Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM8EBRI)

• DOT Name: Large ribosomal subunit protein uL18 (RPL5)
• Synonyms: 60S ribosomal protein L5
• Gene Name: RPL5
• Related Disease:
  Diamond-Blackfan anemia 6
  Multiple sclerosis
  Atypical teratoid/rhabdoid tumour
  Cleft lip
  Cleft palate
  Cytomegalovirus infection
  Isolated cleft lip
  Isolated cleft palate
  Malignant rhabdoid tumour
  Myopathy
  T-cell acute lymphoblastic leukaemia
  Diamond-Blackfan anemia
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Glioblastoma multiforme
  Melanoma
  Neoplasm
  Plasma cell myeloma
  Venous thromboembolism
• UniProt ID: RL5_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 ; 7OW7 ; 7QVP ; 7XNX ; 7XNY ; 8A3D ; 8BGU ; 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: PF14204 ; PF17144
• Sequence:
  MGFVKVVKNKAYFKRYQVKFRRRREGKTDYYARKRLVIQDKNKYNTPKYRMIVRVTNRDI
  ICQIAYARIEGDMIVCAAYAHELPKYGVKVGLTNYAAAYCTGLLLARRLLNRFGMDKIYE
  GQVEVTGDEYNVESIDGQPGAFTCYLDAGLARTTTGNKVFGALKGAVDGGLSIPHSTKRF
  PGYDSESKEFNAEVHRKHIMGQNVADYMRYLMEEDEDAYKKQFSQYIKNSVTPDMMEEMY
  KKAHAAIRENPVYEKKPKKEVKKKRWNRPKMSLAQKKDRVAQKKASFLRAQERAAES
• Function: Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel. As part of the 5S RNP/5S ribonucleoprotein particle it is an essential component of the LSU, required for its formation and the maturation of rRNAs. It also couples ribosome biogenesis to p53/TP53 activation. As part of the 5S RNP it accumulates in the nucleoplasm and inhibits MDM2, when ribosome biogenesis is perturbed, mediating the stabilization and the activation of TP53.
• 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

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diamond-Blackfan anemia 6	DIS4FKKF	Definitive	Autosomal dominant	[1]
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[2]
Atypical teratoid/rhabdoid tumour	DIS1FA0D	Strong	Biomarker	[3]
Cleft lip	DISV3XW6	Strong	Genetic Variation	[4]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[5]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[6]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[4]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[5]
Malignant rhabdoid tumour	DIS46HZU	Strong	Biomarker	[3]
Myopathy	DISOWG27	Strong	Biomarker	[7]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[8]
Diamond-Blackfan anemia	DISI2SNW	Supportive	Autosomal dominant	[9]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[10]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[11]
Breast cancer	DIS7DPX1	Limited	Biomarker	[10]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[10]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[10]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[12]
Venous thromboembolism	DISUR7CR	Limited	Biomarker	[13]

3 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 Large ribosomal subunit protein uL18 (RPL5).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Large ribosomal subunit protein uL18 (RPL5).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Large ribosomal subunit protein uL18 (RPL5).	[24]

13 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 uL18 (RPL5).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Large ribosomal subunit protein uL18 (RPL5).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Large ribosomal subunit protein uL18 (RPL5).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Large ribosomal subunit protein uL18 (RPL5).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Large ribosomal subunit protein uL18 (RPL5).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Large ribosomal subunit protein uL18 (RPL5).	[20]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Large ribosomal subunit protein uL18 (RPL5).	[21]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Large ribosomal subunit protein uL18 (RPL5).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Large ribosomal subunit protein uL18 (RPL5).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Large ribosomal subunit protein uL18 (RPL5).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Large ribosomal subunit protein uL18 (RPL5).	[27]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Large ribosomal subunit protein uL18 (RPL5).	[28]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Large ribosomal subunit protein uL18 (RPL5).	[29]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Multiple sclerosis susceptibility-associated SNPs do not influence disease severity measures in a cohort of Australian MS patients.PLoS One. 2010 Apr 2;5(4):e10003. doi: 10.1371/journal.pone.0010003.
• [3] Identification of RPL5 and RPL10 as novel diagnostic biomarkers of Atypical teratoid/rhabdoid tumors.Cancer Cell Int. 2018 Nov 20;18:190. doi: 10.1186/s12935-018-0681-1. eCollection 2018.
• [4] Molecular pathogenesis in Diamond-Blackfan anemia.Int J Hematol. 2010 Oct;92(3):413-8. doi: 10.1007/s12185-010-0693-7. Epub 2010 Sep 30.
• [5] Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008 Dec;83(6):769-80. doi: 10.1016/j.ajhg.2008.11.004.
• [6] Immune modulation by the human cytomegalovirus-encoded molecule UL18, a mystery yet to be solved.J Immunol. 2008 Jan 1;180(1):19-24. doi: 10.4049/jimmunol.180.1.19.
• [7] Stable reference genes for expression studies in breast muscle of normal and white striping-affected chickens.Mol Biol Rep. 2020 Jan;47(1):45-53. doi: 10.1007/s11033-019-05103-z. Epub 2019 Oct 3.
• [8] Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia.Nat Genet. 2013 Feb;45(2):186-90. doi: 10.1038/ng.2508. Epub 2012 Dec 23.
• [9] Diamond-Blackfan Anemia. 2009 Jun 25 [updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [10] The ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in multiple cancer types.Oncotarget. 2017 Feb 28;8(9):14462-14478. doi: 10.18632/oncotarget.14895.
• [11] p53-Dependent Apoptotic Effect of Puromycin via Binding of Ribosomal Protein L5 and L11 to MDM2 and its Combination Effect with RITA or Doxorubicin.Cancers (Basel). 2019 Apr 24;11(4):582. doi: 10.3390/cancers11040582.
• [12] RPL5 on 1p22.1 is recurrently deleted in multiple myeloma and its expression is linked to bortezomib response.Leukemia. 2017 Aug;31(8):1706-1714. doi: 10.1038/leu.2016.370. Epub 2016 Dec 2.
• [13] Identification of biomarkers of venous thromboembolism by bioinformatics analyses.Medicine (Baltimore). 2018 Apr;97(14):e0152. doi: 10.1097/MD.0000000000010152.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [20] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [21] 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.
• [22] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [28] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [29] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.