Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7P9V67)

• DOT Name: Small ribosomal subunit protein mS34 (MRPS34)
• Synonyms: 28S ribosomal protein S34, mitochondrial; MRP-S34; S34mt
• Gene Name: MRPS34
• Related Disease:
  Combined oxidative phosphorylation deficiency 32
  Leigh syndrome
• UniProt ID: RT34_HUMAN
• PDB ID: 3J9M ; 6NU2 ; 6RW4 ; 6RW5 ; 6VLZ ; 6VMI ; 6ZM5 ; 6ZM6 ; 6ZS9 ; 6ZSA ; 6ZSB ; 6ZSC ; 6ZSD ; 6ZSE ; 6ZSG ; 7A5F ; 7A5G ; 7A5I ; 7A5K ; 7L08 ; 7OG4 ; 7P2E ; 7PNX ; 7PNY ; 7PNZ ; 7PO0 ; 7PO1 ; 7PO2 ; 7PO3 ; 7QI4 ; 7QI5 ; 7QI6 ; 8ANY ; 8CSP ; 8CSQ ; 8CSR ; 8CSS ; 8CST ; 8CSU ; 8OIR ; 8OIS
• Pfam ID: PF16053
• Sequence:
  MARKKVRPRLIAELARRVRALREQLNRPRDSQLYAVDYETLTRPFSGRRLPVRAWADVRR
  ESRLLQLLGRLPLFGLGRLVTRKSWLWQHDEPCYWRLTRVRPDYTAQNLDHGKAWGILTF
  KGKTESEAREIEHVMYHDWRLVPKHEEEAFTAFTPAPEDSLASVPYPPLLRAMIIAERQK
  NGDTSTEEPMLNVQRIRMEPWDYPAKQEDKGRAKGTPV
• Function: Required for mitochondrial translation, plays a role in maintaining the stability of the small ribosomal subunit and the 12S rRNA that are required for mitoribosome formation.
• Reactome Pathway:
  Mitochondrial translation elongation (R-HSA-5389840)
  Mitochondrial translation termination (R-HSA-5419276)
  Mitochondrial translation initiation (R-HSA-5368286)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined oxidative phosphorylation deficiency 32	DISHJMNW	Strong	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Small ribosomal subunit protein mS34 (MRPS34).	[3]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Small ribosomal subunit protein mS34 (MRPS34).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Small ribosomal subunit protein mS34 (MRPS34).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Small ribosomal subunit protein mS34 (MRPS34).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Small ribosomal subunit protein mS34 (MRPS34).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Small ribosomal subunit protein mS34 (MRPS34).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Small ribosomal subunit protein mS34 (MRPS34).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small ribosomal subunit protein mS34 (MRPS34).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Small ribosomal subunit protein mS34 (MRPS34).	[11]

References

• [1] Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome. Am J Hum Genet. 2017 Aug 3;101(2):239-254. doi: 10.1016/j.ajhg.2017.07.005.
• [2] 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.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.