Details of Drug Off-Target (DOT)

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

• DOT Name: Y+L amino acid transporter 1 (SLC7A7)
• Synonyms: Monocyte amino acid permease 2; MOP-2; Solute carrier family 7 member 7; y(+)L-type amino acid transporter 1; Y+LAT1; y+LAT-1
• Gene Name: SLC7A7
• Related Disease: Lysinuric protein intolerance
• UniProt ID: YLAT1_HUMAN
• Pfam ID: PF13520
• Sequence:
  MVDSTEYEVASQPEVETSPLGDGASPGPEQVKLKKEISLLNGVCLIVGNMIGSGIFVSPK
  GVLIYSASFGLSLVIWAVGGLFSVFGALCYAELGTTIKKSGASYAYILEAFGGFLAFIRL
  WTSLLIIEPTSQAIIAITFANYMVQPLFPSCFAPYAASRLLAAACICLLTFINCAYVKWG
  TLVQDIFTYAKVLALIAVIVAGIVRLGQGASTHFENSFEGSSFAVGDIALALYSALFSYS
  GWDTLNYVTEEIKNPERNLPLSIGISMPIVTIIYILTNVAYYTVLDMRDILASDAVAVTF
  ADQIFGIFNWIIPLSVALSCFGGLNASIVAASRLFFVGSREGHLPDAICMIHVERFTPVP
  SLLFNGIMALIYLCVEDIFQLINYYSFSYWFFVGLSIVGQLYLRWKEPDRPRPLKLSVFF
  PIVFCLCTIFLVAVPLYSDTINSLIGIAIALSGLPFYFLIIRVPEHKRPLYLRRIVGSAT
  RYLQVLCMSVAAEMDLEDGGEMPKQRDPKSN
• Function: Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids from inside the cells in exchange with neutral amino acids plus sodium ions and may participate in nitric oxide synthesis via the transport of L-arginine. Also mediates arginine transport in non-polarized cells, such as monocytes, and is essential for the correct function of these cells. The transport mechanism is electroneutral and operates with a stoichiometry of 1:1. In vitro, Na(+) and Li(+), but also H(+), are cotransported with the neutral amino acids.
• Tissue Specificity: Highest expression in kidney and peripheral blood leukocytes . Weaker expression is observed in lung, heart, placenta, spleen, testis and small intestine . Expressed in normal fibroblasts and those from LPI patients . Also expressed in HUVECs, monocytes, retinal pigment epithelial cells, and various carcinoma cell lines, with highest expression in a colon-carcinoma cell line .
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Amino acid transport across the plasma membrane (R-HSA-352230)
  Defective SLC7A7 causes lysinuric protein intolerance (LPI) (R-HSA-5660862)
  Basigin interactions (R-HSA-210991)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lysinuric protein intolerance	DIS5F4A8	Definitive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Nitric Oxide	DM1RBYG	Approved	Y+L amino acid transporter 1 (SLC7A7) decreases the abundance of Nitric Oxide.	[19]

16 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 1 (SLC7A7).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Y+L amino acid transporter 1 (SLC7A7).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Y+L amino acid transporter 1 (SLC7A7).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Y+L amino acid transporter 1 (SLC7A7).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Y+L amino acid transporter 1 (SLC7A7).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Y+L amino acid transporter 1 (SLC7A7).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Y+L amino acid transporter 1 (SLC7A7).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Y+L amino acid transporter 1 (SLC7A7).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Y+L amino acid transporter 1 (SLC7A7).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Y+L amino acid transporter 1 (SLC7A7).	[11]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Y+L amino acid transporter 1 (SLC7A7).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Y+L amino acid transporter 1 (SLC7A7).	[13]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Y+L amino acid transporter 1 (SLC7A7).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Y+L amino acid transporter 1 (SLC7A7).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Y+L amino acid transporter 1 (SLC7A7).	[17]
Choline	DM5D9YK	Investigative	Choline affects the expression of Y+L amino acid transporter 1 (SLC7A7).	[18]

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 1 (SLC7A7).	[15]

References

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• [2] 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.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Arsenic exposure from drinking water is associated with decreased gene expression and increased DNA methylation in peripheral blood. Toxicol Appl Pharmacol. 2017 Apr 15;321:57-66. doi: 10.1016/j.taap.2017.02.019. Epub 2017 Feb 24.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] 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.
• [12] High folic acid increases cell turnover and lowers differentiation and iron content in human HT29 colon cancer cells. Br J Nutr. 2008 Apr;99(4):703-8.
• [13] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [14] 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.
• [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] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [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] Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Am J Clin Nutr. 2007 Jul;86(1):230-9. doi: 10.1093/ajcn/86.1.230.
• [19] Vascular endothelial dysfunction resulting from L-arginine deficiency in a patient with lysinuric protein intolerance. J Clin Invest. 2001 Sep;108(5):717-24. doi: 10.1172/JCI11260.