Details of Drug Off-Target (DOT)

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

• DOT Name: Small ribosomal subunit protein uS12 (RPS23)
• Synonyms: 40S ribosomal protein S23
• Gene Name: RPS23
• Related Disease:
  Adenocarcinoma
  Alzheimer disease
  Bipolar disorder
  Herpes simplex infection
  Intervertebral disc degeneration
  Isolated congenital microcephaly
  Brachycephaly, trichomegaly, and developmental delay
• UniProt ID: RS23_HUMAN
• PDB ID: 4CXG ; 4CXH ; 4UG0 ; 4V6X ; 5A2Q ; 5AJ0 ; 5FLX ; 5LKS ; 5OA3 ; 5T2C ; 5VYC ; 6FEC ; 6G18 ; 6G4S ; 6G4W ; 6G51 ; 6G53 ; 6G5H ; 6G5I ; 6IP5 ; 6IP6 ; 6IP8 ; 6OLE ; 6OLF ; 6OLG ; 6OLI ; 6OLZ ; 6OM0 ; 6OM7 ; 6QZP ; 6XA1 ; 6Y0G ; 6Y2L ; 6Y57 ; 6YBW ; 6Z6L ; 6Z6M ; 6Z6N ; 6ZLW ; 6ZM7 ; 6ZME ; 6ZMI ; 6ZMO ; 6ZMT ; 6ZMW ; 6ZN5 ; 6ZOJ ; 6ZOK ; 6ZON ; 6ZP4 ; 6ZUO ; 6ZV6 ; 6ZVH ; 6ZVJ ; 6ZXD ; 6ZXE ; 6ZXF ; 6ZXG ; 6ZXH ; 7A09 ; 7K5I ; 7MQ8 ; 7MQ9 ; 7MQA ; 7QP6 ; 7QP7 ; 7R4X ; 7TQL ; 7WTS ; 7WTT ; 7WTU ; 7WTV ; 7WTW ; 7WTX ; 7WTZ ; 7WU0 ; 7XNX ; 7XNY ; 8JDJ ; 8JDK ; 8JDL ; 8JDM ; 8T4S
• Pfam ID: PF00164
• Sequence:
  MGKCRGLRTARKLRSHRRDQKWHDKQYKKAHLGTALKANPFGGASHAKGIVLEKVGVEAK
  QPNSAIRKCVRVQLIKNGKKITAFVPNDGCLNFIEENDEVLVAGFGRKGHAVGDIPGVRF
  KVVKVANVSLLALYKGKKERPRS
• 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. Plays an important role in translational accuracy. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.
• 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)
  Translation initiation complex formation (R-HSA-72649)
  Formation of a pool of free 40S subunits (R-HSA-72689)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  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)
  SARS-CoV-1 modulates host translation machinery (R-HSA-9735869)
  SARS-CoV-2 modulates host translation machinery (R-HSA-9754678)
  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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[3]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[4]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[5]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[6]
Brachycephaly, trichomegaly, and developmental delay	DISXI2L2	Limited	Unknown	[7]

2 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 Small ribosomal subunit protein uS12 (RPS23).	[8]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Small ribosomal subunit protein uS12 (RPS23).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Small ribosomal subunit protein uS12 (RPS23).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small ribosomal subunit protein uS12 (RPS23).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Small ribosomal subunit protein uS12 (RPS23).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Small ribosomal subunit protein uS12 (RPS23).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Small ribosomal subunit protein uS12 (RPS23).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Small ribosomal subunit protein uS12 (RPS23).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Small ribosomal subunit protein uS12 (RPS23).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Small ribosomal subunit protein uS12 (RPS23).	[17]

References

• [1] Pair-wise comparison analysis of differential expression of mRNAs in early and advanced stage primary colorectal adenocarcinomas.BMJ Open. 2014 Aug 8;4(8):e004930. doi: 10.1136/bmjopen-2014-004930.
• [2] The Rps23rg gene family originated through retroposition of the ribosomal protein s23 mRNA and encodes proteins that decrease Alzheimer's beta-amyloid level and tau phosphorylation.Hum Mol Genet. 2010 Oct 1;19(19):3835-43. doi: 10.1093/hmg/ddq302. Epub 2010 Jul 22.
• [3] Exploring lithium's transcriptional mechanisms of action in bipolar disorder: a multi-step study.Neuropsychopharmacology. 2020 May;45(6):947-955. doi: 10.1038/s41386-019-0556-8. Epub 2019 Oct 25.
• [4] High incidence of genotypic variance between sequential herpes simplex virus type 2 isolates from HIV-1-seropositive patients with recurrent genital herpes.J Infect Dis. 2006 Oct 15;194(8):1115-8. doi: 10.1086/507683. Epub 2006 Sep 8.
• [5] Dysregulated COL3A1 and RPL8, RPS16, and RPS23 in Disc Degeneration Revealed by Bioinformatics Methods.Spine (Phila Pa 1976). 2015 Jul 1;40(13):E745-51. doi: 10.1097/BRS.0000000000000939.
• [6] A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism.Am J Hum Genet. 2017 Mar 2;100(3):506-522. doi: 10.1016/j.ajhg.2017.01.034.
• [7] Structural Abnormalities in the Hair of a Patient with a Novel Ribosomopathy. PLoS One. 2016 Mar 16;11(3):e0149619. doi: 10.1371/journal.pone.0149619. eCollection 2016.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [16] 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.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.