Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX6VXLB)

• DOT Name: Large ribosomal subunit protein uL3 (RPL3)
• Synonyms: 60S ribosomal protein L3; HIV-1 TAR RNA-binding protein B; TARBP-B
• Gene Name: RPL3
• Related Disease:
  Carcinoma
  Myopathy
  Spinal muscular atrophy
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Congenital myopathy
  Neoplasm
  Neuromuscular disease
  Polycystic ovarian syndrome
  Primary biliary cholangitis
  Schizophrenia
  Undifferentiated carcinoma
  Advanced cancer
  Lung cancer
• UniProt ID: RL3_HUMAN
• PDB ID: 4UG0 ; 4V6X ; 5AJ0 ; 5LKS ; 5T2C ; 6IP5 ; 6IP6 ; 6IP8 ; 6LQM ; 6LSR ; 6LSS ; 6LU8 ; 6OLE ; 6OLF ; 6OLG ; 6OLI ; 6OLZ ; 6OM0 ; 6OM7 ; 6QZP ; 6W6L ; 6XA1 ; 6Y0G ; 6Y2L ; 6Y57 ; 6Y6X ; 6Z6L ; 6Z6M ; 6Z6N ; 6ZM7 ; 6ZME ; 6ZMI ; 6ZMO ; 7BHP ; 7F5S ; 7QVP ; 7XNX ; 7XNY ; 8A3D ; 8FKP ; 8FKQ ; 8FKR ; 8FKS ; 8FKT ; 8FKU ; 8FKV ; 8FKW ; 8FKX ; 8FKY ; 8FKZ ; 8FL0 ; 8FL2 ; 8FL3 ; 8FL4 ; 8FL6 ; 8FL7 ; 8FL9 ; 8FLA ; 8FLB ; 8FLC ; 8FLD ; 8FLE ; 8FLF ; 8G5Y ; 8G5Z ; 8G60 ; 8G61 ; 8G6J ; 8GLP ; 8IDT ; 8IDY ; 8IE3 ; 8INE ; 8INF ; 8INK ; 8IPD ; 8IPX ; 8IPY ; 8IR1 ; 8IR3 ; 8JDJ ; 8JDK ; 8JDL ; 8JDM
• Pfam ID: PF00297
• Sequence:
  MSHRKFSAPRHGSLGFLPRKRSSRHRGKVKSFPKDDPSKPVHLTAFLGYKAGMTHIVREV
  DRPGSKVNKKEVVEAVTIVETPPMVVVGIVGYVETPRGLRTFKTVFAEHISDECKRRFYK
  NWHKSKKKAFTKYCKKWQDEDGKKQLEKDFSSMKKYCQVIRVIAHTQMRLLPLRQKKAHL
  MEIQVNGGTVAEKLDWARERLEQQVPVNQVFGQDEMIDVIGVTKGKGYKGVTSRWHTKKL
  PRKTHRGLRKVACIGAWHPARVAFSVARAGQKGYHHRTEINKKIYKIGQGYLIKDGKLIK
  NNASTDYDLSDKSINPLGGFVHYGEVTNDFVMLKGCVVGTKKRVLTLRKSLLVQTKRRAL
  EKIDLKFIDTTSKFGHGRFQTMEEKKAFMGPLKKDRIAKEEGA
• Function: Component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
• KEGG Pathway:
  Ribosome (hsa03010)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Peptide chain elongation (R-HSA-156902)
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)
  Viral mRNA Translation (R-HSA-192823)
  Selenocysteine synthesis (R-HSA-2408557)
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  Eukaryotic Translation Termination (R-HSA-72764)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) (R-HSA-975956)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Biomarker	[1]
Myopathy	DISOWG27	Definitive	Biomarker	[2]
Spinal muscular atrophy	DISTLKOB	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[4]
Congenital myopathy	DISLSK9G	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[5]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[6]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[7]
Schizophrenia	DISSRV2N	Strong	Biomarker	[8]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Lung cancer	DISCM4YA	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Large ribosomal subunit protein uL3 (RPL3).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Large ribosomal subunit protein uL3 (RPL3).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Large ribosomal subunit protein uL3 (RPL3).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Large ribosomal subunit protein uL3 (RPL3).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Large ribosomal subunit protein uL3 (RPL3).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Large ribosomal subunit protein uL3 (RPL3).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Large ribosomal subunit protein uL3 (RPL3).	[17]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Large ribosomal subunit protein uL3 (RPL3).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Large ribosomal subunit protein uL3 (RPL3).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Large ribosomal subunit protein uL3 (RPL3).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Large ribosomal subunit protein uL3 (RPL3).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Large ribosomal subunit protein uL3 (RPL3).	[24]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Large ribosomal subunit protein uL3 (RPL3).	[25]

3 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 ribosomal subunit protein uL3 (RPL3).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Large ribosomal subunit protein uL3 (RPL3).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Large ribosomal subunit protein uL3 (RPL3).	[22]

References

• [1] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [2] ASC-1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy.Ann Neurol. 2020 Feb;87(2):217-232. doi: 10.1002/ana.25660. Epub 2019 Dec 27.
• [3] Negative cooperativity between alpha 3 beta 1 and alpha 2 beta 1 integrins in human mammary carcinoma MDA MB 231 cells.Exp Cell Res. 1998 May 1;240(2):368-76. doi: 10.1006/excr.1998.4012.
• [4] Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles.Oncotarget. 2016 Nov 29;7(48):79670-79687. doi: 10.18632/oncotarget.13216.
• [5] The new neuromuscular disease related with defects in the ASC-1 complex: report of a second case confirms ASCC1 involvement.Clin Genet. 2017 Oct;92(4):434-439. doi: 10.1111/cge.12997. Epub 2017 Mar 31.
• [6] Correlation between thrombophilia and recurrent pregnancy loss in patients with polycystic ovary syndrome: a comparative study.J Chin Med Assoc. 2013 May;76(5):282-8. doi: 10.1016/j.jcma.2013.01.009. Epub 2013 Mar 20.
• [7] Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2011 Mar 13;43(4):329-32. doi: 10.1038/ng.789.
• [8] Expression of D-serine and glycine transporters in the prefrontal cortex and cerebellum in schizophrenia.Schizophr Res. 2008 Jul;102(1-3):283-94. doi: 10.1016/j.schres.2008.02.009. Epub 2008 Apr 8.
• [9] 5-FU targets rpL3 to induce mitochondrial apoptosis via cystathionine--synthase in colon cancer cells lacking p53.Oncotarget. 2016 Aug 2;7(31):50333-50348. doi: 10.18632/oncotarget.10385.
• [10] rpL3 promotes the apoptosis of p53 mutated lung cancer cells by down-regulating CBS and NFB upon 5-FU treatment.Sci Rep. 2016 Dec 7;6:38369. doi: 10.1038/srep38369.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] 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.
• [16] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [17] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [18] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [19] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [20] 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.
• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [22] 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.
• [23] 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.
• [24] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [25] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.