Details of Drug Off-Target (DOT)

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

• DOT Name: Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15)
• Synonyms: Sodium- and chloride-dependent neurotransmitter transporter NTT73; Sodium-coupled branched-chain amino-acid transporter 1; Solute carrier family 6 member 15; Transporter v7-3
• Gene Name: SLC6A15
• UniProt ID: S6A15_HUMAN
• Pfam ID: PF00209
• Sequence:
  MPKNSKVVKRELDDDVTESVKDLLSNEDAADDAFKTSELIVDGQEEKDTDVEEGSEVEDE
  RPAWNSKLQYILAQVGFSVGLGNVWRFPYLCQKNGGGAYLLPYLILLMVIGIPLFFLELS
  VGQRIRRGSIGVWNYISPKLGGIGFASCVVCYFVALYYNVIIGWSLFYFSQSFQQPLPWD
  QCPLVKNASHTFVEPECEQSSATTYYWYREALNISSSISESGGLNWKMTICLLAAWVMVC
  LAMIKGIQSSGKIIYFSSLFPYVVLICFLIRAFLLNGSIDGIRHMFTPKLEIMLEPKVWR
  EAATQVFFALGLGFGGVIAFSSYNKRDNNCHFDAVLVSFINFFTSVLATLVVFAVLGFKA
  NVINEKCITQNSETIMKFLKMGNISQDIIPHHINLSTVTAEDYHLVYDIIQKVKEEEFPA
  LHLNSCKIEEELNKAVQGTGLAFIAFTEAMTHFPASPFWSVMFFLMLVNLGLGSMFGTIE
  GIVTPIVDTFKVRKEILTVICCLLAFCIGLIFVQRSGNYFVTMFDDYSATLPLLIVVILE
  NIAVCFVYGIDKFMEDLKDMLGFAPSRYYYYMWKYISPLMLLSLLIASVVNMGLSPPGYN
  AWIEDKASEEFLSYPTWGLVVCVSLVVFAILPVPVVFIVRRFNLIDDSSGNLASVTYKRG
  RVLKEPVNLEGDDTSLIHGKIPSEMPSPNFGKNIYRKQSGSPTLDTAPNGRYGIGYLMAD
  IMPDMPESDL
• Function: Functions as a sodium-dependent neutral amino acid transporter. Exhibits preference for the branched-chain amino acids, particularly leucine, valine and isoleucine and methionine. Can also transport low-affinity substrates such as alanine, phenylalanine, glutamine and pipecolic acid. Mediates the saturable, pH-sensitive and electrogenic cotransport of proline and sodium ions with a stoichiometry of 1:1. May have a role as transporter for neurotransmitter precursors into neurons. In contrast to other members of the neurotransmitter transporter family, does not appear to be chloride-dependent.
• Tissue Specificity: Almost exclusively expressed in the brain.
• Reactome Pathway:
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Amino acid transport across the plasma membrane (R-HSA-352230)

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 Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[8]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[9]
Fenfluramine	DM0762O	Phase 3	Fenfluramine increases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[10]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[14]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Sodium-dependent neutral amino acid transporter B(0)AT2 (SLC6A15).	[13]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [10] Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. Pulm Circ. 2011 Jul-Sep;1(3):405-18. doi: 10.4103/2045-8932.87310.
• [11] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.