Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE2H26Q)

• DOT Name: Neutral amino acid transporter B(0) (SLC1A5)
• Synonyms: ATB(0); Baboon M7 virus receptor; RD114/simian type D retrovirus receptor; Sodium-dependent neutral amino acid transporter type 2; Solute carrier family 1 member 5
• Gene Name: SLC1A5
• UniProt ID: AAAT_HUMAN
• PDB ID: 5LLM; 5LLU; 5LM4; 5MJU; 6GCT; 6MP6; 6MPB; 6RVX; 6RVY; 7BCQ; 7BCS; 7BCT
• Pfam ID: PF00375
• Sequence:
  MVADPPRDSKGLAAAEPTANGGLALASIEDQGAAAGGYCGSRDQVRRCLRANLLVLLTVV
  AVVAGVALGLGVSGAGGALALGPERLSAFVFPGELLLRLLRMIILPLVVCSLIGGAASLD
  PGALGRLGAWALLFFLVTTLLASALGVGLALALQPGAASAAINASVGAAGSAENAPSKEV
  LDSFLDLARNIFPSNLVSAAFRSYSTTYEERNITGTRVKVPVGQEVEGMNILGLVVFAIV
  FGVALRKLGPEGELLIRFFNSFNEATMVLVSWIMWYAPVGIMFLVAGKIVEMEDVGLLFA
  RLGKYILCCLLGHAIHGLLVLPLIYFLFTRKNPYRFLWGIVTPLATAFGTSSSSATLPLM
  MKCVEENNGVAKHISRFILPIGATVNMDGAALFQCVAAVFIAQLSQQSLDFVKIITILVT
  ATASSVGAAGIPAGGVLTLAIILEAVNLPVDHISLILAVDWLVDRSCTVLNVEGDALGAG
  LLQNYVDRTESRSTEPELIQVKSELPLDPLPVPTEEGNPLLKHYRGPAGDATVASEKESV
  M
• Function: Sodium-coupled antiporter of neutral amino acids. In a tri-substrate transport cycle, exchanges neutral amino acids between the extracellular and intracellular compartments, coupled to the inward cotransport of at least one sodium ion. The preferred substrate is the essential amino acid L-glutamine, a precursor for biosynthesis of proteins, nucleotides and amine sugars as well as an alternative fuel for mitochondrial oxidative phosphorylation. Exchanges L-glutamine with other neutral amino acids such as L-serine, L-threonine and L-asparagine in a bidirectional way. Provides L-glutamine to proliferating stem and activated cells driving the metabolic switch toward cell differentiation. The transport cycle is usually pH-independent, with the exception of L-glutamate. Transports extracellular L-glutamate coupled to the cotransport of one proton and one sodium ion in exchange for intracellular L-glutamine counter-ion. May provide for L-glutamate uptake in glial cells regulating glutamine/glutamate cycle in the nervous system. Can transport D-amino acids. Mediates D-serine release from the retinal glia potentially affecting NMDA receptor function in retinal neurons. Displays sodium- and amino acid-dependent but uncoupled channel-like anion conductance with a preference SCN(-) >> NO3(-) > I(-) > Cl(-). Through binding of the fusogenic protein syncytin-1/ERVW-1 may mediate trophoblasts syncytialization, the spontaneous fusion of their plasma membranes, an essential process in placental development ; (Microbial infection) Acts as a cell surface receptor for Feline endogenous virus RD114; (Microbial infection) Acts as a cell surface receptor for Baboon M7 endogenous virus; (Microbial infection) Acts as a cell surface receptor for type D simian retroviruses.
• Tissue Specificity: Placenta, lung, skeletal muscle, kidney, pancreas, and intestine . Expressed in CD34-positive hematopoietic progenitors (at protein level) .
• KEGG Pathway:
  Protein digestion and absorption (hsa04974)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOH GTPase cycle (R-HSA-9013407)
  RHOJ GTPase cycle (R-HSA-9013409)
  RAC3 GTPase cycle (R-HSA-9013423)
  Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Neutral amino acid transporter B(0) (SLC1A5).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Neutral amino acid transporter B(0) (SLC1A5).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Neutral amino acid transporter B(0) (SLC1A5).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Neutral amino acid transporter B(0) (SLC1A5).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[9]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[5]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[5]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[10]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[9]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[9]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[9]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[5]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[5]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[5]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[11]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[2]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[17]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of Neutral amino acid transporter B(0) (SLC1A5).	[18]

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] 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.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] 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.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [11] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [12] Synthetic oleanane triterpenoid derivative CDDO-Me disrupts cellular bioenergetics to suppress pancreatic ductal adenocarcinoma via targeting SLC1A5. J Biochem Mol Toxicol. 2022 Nov;36(11):e23192. doi: 10.1002/jbt.23192. Epub 2022 Aug 5.
• [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] 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.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [18] Effects of valproic acid on syncytialization in human placental trophoblast cell lines. Toxicol Appl Pharmacol. 2023 Sep 1;474:116611. doi: 10.1016/j.taap.2023.116611. Epub 2023 Jun 28.