Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV5OHBT)

• DOT Name: Sodium-coupled neutral amino acid transporter 4 (SLC38A4)
• Synonyms: Amino acid transporter A3; Na(+)-coupled neutral amino acid transporter 4; Solute carrier family 38 member 4; System A amino acid transporter 3; System N amino acid transporter 3
• Gene Name: SLC38A4
• UniProt ID: S38A4_HUMAN
• Pfam ID: PF01490
• Sequence:
  MDPMELRNVNIEPDDESSSGESAPDSYIGIGNSEKAAMSSQFANEDTESQKFLTNGFLGK
  KKLADYADEHHPGTTSFGMSSFNLSNAIMGSGILGLSYAMANTGIILFIIMLLAVAILSL
  YSVHLLLKTAKEGGSLIYEKLGEKAFGWPGKIGAFVSITMQNIGAMSSYLFIIKYELPEV
  IRAFMGLEENTGEWYLNGNYLIIFVSVGIILPLSLLKNLGYLGYTSGFSLTCMVFFVSVV
  IYKKFQIPCPLPVLDHSVGNLSFNNTLPMHVVMLPNNSESSDVNFMMDYTHRNPAGLDEN
  QAKGSLHDSGVEYEAHSDDKCEPKYFVFNSRTAYAIPILVFAFVCHPEVLPIYSELKDRS
  RRKMQTVSNISITGMLVMYLLAALFGYLTFYGEVEDELLHAYSKVYTLDIPLLMVRLAVL
  VAVTLTVPIVLFPIRTSVITLLFPKRPFSWIRHFLIAAVLIALNNVLVILVPTIKYIFGF
  IGASSATMLIFILPAVFYLKLVKKETFRSPQKVGALIFLVVGIFFMIGSMALIIIDWIYD
  PPNSKHH
• Function: Symporter that cotransports neutral amino acids and sodium ions from the extraccellular to the intracellular side of the cell membrane. The transport is electrogenic, pH dependent and partially tolerates substitution of Na(+) by Li(+). Preferentially transports smaller amino acids, such as glycine, L-alanine, L-serine, L-asparagine and L-threonine, followed by L-cysteine, L-histidine, L-proline and L-glutamine and L-methionine.
• Tissue Specificity: Expressed almost exclusively in embryonic and adult liver, and at lower levels in the kidney . Expressed at lower levels in adult muscle and pancreas . Detected in fetal blood vessels . Expressed in syncytiotrophoblas of placenta during first trimester and at term . Highly expressed in first trimester placenta compared to term placenta .
• Reactome Pathway: Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[13]

18 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-coupled neutral amino acid transporter 4 (SLC38A4).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[4]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[5]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[6]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[7]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[8]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[16]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[17]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Sodium-coupled neutral amino acid transporter 4 (SLC38A4).	[18]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [7] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [8] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] 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.
• [13] 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.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [17] 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.
• [18] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.