Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMNY2WA)

• DOT Name: b(0,+)-type amino acid transporter 1 (SLC7A9)
• Synonyms: b(0,+)AT1; Glycoprotein-associated amino acid transporter b0,+AT1; Solute carrier family 7 member 9
• Gene Name: SLC7A9
• Related Disease:
  Cystinuria
  Cystinuria type B
• UniProt ID: BAT1_HUMAN
• PDB ID: 6LI9; 6LID; 6YUP; 6YV1
• Pfam ID: PF13520
• Sequence:
  MGDTGLRKRREDEKSIQSQEPKTTSLQKELGLISGISIIVGTIIGSGIFVSPKSVLSNTE
  AVGPCLIIWAACGVLATLGALCFAELGTMITKSGGEYPYLMEAYGPIPAYLFSWASLIVI
  KPTSFAIICLSFSEYVCAPFYVGCKPPQIVVKCLAAAAILFISTVNSLSVRLGSYVQNIF
  TAAKLVIVAIIIISGLVLLAQGNTKNFDNSFEGAQLSVGAISLAFYNGLWAYDGWNQLNY
  ITEELRNPYRNLPLAIIIGIPLVTACYILMNVSYFTVMTATELLQSQAVAVTFGDRVLYP
  ASWIVPLFVAFSTIGAANGTCFTAGRLIYVAGREGHMLKVLSYISVRRLTPAPAIIFYGI
  IATIYIIPGDINSLVNYFSFAAWLFYGLTILGLIVMRFTRKELERPIKVPVVIPVLMTLI
  SVFLVLAPIISKPTWEYLYCVLFILSGLLFYFLFVHYKFGWAQKISKPITMHLQMLMEVV
  PPEEDPE
• Function: Associates with SLC3A1 to form a functional transporter complex that mediates the electrogenic exchange between cationic amino acids and neutral amino acids, with a stoichiometry of 1:1. Has system b(0,+)-like activity with high affinity for extracellular cationic amino acids and L-cystine and lower affinity for intracellular neutral amino acids. Substrate exchange is driven by high concentration of intracellular neutral amino acids and the intracellular reduction of L-cystine to L-cysteine. Required for reabsorption of L-cystine and dibasic amino acids across the brush border membrane in renal proximal tubules.
• Tissue Specificity: Expressed in the brush border membrane in the kidney (at protein level). Kidney, small intestine, liver and placenta.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Amino acid transport across the plasma membrane (R-HSA-352230)
  Defective SLC3A1 causes cystinuria (CSNU) (R-HSA-5619113)
  Defective SLC7A9 causes cystinuria (CSNU) (R-HSA-5660883)
  Basigin interactions (R-HSA-210991)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cystinuria	DISCU7CO	Definitive	Autosomal recessive	[1]
Cystinuria type B	DISZ0XA4	Supportive	Semidominant	[2]

8 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 b(0,+)-type amino acid transporter 1 (SLC7A9).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of b(0,+)-type amino acid transporter 1 (SLC7A9).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of b(0,+)-type amino acid transporter 1 (SLC7A9).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of b(0,+)-type amino acid transporter 1 (SLC7A9).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of b(0,+)-type amino acid transporter 1 (SLC7A9).	[7]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of b(0,+)-type amino acid transporter 1 (SLC7A9).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of b(0,+)-type amino acid transporter 1 (SLC7A9).	[9]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of b(0,+)-type amino acid transporter 1 (SLC7A9).	[10]

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] Clinical, biochemical and molecular characterization of cystinuria in a cohort of 12 patients. Clin Genet. 2012 Jan;81(1):47-55. doi: 10.1111/j.1399-0004.2011.01638.x. Epub 2011 Feb 14.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [9] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [10] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.