Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX4Q83J)

• DOT Name: Sodium-coupled neutral amino acid transporter 5 (SLC38A5)
• Synonyms: Solute carrier family 38 member 5; System N transporter 2
• Gene Name: SLC38A5
• UniProt ID: S38A5_HUMAN
• Pfam ID: PF01490
• Sequence:
  MELQDPKMNGALPSDAVGYRQEREGFLPSRGPAPGSKPVQFMDFEGKTSFGMSVFNLSNA
  IMGSGILGLAYAMAHTGVIFFLALLLCIALLSSYSIHLLLTCAGIAGIRAYEQLGQRAFG
  PAGKVVVATVICLHNVGAMSSYLFIIKSELPLVIGTFLYMDPEGDWFLKGNLLIIIVSVL
  IILPLALMKHLGYLGYTSGLSLTCMLFFLVSVIYKKFQLGCAIGHNETAMESEALVGLPS
  QGLNSSCEAQMFTVDSQMSYTVPIMAFAFVCHPEVLPIYTELCRPSKRRMQAVANVSIGA
  MFCMYGLTATFGYLTFYSSVKAEMLHMYSQKDPLILCVRLAVLLAVTLTVPVVLFPIRRA
  LQQLLFPGKAFSWPRHVAIALILLVLVNVLVICVPTIRDIFGVIGSTSAPSLIFILPSIF
  YLRIVPSEVEPFLSWPKIQALCFGVLGVLFMAVSLGFMFANWATGQSRMSGH
• Function: Symporter that cotransports neutral amino acids and sodium ions, coupled to an H(+) antiporter activity. Releases L-glutamine and glycine from astroglial cells and may participate in the glutamate/GABA-L-glutamine cycle and the NMDA receptors activation. In addition, contributes significantly to L-glutamine uptake in retina, namely in ganglion and Mueller cells therefore, participates in the retinal glutamate-glutamine cycle. The transport activity is pH sensitive and Li(+) tolerant. Moreover functions in both direction and is associated with large uncoupled fluxes of protons. The transport is electroneutral coupled to the cotransport of 1 Na(+) and the antiport of 1 H(+). May have a particular importance for modulation of net hepatic glutamine flux.
• Tissue Specificity: Predominantly expressed in stomach, brain, liver, lung and intestinal tract.
• KEGG Pathway: GABAergic sy.pse (hsa04727)
• Reactome Pathway: Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[2]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[3]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[4]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[10]

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 decreases the methylation of Sodium-coupled neutral amino acid transporter 5 (SLC38A5).	[7]

References

• [1] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [2] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [5] 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.
• [6] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [7] 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.
• [8] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [9] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.