Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHMZ1R9)

• DOT Name: Large ribosomal subunit protein uL2 (RPL8)
• Synonyms: 60S ribosomal protein L8
• Gene Name: RPL8
• Related Disease:
  Breast carcinoma
  Hepatocellular carcinoma
  Melanoma
  Neoplasm
  Diamond-Blackfan anemia
  Glioblastoma multiforme
• UniProt ID: RL8_HUMAN
• PDB ID: 4CCM ; 4CCN ; 4CCO ; 4UG0 ; 4V6X ; 4Y3O ; 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 ; 7OW7 ; 7UN3 ; 7XNX ; 7XNY ; 8A3D ; 8FKZ ; 8FL2 ; 8FL3 ; 8FL4 ; 8FL6 ; 8FL7 ; 8FL9 ; 8FLA ; 8FLB ; 8FLC ; 8FLD ; 8FLE ; 8FLF ; 8IDT ; 8IDY ; 8IE3 ; 8INE ; 8INF ; 8INK ; 8IPD ; 8IPX ; 8IPY ; 8IR1 ; 8IR3 ; 8JDJ ; 8JDK ; 8JDL ; 8JDM
• Pfam ID: PF00181 ; PF03947
• Sequence:
  MGRVIRGQRKGAGSVFRAHVKHRKGAARLRAVDFAERHGYIKGIVKDIIHDPGRGAPLAK
  VVFRDPYRFKKRTELFIAAEGIHTGQFVYCGKKAQLNIGNVLPVGTMPEGTIVCCLEEKP
  GDRGKLARASGNYATVISHNPETKKTRVKLPSGSKKVISSANRAVVGVVAGGGRIDKPIL
  KAGRAYHKYKAKRNCWPRVRGVAMNPVEHPFGGGNHQHIGKPSTIRRDAPAGRKVGLIAA
  RRTGRLRGTKTVQEKEN
• 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)
  Protein hydroxylation (R-HSA-9629569)
  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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Melanoma	DIS1RRCY	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Diamond-Blackfan anemia	DISI2SNW	Limited	Autosomal dominant	[3]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Large ribosomal subunit protein uL2 (RPL8).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Large ribosomal subunit protein uL2 (RPL8).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Large ribosomal subunit protein uL2 (RPL8).	[7]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Large ribosomal subunit protein uL2 (RPL8).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Large ribosomal subunit protein uL2 (RPL8).	[11]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Large ribosomal subunit protein uL2 (RPL8).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Large ribosomal subunit protein uL2 (RPL8).	[14]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Large ribosomal subunit protein uL2 (RPL8).	[15]

3 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 affects the methylation of Large ribosomal subunit protein uL2 (RPL8).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Large ribosomal subunit protein uL2 (RPL8).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Large ribosomal subunit protein uL2 (RPL8).	[12]

References

• [1] Shared MHC class II-dependent melanoma ribosomal protein L8 identified by phage display.Cancer Res. 2007 Apr 15;67(8):3555-9. doi: 10.1158/0008-5472.CAN-06-2763.
• [2] Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray.Oncol Rep. 2007 Oct;18(4):943-51.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Identification of Key Candidate Proteins and Pathways Associated with Temozolomide Resistance in Glioblastoma Based on Subcellular Proteomics and Bioinformatical Analysis.Biomed Res Int. 2018 Mar 1;2018:5238760. doi: 10.1155/2018/5238760. eCollection 2018.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Folic acid induces cell type-specific changes in the transcriptome of breast cancer cell lines: a proof-of-concept study. J Nutr Sci. 2016 Apr 26;5:e17. doi: 10.1017/jns.2016.8. eCollection 2016.
• [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] 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.
• [11] 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.
• [12] 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.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [14] 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.
• [15] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.