome Pathway:
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)
  Transport of inorganic cations/anions and amino acids/oligopeptides (R-HSA-425393)
  Defective SLC1A3 causes episodic ataxia 6 (EA6) (R-HSA-5619062)
  Astrocytic Glutamate-Glutamine Uptake And Metabolism (R-HSA-210455)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Episodic ataxia type 6	DIS9P3RQ	Definitive	Autosomal dominant	[1]

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 1 (SLC1A3) affects the response to substance of Cisplatin.	[24]

21 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 Excitatory amino acid transporter 1 (SLC1A3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Excitatory amino acid transporter 1 (SLC1A3).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[9]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[15]
ANW-32821	DMMJOZD	Phase 2	ANW-32821 increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Excitatory amino acid transporter 1 (SLC1A3).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Excitatory amino acid transporter 1 (SLC1A3).	[21]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Excitatory amino acid transporter 1 (SLC1A3).	[23]

References

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• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
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• [15] Capturing time-dependent activation of genes and stress-response pathways using transcriptomics in iPSC-derived renal proximal tubule cells. Cell Biol Toxicol. 2023 Aug;39(4):1773-1793. doi: 10.1007/s10565-022-09783-5. Epub 2022 Dec 31.
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• [24] Role of transporter genes in cisplatin resistance. In Vivo. 2008 May-Jun;22(3):279-83.