Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4WV1WL)

• DOT Name: Large ribosomal subunit protein uL3m (MRPL3)
• Synonyms: 39S ribosomal protein L3, mitochondrial; L3mt; MRP-L3
• Gene Name: MRPL3
• Related Disease:
  Colon carcinoma
  Combined oxidative phosphorylation defect type 9
  Mitochondrial disease
  Hypertrophic cardiomyopathy
• UniProt ID: RM03_HUMAN
• PDB ID: 3J7Y ; 3J9M ; 5OOL ; 5OOM ; 6I9R ; 6NU2 ; 6NU3 ; 6VLZ ; 6VMI ; 6ZM5 ; 6ZM6 ; 6ZS9 ; 6ZSA ; 6ZSB ; 6ZSC ; 6ZSD ; 6ZSE ; 6ZSG ; 7A5F ; 7A5G ; 7A5H ; 7A5I ; 7A5J ; 7A5K ; 7L08 ; 7L20 ; 7O9K ; 7O9M ; 7ODR ; 7ODS ; 7ODT ; 7OF0 ; 7OF2 ; 7OF3 ; 7OF4 ; 7OF5 ; 7OF6 ; 7OF7 ; 7OG4 ; 7OI6 ; 7OI7 ; 7OI8 ; 7OI9 ; 7OIA ; 7OIB ; 7OIC ; 7OID ; 7OIE ; 7PD3 ; 7PO4 ; 7QH6 ; 7QH7 ; 7QI4 ; 7QI5 ; 7QI6 ; 8ANY ; 8OIR ; 8OIT
• Pfam ID: PF00297
• Sequence:
  MPGWRLLTQVGAQVLGRLGDGLGAALGPGNRTHIWLFVRGLHGKSGTWWDEHLSEENVPF
  IKQLVSDEDKAQLASKLCPLKDEPWPIHPWEPGSFRVGLIALKLGMMPLWTKDGQKHVVT
  LLQVQDCHVLKYTSKENCNGKMATLSVGGKTVSRFRKATSILEFYRELGLPPKQTVKIFN
  ITDNAAIKPGTPLYAAHFRPGQYVDVTAKTIGKGFQGVMKRWGFKGQPATHGQTKTHRRP
  GAVATGDIGRVWPGTKMPGKMGNIYRTEYGLKVWRINTKHNIIYVNGSVPGHKNCLVKVK
  DSKLPAYKDLGKNLPFPTYFPDGDEEELPEDLYDENVCQPGAPSITFA
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[1]
Combined oxidative phosphorylation defect type 9	DISX0BGN	Strong	Autosomal recessive	[2]
Mitochondrial disease	DISKAHA3	Moderate	Autosomal recessive	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Large ribosomal subunit protein uL3m (MRPL3).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Large ribosomal subunit protein uL3m (MRPL3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Large ribosomal subunit protein uL3m (MRPL3).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Large ribosomal subunit protein uL3m (MRPL3).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Large ribosomal subunit protein uL3m (MRPL3).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Large ribosomal subunit protein uL3m (MRPL3).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Large ribosomal subunit protein uL3m (MRPL3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Large ribosomal subunit protein uL3m (MRPL3).	[12]

References

• [1] Cloning and characterization of a human ribosomal protein gene with enhanced expression in fetal and neoplastic cells.Nucleic Acids Res. 1987 Nov 11;15(21):8919-34. doi: 10.1093/nar/15.21.8919.
• [2] Active-site mutants altering the cooperativity of E. coli phosphofructokinase. Nature. 1990 Feb 8;343(6258):575-6. doi: 10.1038/343575a0.
• [3] 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.
• [4] Exome sequencing identifies MRPL3 mutation in mitochondrial cardiomyopathy.Hum Mutat. 2011 Nov;32(11):1225-31. doi: 10.1002/humu.21562. Epub 2011 Sep 14.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [11] 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.
• [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.