Details of Drug Off-Target (DOT)

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

• DOT Name: Sodium-coupled neutral amino acid symporter 2 (SLC38A2)
• Synonyms: Amino acid transporter A2; Protein 40-9-1; Solute carrier family 38 member 2; System A amino acid transporter 2; System A transporter 1; System N amino acid transporter 2
• Gene Name: SLC38A2
• UniProt ID: S38A2_HUMAN
• Pfam ID: PF01490
• Sequence:
  MKKAEMGRFSISPDEDSSSYSSNSDFNYSYPTKQAALKSHYADVDPENQNFLLESNLGKK
  KYETEFHPGTTSFGMSVFNLSNAIVGSGILGLSYAMANTGIALFIILLTFVSIFSLYSVH
  LLLKTANEGGSLLYEQLGYKAFGLVGKLAASGSITMQNIGAMSSYLFIVKYELPLVIQAL
  TNIEDKTGLWYLNGNYLVLLVSLVVILPLSLFRNLGYLGYTSGLSLLCMVFFLIVVICKK
  FQVPCPVEAALIINETINTTLTQPTALVPALSHNVTENDSCRPHYFIFNSQTVYAVPILI
  FSFVCHPAVLPIYEELKDRSRRRMMNVSKISFFAMFLMYLLAALFGYLTFYEHVESELLH
  TYSSILGTDILLLIVRLAVLMAVTLTVPVVIFPIRSSVTHLLCASKDFSWWRHSLITVSI
  LAFTNLLVIFVPTIRDIFGFIGASAASMLIFILPSAFYIKLVKKEPMKSVQKIGALFFLL
  SGVLVMTGSMALIVLDWVHNAPGGGH
• Function: Symporter that cotransports neutral amino acids and sodium ions from the extraccellular to the intracellular side of the cell membrane. The trasnport is pH-sensitive, Li(+)-intolerant, electrogenic, driven by the Na(+) electrochemical gradient and cotransports of neutral amino acids and sodium ions with a stoichiometry of 1:1. May function in the transport of amino acids at the blood-brain barrier. May function in the transport of amino acids in the supply of maternal nutrients to the fetus through the placenta. Maintains a key metabolic glutamine/glutamate balance underpinning retrograde signaling by dendritic release of the neurotransmitter glutamate. Transports L-proline in differentiating osteoblasts for the efficient synthesis of proline-enriched proteins and provides proline essential for osteoblast differentiation and bone formation during bone development.
• Tissue Specificity: Ubiquitously expressed . Expressed in neocortex . Widely expressed in the central nervous system with higher concentrations in caudal regions. Expressed by glutamatergic and GABAergic neurons together with astrocytes and other non-neuronal cells in the cerebral cortex (at protein level) .
• KEGG Pathway:
  Glutamatergic sy.pse (hsa04724)
  GABAergic sy.pse (hsa04727)
  Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Amino acid transport across the plasma membrane (R-HSA-352230)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Sodium-coupled neutral amino acid symporter 2 (SLC38A2) affects the response to substance of Doxorubicin.	[25]

3 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 Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[18]

22 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 Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[8]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[10]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[11]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[12]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[12]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[22]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid affects the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[23]
5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole	DM3JB6S	Investigative	5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole affects the expression of Sodium-coupled neutral amino acid symporter 2 (SLC38A2).	[24]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] Transcriptional responses to estrogen and progesterone in mammary gland identify networks regulating p53 activity. Endocrinology. 2008 Oct;149(10):4809-20. doi: 10.1210/en.2008-0035. Epub 2008 Jun 12.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [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] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [9] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [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] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [12] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [13] Screening autism-associated environmental factors in differentiating human neural progenitors with fractional factorial design-based transcriptomics. Sci Rep. 2023 Jun 29;13(1):10519. doi: 10.1038/s41598-023-37488-0.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] 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.
• [19] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [23] Combined effects of arsenic and palmitic acid on oxidative stress and lipid metabolism disorder in human hepatoma HepG2 cells. Sci Total Environ. 2021 May 15;769:144849. doi: 10.1016/j.scitotenv.2020.144849. Epub 2021 Jan 19.
• [24] The synthesis of SNAT2 transporters is required for the hypertonic stimulation of system A transport activity. Biochim Biophys Acta. 2004 Dec 15;1667(2):157-66. doi: 10.1016/j.bbamem.2004.09.012.
• [25] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.