Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOH0P68)

• DOT Name: Y+L amino acid transporter 2 (SLC7A6)
• Synonyms: Cationic amino acid transporter, y+ system; Solute carrier family 7 member 6; y(+)L-type amino acid transporter 2; Y+LAT2; y+LAT-2
• Gene Name: SLC7A6
• UniProt ID: YLAT2_HUMAN
• Pfam ID: PF13520
• Sequence:
  MEAREPGRPTPTYHLVPNTSQSQVEEDVSSPPQRSSETMQLKKEISLLNGVSLVVGNMIG
  SGIFVSPKGVLVHTASYGMSLIVWAIGGLFSVVGALCYAELGTTITKSGASYAYILEAFG
  GFIAFIRLWVSLLVVEPTGQAIIAITFANYIIQPSFPSCDPPYLACRLLAAACICLLTFV
  NCAYVKWGTRVQDTFTYAKVVALIAIIVMGLVKLCQGHSEHFQDAFEGSSWDMGNLSLAL
  YSALFSYSGWDTLNFVTEEIKNPERNLPLAIGISMPIVTLIYILTNVAYYTVLNISDVLS
  SDAVAVTFADQTFGMFSWTIPIAVALSCFGGLNASIFASSRLFFVGSREGHLPDLLSMIH
  IERFTPIPALLFNCTMALIYLIVEDVFQLINYFSFSYWFFVGLSVVGQLYLRWKEPKRPR
  PLKLSVFFPIVFCICSVFLVIVPLFTDTINSLIGIGIALSGVPFYFMGVYLPESRRPLFI
  RNVLAAITRGTQQLCFCVLTELDVAEEKKDERKTD
• Function: Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids such as L-arginine from inside the cells in exchange with neutral amino acids like L-leucine, L-glutamine and isoleucine, plus sodium ions and may participate in nitric oxide synthesis. Also exchanges L-arginine with L-lysine in a sodium-independent manner. The transport mechanism is electroneutral and operates with a stoichiometry of 1:1. Contributes to ammonia-induced increase of L-arginine uptake in cerebral cortical astrocytes leading to ammonia-dependent increase of nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) induction, and protein nitration. May mediate transport of ornithine in retinal pigment epithelial (RPE) cells. May also transport glycine betaine in a sodium dependent manner from the cumulus granulosa into the enclosed oocyte.
• Tissue Specificity: Expressed in normal fibroblasts and those from LPI patients . Also expressed in HUVECs, monocytes, RPE cells, and various carcinoma cell lines . Expressed in brain, heart, testis, kidney, small intestine and parotis . Highly expressed in T lymphocytes .
• Reactome Pathway:
  Amino acid transport across the plasma membrane (R-HSA-352230)
  Basigin interactions (R-HSA-210991)
• BioCyc Pathway: MetaCyc:ENSG00000103064-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

12 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 Y+L amino acid transporter 2 (SLC7A6).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Y+L amino acid transporter 2 (SLC7A6).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Y+L amino acid transporter 2 (SLC7A6).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Y+L amino acid transporter 2 (SLC7A6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Y+L amino acid transporter 2 (SLC7A6).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Y+L amino acid transporter 2 (SLC7A6).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Y+L amino acid transporter 2 (SLC7A6).	[7]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Y+L amino acid transporter 2 (SLC7A6).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Y+L amino acid transporter 2 (SLC7A6).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Y+L amino acid transporter 2 (SLC7A6).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Y+L amino acid transporter 2 (SLC7A6).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Y+L amino acid transporter 2 (SLC7A6).	[13]

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 Y+L amino acid transporter 2 (SLC7A6).	[10]

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] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] 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.
• [8] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.