Details of Drug Off-Target (DOT)

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

• DOT Name: Large neutral amino acids transporter small subunit 4 (SLC43A2)
• Synonyms: L-type amino acid transporter 4; Solute carrier family 43 member 2
• Gene Name: SLC43A2
• UniProt ID: LAT4_HUMAN
• Pfam ID: PF07690
• Sequence:
  MAPTLATAHRRRWWMACTAVLENLLFSAVLLGWGSLLIMLKSEGFYSYLCTEPENVTNGT
  VGGTAEPGHEEVSWMNGWLSCQAQDEMLNLAFTVGSFLLSAITLPLGIVMDKYGPRKLRL
  LGSACFAVSCLLIAYGASKPNALSVLIFIALALNGFGGMCMTFTSLTLPNMFGDLRSTFI
  ALMIGSYASSAVTFPGIKLIYDAGVSFIVVLVVWAGCSGLVFLNCFFNWPLEPFPGPEDM
  DYSVKIKFSWLGFDHKITGKQFYKQVTTVGRRLSVGSSMRSAKEQVALQEGHKLCLSTVD
  LEVKCQPDAAVAPSFMHSVFSPILLLSLVTMCVTQLRLIFYMGAMNNILKFLVSGDQKTV
  GLYTSIFGVLQLLCLLTAPVIGYIMDWRLKECEDASEEPEEKDANQGEKKKKKRDRQIQK
  ITNAMRAFAFTNLLLVGFGVTCLIPNLPLQILSFILHTIVRGFIHSAVGGLYAAVYPSTQ
  FGSLTGLQSLISALFALLQQPLFLAMMGPLQGDPLWVNVGLLLLSLLGFCLPLYLICYRR
  QLERQLQQRQEDDKLFLKINGSSNQEAFV
• Function: Uniporter that mediates the transport of the stereospecific L-phenylalanine, L-methionine and L-branched-chain amino acids, between the extracellular space and the cytoplasm and may control the transepithelial (re)absorption of neutral amino acid in kidney and small intestine. The transport activity is mediated through facilitated diffusion and is sodium ions-, chloride ions- and pH-independent.
• Tissue Specificity: Detected in several tissues with higher expression in placenta, kidney and peripheral blood leukocytes . In the kidney, is detected in epithelial cells of the distal tubule and collecting duct . In the intestine, is expressed mainly in crypt cells of the intestinal microvilli and epithelial cells in the base of the villus .
• Reactome Pathway: Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[15]

11 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 Large neutral amino acids transporter small subunit 4 (SLC43A2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[8]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Large neutral amino acids transporter small subunit 4 (SLC43A2).	[13]

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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact. 2010 Oct 6;188(1):214-9.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [9] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] 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.
• [15] 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.