Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT56V01A)

• DOT Name: Amino acid transporter heavy chain SLC3A1 (SLC3A1)
• Synonyms: D2h; Neutral and basic amino acid transport protein; NBAT; Solute carrier family 3 member 1; b(0,+)-type amino acid transporter-related heavy chain; rBAT
• Gene Name: SLC3A1
• Related Disease:
  Cystinuria
  Cystinuria type A
• UniProt ID: SLC31_HUMAN
• PDB ID: 6LI9; 6LID; 6YUP; 6YUZ
• Pfam ID: PF00128
• Sequence:
  MAEDKSKRDSIEMSMKGCQTNNGFVHNEDILEQTPDPGSSTDNLKHSTRGILGSQEPDFK
  GVQPYAGMPKEVLFQFSGQARYRIPREILFWLTVASVLVLIAATIAIIALSPKCLDWWQE
  GPMYQIYPRSFKDSNKDGNGDLKGIQDKLDYITALNIKTVWITSFYKSSLKDFRYGVEDF
  REVDPIFGTMEDFENLVAAIHDKGLKLIIDFIPNHTSDKHIWFQLSRTRTGKYTDYYIWH
  DCTHENGKTIPPNNWLSVYGNSSWHFDEVRNQCYFHQFMKEQPDLNFRNPDVQEEIKEIL
  RFWLTKGVDGFSLDAVKFLLEAKHLRDEIQVNKTQIPDTVTQYSELYHDFTTTQVGMHDI
  VRSFRQTMDQYSTEPGRYRFMGTEAYAESIDRTVMYYGLPFIQEADFPFNNYLSMLDTVS
  GNSVYEVITSWMENMPEGKWPNWMIGGPDSSRLTSRLGNQYVNVMNMLLFTLPGTPITYY
  GEEIGMGNIVAANLNESYDINTLRSKSPMQWDNSSNAGFSEASNTWLPTNSDYHTVNVDV
  QKTQPRSALKLYQDLSLLHANELLLNRGWFCHLRNDSHYVVYTRELDGIDRIFIVVLNFG
  ESTLLNLHNMISGLPAKMRIRLSTNSADKGSKVDTSGIFLDKGEGLIFEHNTKNLLHRQT
  AFRDRCFVSNRACYSSVLNILYTSC
• Function: Acts as a chaperone that facilitates biogenesis and trafficking of functional transporter heteromers to the plasma membrane. Associates with SLC7A9 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. SLC7A9-SLC3A1 transporter 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. SLC7A9-SLC3A1 acts as a major transporter for reabsorption of L-cystine and dibasic amino acids across the brush border membrane in early proximal tubules. Associates with SLC7A13 to form a functional complex that transports anionic and neutral amino acids via exchange or facilitated diffusion. SLC7A13-SLC3A1 may act as a major transporter for L-cystine in late proximal tubules, ensuring its reabsorption from the luminal fluid in exchange for cytosolic L-glutamate or L-aspartate.
• Tissue Specificity: Expressed in the brush border membrane in the kidney (at protein level). Predominantly expressed in the kidney, small intestine and pancreas. Weakly expressed in liver.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Defective SLC3A1 causes cystinuria (CSNU) (R-HSA-5619113)
  Defective SLC7A9 causes cystinuria (CSNU) (R-HSA-5660883)
  Amino acid transport across the plasma membrane (R-HSA-352230)

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 A	DIS3SHAH	Supportive	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
L-Cysteine	DMCMOS8	Clinical trial	Amino acid transporter heavy chain SLC3A1 (SLC3A1) increases the uptake of L-Cysteine.	[14]
L-methionine	DME8G1U	Investigative	Amino acid transporter heavy chain SLC3A1 (SLC3A1) increases the uptake of L-methionine.	[14]

10 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 Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[6]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[7]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[5]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[8]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[11]

2 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 increases the methylation of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Amino acid transporter heavy chain SLC3A1 (SLC3A1).	[13]

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] Evidence for a role of claudin 2 as a proximal tubular stress responsive paracellular water channel. Toxicol Appl Pharmacol. 2014 Sep 1;279(2):163-72.
• [4] 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.
• [5] Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
• [6] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [7] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [8] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [9] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [12] 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.
• [13] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [14] Characteristics of transport of selenoamino acids by epithelial amino acid transporters. Chem Biol Interact. 2009 Feb 12;177(3):234-41. doi: 10.1016/j.cbi.2008.09.008. Epub 2008 Sep 19.