Details of Drug Off-Target (DOT)

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

• DOT Name: Neutral amino acid transporter A (SLC1A4)
• Synonyms: Alanine/serine/cysteine/threonine transporter 1; ASCT-1; Solute carrier family 1 member 4
• Gene Name: SLC1A4
• Related Disease: Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome
• UniProt ID: SATT_HUMAN
• PDB ID: 7P4I
• Pfam ID: PF00375
• Sequence:
  MEKSNETNGYLDSAQAGPAAGPGAPGTAAGRARRCAGFLRRQALVLLTVSGVLAGAGLGA
  ALRGLSLSRTQVTYLAFPGEMLLRMLRMIILPLVVCSLVSGAASLDASCLGRLGGIAVAY
  FGLTTLSASALAVALAFIIKPGSGAQTLQSSDLGLEDSGPPPVPKETVDSFLDLARNLFP
  SNLVVAAFRTYATDYKVVTQNSSSGNVTHEKIPIGTEIEGMNILGLVLFALVLGVALKKL
  GSEGEDLIRFFNSLNEATMVLVSWIMWYVPVGIMFLVGSKIVEMKDIIVLVTSLGKYIFA
  SILGHVIHGGIVLPLIYFVFTRKNPFRFLLGLLAPFATAFATCSSSATLPSMMKCIEENN
  GVDKRISRFILPIGATVNMDGAAIFQCVAAVFIAQLNNVELNAGQIFTILVTATASSVGA
  AGVPAGGVLTIAIILEAIGLPTHDLPLILAVDWIVDRTTTVVNVEGDALGAGILHHLNQK
  ATKKGEQELAEVKVEAIPNCKSEEETSPLVTHQNPAGPVASAPELESKESVL
• Function: Sodium-dependent neutral amino-acid transporter that mediates transport of alanine, serine, cysteine, proline, hydroxyproline and threonine.
• Tissue Specificity: Expressed mostly in brain, muscle, and pancreas but detected in all tissues examined.
• 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
Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome	DISDJVPL	Definitive	Autosomal recessive	[1]

28 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 Neutral amino acid transporter A (SLC1A4).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Neutral amino acid transporter A (SLC1A4).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neutral amino acid transporter A (SLC1A4).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neutral amino acid transporter A (SLC1A4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Neutral amino acid transporter A (SLC1A4).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Neutral amino acid transporter A (SLC1A4).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neutral amino acid transporter A (SLC1A4).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Neutral amino acid transporter A (SLC1A4).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Neutral amino acid transporter A (SLC1A4).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Neutral amino acid transporter A (SLC1A4).	[11]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Neutral amino acid transporter A (SLC1A4).	[12]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Neutral amino acid transporter A (SLC1A4).	[7]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Neutral amino acid transporter A (SLC1A4).	[13]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Neutral amino acid transporter A (SLC1A4).	[7]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Neutral amino acid transporter A (SLC1A4).	[7]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Neutral amino acid transporter A (SLC1A4).	[14]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Neutral amino acid transporter A (SLC1A4).	[15]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Neutral amino acid transporter A (SLC1A4).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Neutral amino acid transporter A (SLC1A4).	[8]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of Neutral amino acid transporter A (SLC1A4).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Neutral amino acid transporter A (SLC1A4).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Neutral amino acid transporter A (SLC1A4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Neutral amino acid transporter A (SLC1A4).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Neutral amino acid transporter A (SLC1A4).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Neutral amino acid transporter A (SLC1A4).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Neutral amino acid transporter A (SLC1A4).	[23]
CH-223191	DMMJZYC	Investigative	CH-223191 increases the expression of Neutral amino acid transporter A (SLC1A4).	[24]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Neutral amino acid transporter A (SLC1A4).	[25]

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 Neutral amino acid transporter A (SLC1A4).	[17]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] Expression profiling of the estrogen responsive genes in response to phytoestrogens using a customized DNA microarray. FEBS Lett. 2005 Mar 14;579(7):1732-40.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] 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.
• [11] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [12] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [13] 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.
• [14] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [15] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [16] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [17] 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.
• [18] 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.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] Gene expression profiling analysis of bisphenol A-induced perturbation in biological processes in ER-negative HEK293 cells. PLoS One. 2014 Jun 5;9(6):e98635.
• [21] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [24] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [25] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.