Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCHH25G)

• DOT Name: Sodium-coupled neutral amino acid transporter 3 (SLC38A3)
• Synonyms: N-system amino acid transporter 1; Na(+)-coupled neutral amino acid transporter 3; Solute carrier family 38 member 3; System N amino acid transporter 1
• Gene Name: SLC38A3
• Related Disease: Developmental and epileptic encephalopathy 102
• UniProt ID: S38A3_HUMAN
• Pfam ID: PF01490
• Sequence:
  MEAPLQTEMVELVPNGKHSEGLLPVITPMAGNQRVEDPARSCMEGKSFLQKSPSKEPHFT
  DFEGKTSFGMSVFNLSNAIMGSGILGLAYAMANTGIILFLFLLTAVALLSSYSIHLLLKS
  SGVVGIRAYEQLGYRAFGTPGKLAAALAITLQNIGAMSSYLYIIKSELPLVIQTFLNLEE
  KTSDWYMNGNYLVILVSVTIILPLALMRQLGYLGYSSGFSLSCMVFFLIAVIYKKFHVPC
  PLPPNFNNTTGNFSHVEIVKEKVQLQVEPEASAFCTPSYFTLNSQTAYTIPIMAFAFVCH
  PEVLPIYTELKDPSKKKMQHISNLSIAVMYIMYFLAALFGYLTFYNGVESELLHTYSKVD
  PFDVLILCVRVAVLTAVTLTVPIVLFPVRRAIQQMLFPNQEFSWLRHVLIAVGLLTCINL
  LVIFAPNILGIFGVIGATSAPFLIFIFPAIFYFRIMPTEKEPARSTPKILALCFAMLGFL
  LMTMSLSFIIIDWASGTSRHGGNH
• Function: Symporter that cotransports specific neutral amino acids and sodium ions, coupled to an H(+) antiporter activity. Mainly participates in the glutamate-GABA-glutamine cycle in brain where it transports L-glutamine from astrocytes in the intercellular space for the replenishment of both neurotransmitters glutamate and gamma-aminobutyric acid (GABA) in neurons and also functions as the major influx transporter in ganglion cells mediating the uptake of glutamine. The transport activity is specific for L-glutamine, L-histidine and L-asparagine. The transport is electroneutral coupled to the cotransport of 1 Na(+) and the antiport of 1 H(+). The transport is pH dependent, saturable, Li(+) tolerant and functions in both direction depending on the concentration gradients of its substrates and cotransported ions. Also mediates an amino acid-gated H(+) conductance that is not stoichiometrically coupled to the amino acid transport but which influences the ionic gradients that drive the amino acid transport. In addition, may play a role in nitrogen metabolism, amino acid homeostasis, glucose metabolism and renal ammoniagenesis.
• KEGG Pathway:
  Glutamatergic sy.pse (hsa04724)
  GABAergic sy.pse (hsa04727)
  Proximal tubule bicarbo.te reclamation (hsa04964)
• Reactome Pathway: Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy 102	DISBVQ7G	Strong	Autosomal recessive	[1]

16 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 Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine increases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[8]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[10]
Propofol	DMB4OLE	Approved	Propofol decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[17]

2 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 Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sodium-coupled neutral amino acid transporter 3 (SLC38A3).	[14]

References

• [1] Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy. Brain. 2022 Apr 29;145(3):909-924. doi: 10.1093/brain/awab369.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine. Clin Pharmacol Ther. 2006 Nov;80(5):440-456.
• [9] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [10] 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.
• [11] Propofol suppresses proliferation, migration, invasion, and tumor growth of liver cancer cells via suppressing cancer susceptibility candidate 9/phosphatase and tensin homolog/AKT serine/threonine kinase/mechanistic target of rapamycin kinase axis. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271211065972. doi: 10.1177/09603271211065972.
• [12] 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.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.