Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU41AM0)

• DOT Name: Large ribosomal subunit protein bL12m (MRPL12)
• Synonyms: 39S ribosomal protein L12, mitochondrial; L12mt; MRP-L12; 5c5-2
• Gene Name: MRPL12
• Related Disease:
  Lung adenocarcinoma
  Non-insulin dependent diabetes
  Combined oxidative phosphorylation deficiency 45
• UniProt ID: RM12_HUMAN
• PDB ID: 6VLZ; 6VMI; 6ZM5; 6ZM6; 6ZS9; 6ZSA; 6ZSB; 6ZSC; 6ZSD; 6ZSE; 6ZSG; 7L08; 7L20; 7O9K; 7O9M; 7OG4; 7PO2; 7PO4; 7QI4; 7QI5; 7QI6; 8ANY; 8OIR; 8OIT
• Pfam ID: PF00542 ; PF16320
• Sequence:
  MLPAAARPLWGPCLGLRAAAFRLARRQVPCVCAVRHMRSSGHQRCEALAGAPLDNAPKEY
  PPKIQQLVQDIASLTLLEISDLNELLKKTLKIQDVGLVPMGGVMSGAVPAAAAQEAVEED
  IPIAKERTHFTVRLTEAKPVDKVKLIKEIKNYIQGINLVQAKKLVESLPQEIKANVAKAE
  AEKIKAALEAVGGTVVLE
• Function: As a component of the mitochondrial large ribosomal subunit, it plays a role in mitochondrial translation. Associates with mitochondrial RNA polymerase to activate transcription.
• KEGG Pathway: Ribosome (hsa03010)
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[2]
Combined oxidative phosphorylation deficiency 45	DIS9YQPN	Limited	Unknown	[3]

1 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 Large ribosomal subunit protein bL12m (MRPL12).	[4]

13 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 Large ribosomal subunit protein bL12m (MRPL12).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Large ribosomal subunit protein bL12m (MRPL12).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Large ribosomal subunit protein bL12m (MRPL12).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Large ribosomal subunit protein bL12m (MRPL12).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Large ribosomal subunit protein bL12m (MRPL12).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Large ribosomal subunit protein bL12m (MRPL12).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Large ribosomal subunit protein bL12m (MRPL12).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Large ribosomal subunit protein bL12m (MRPL12).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Large ribosomal subunit protein bL12m (MRPL12).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Large ribosomal subunit protein bL12m (MRPL12).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Large ribosomal subunit protein bL12m (MRPL12).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Large ribosomal subunit protein bL12m (MRPL12).	[15]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Large ribosomal subunit protein bL12m (MRPL12).	[16]

References

• [1] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [2] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [3] Mutations in mitochondrial ribosomal protein MRPL12 leads to growth retardation, neurological deterioration and mitochondrial translation deficiency. Biochim Biophys Acta. 2013 Aug;1832(8):1304-12. doi: 10.1016/j.bbadis.2013.04.014. Epub 2013 Apr 18.
• [4] 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.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [15] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [16] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.