Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN51IPT)

• DOT Name: Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14)
• Synonyms: Amino acid transporter ATB0+; Solute carrier family 6 member 14
• Gene Name: SLC6A14
• UniProt ID: S6A14_HUMAN
• Pfam ID: PF00209
• Sequence:
  MDKLKCPSFFKCREKEKVSASSENFHVGENDENQDRGNWSKKSDYLLSMIGYAVGLGNVW
  RFPYLTYSNGGGAFLIPYAIMLALAGLPLFFLECSLGQFASLGPVSVWRILPLFQGVGIT
  MVLISIFVTIYYNVIIAYSLYYMFASFQSELPWKNCSSWSDKNCSRSPIVTHCNVSTVNK
  GIQEIIQMNKSWVDINNFTCINGSEIYQPGQLPSEQYWNKVALQRSSGMNETGVIVWYLA
  LCLLLAWLIVGAALFKGIKSSGKVVYFTALFPYVVLLILLVRGATLEGASKGISYYIGAQ
  SNFTKLKEAEVWKDAATQIFYSLSVAWGGLVALSSYNKFKNNCFSDAIVVCLTNCLTSVF
  AGFAIFSILGHMAHISGKEVSQVVKSGFDLAFIAYPEALAQLPGGPFWSILFFFMLLTLG
  LDSQFASIETITTTIQDLFPKVMKKMRVPITLGCCLVLFLLGLVCVTQAGIYWVHLIDHF
  CAGWGILIAAILELVGIIWIYGGNRFIEDTEMMIGAKRWIFWLWWRACWFVITPILLIAI
  FIWSLVQFHRPNYGAIPYPDWGVALGWCMIVFCIIWIPIMAIIKIIQAKGNIFQRLISCC
  RPASNWGPYLEQHRGERYKDMVDPKKEADHEIPTVSGSRKPE
• Function: Amino acid transporter that plays an important role in the absorption of amino acids in the intestinal tract. Mediates the uptake of a broad range of neutral and cationic amino acids (with the exception of proline) in a Na(+)/Cl(-)-dependent manner. Transports non-alpha-amino acids such as beta-alanine with low affinity, and has a higher affinity for dipolar and cationic amino acids such as leucine and lysine. Can also transport carnitine, butirylcarnitine and propionylcarnitine coupled to the transmembrane gradients of Na(+) and Cl(-).
• Tissue Specificity: Levels are highest in adult and fetal lung, in trachea and salivary gland. Lower levels detected in mammary gland, stomach and pituitary gland, and very low levels in colon, uterus, prostate and testis.
• Reactome Pathway:
  Na+/Cl- dependent neurotransmitter transporters (R-HSA-442660)
  Variant SLC6A14 may confer susceptibility towards obesity (R-HSA-5619094)
  Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

13 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 Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[4]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[4]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[5]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[6]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[8]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[5]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[12]

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 Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14).	[10]

References

• [1] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [2] 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.
• [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] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [5] Oestrogenic potencies of Zeranol, oestradiol, diethylstilboestrol, Bisphenol-A and genistein: implications for exposure assessment of potential endocrine disrupters. Hum Reprod. 2001 May;16(5):1037-45.
• [6] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.