Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQJQY3S)

• DOT Name: Large neutral amino acids transporter small subunit 3 (SLC43A1)
• Synonyms: L-type amino acid transporter 3; Prostate cancer overexpressed gene 1 protein; Solute carrier family 43 member 1
• Gene Name: SLC43A1
• UniProt ID: LAT3_HUMAN
• Pfam ID: PF07690
• Sequence:
  MAPTLQQAYRRRWWMACTAVLENLFFSAVLLGWGSLLIILKNEGFYSSTCPAESSTNTTQ
  DEQRRWPGCDQQDEMLNLGFTIGSFVLSATTLPLGILMDRFGPRPVRLVGSACFTASCTL
  MALASRDVEALSPLIFLALSLNGFGGICLTFTSLTLPNMFGNLRSTLMALMIGSYASSAI
  TFPGIKLIYDAGVAFVVIMFTWSGLACLIFLNCTLNWPIEAFPAPEEVNYTKKIKLSGLA
  LDHKVTGDLFYTHVTTMGQRLSQKAPSLEDGSDAFMSPQDVRGTSENLPERSVPLRKSLC
  SPTFLWSLLTMGMTQLRIIFYMAAVNKMLEYLVTGGQEHETNEQQQKVAETVGFYSSVFG
  AMQLLCLLTCPLIGYIMDWRIKDCVDAPTQGTVLGDARDGVATKSIRPRYCKIQKLTNAI
  SAFTLTNLLLVGFGITCLINNLHLQFVTFVLHTIVRGFFHSACGSLYAAVFPSNHFGTLT
  GLQSLISAVFALLQQPLFMAMVGPLKGEPFWVNLGLLLFSLLGFLLPSYLFYYRARLQQE
  YAANGMGPLKVLSGSEVTA
• Function: Uniport that mediates the transport of neutral amino acids such as L-leucine, L-isoleucine, L-valine, and L-phenylalanine. The transport activity is sodium ions-independent, electroneutral and mediated by a facilitated diffusion.
• Tissue Specificity: Ubiquitously expressed in fetus and adult . Highest expression in adult pancreas, liver, skeletal muscle . In fetus, highest expression in liver and lower levels in kidney, and lung . Exclusively expressed in the glomeruli along the glomerular capillary walls .
• Reactome Pathway: Amino acid transport across the plasma membrane (R-HSA-352230)

Molecular Interaction Atlas (MIA) of This DOT

26 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[11]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[8]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[12]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[13]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[14]
Isoflavone	DM7U58J	Phase 4	Isoflavone decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[8]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Large neutral amino acids transporter small subunit 3 (SLC43A1).	[18]

References

• [1] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [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] 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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] 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.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [13] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [14] 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.
• [15] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] 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.
• [18] 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.
• [19] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [20] 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.
• [21] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.