Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT27ZC26)

• DOT Name: Large ribosomal subunit protein mL44 (MRPL44)
• Synonyms: EC 3.1.26.-; 39S ribosomal protein L44, mitochondrial; L44mt; MRP-L44
• Gene Name: MRPL44
• Related Disease:
  Asthma
  Mitochondrial disease
  Cytochrome-c oxidase deficiency disease
  Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency
  Hypertrophic cardiomyopathy
  Thyroid gland papillary carcinoma
• UniProt ID: RM44_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
• EC Number: 3.1.26.-
• Sequence:
  MASGLVRLLQQGHRCLLAPVAPKLVPPVRGVKKGFRAAFRFQKELERQRLLRCPPPPVRR
  SEKPNWDYHAEIQAFGHRLQENFSLDLLKTAFVNSCYIKSEEAKRQQLGIEKEAVLLNLK
  SNQELSEQGTSFSQTCLTQFLEDEYPDMPTEGIKNLVDFLTGEEVVCHVARNLAVEQLTL
  SEEFPVPPAVLQQTFFAVIGALLQSSGPERTALFIRDFLITQMTGKELFEMWKIINPMGL
  LVEELKKRNVSAPESRLTRQSGGTTALPLYFVGLYCDKKLIAEGPGETVLVAEEEAARVA
  LRKLYGFTENRRPWNYSKPKETLRAEKSITAS
• Function: Component of the 39S subunit of mitochondrial ribosome. May have a function in the assembly/stability of nascent mitochondrial polypeptides exiting the ribosome.
• 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Definitive	Biomarker	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Altered Expression	[3]
Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency	DISJC8N8	Strong	Autosomal recessive	[3]
Hypertrophic cardiomyopathy	DISQG2AI	Limited	Genetic Variation	[4]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[5]

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 Large ribosomal subunit protein mL44 (MRPL44).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Large ribosomal subunit protein mL44 (MRPL44).	[13]

8 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 Large ribosomal subunit protein mL44 (MRPL44).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Large ribosomal subunit protein mL44 (MRPL44).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Large ribosomal subunit protein mL44 (MRPL44).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Large ribosomal subunit protein mL44 (MRPL44).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Large ribosomal subunit protein mL44 (MRPL44).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Large ribosomal subunit protein mL44 (MRPL44).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Large ribosomal subunit protein mL44 (MRPL44).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Large ribosomal subunit protein mL44 (MRPL44).	[14]

References

• [1] Exploring rare and low-frequency variants in the Saguenay-Lac-Saint-Jean population identified genes associated with asthma and allergy traits.Eur J Hum Genet. 2019 Jan;27(1):90-101. doi: 10.1038/s41431-018-0266-4. Epub 2018 Sep 11.
• [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] Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy. J Med Genet. 2013 Mar;50(3):151-9. doi: 10.1136/jmedgenet-2012-101375. Epub 2013 Jan 12.
• [4] MRPL44 mutations cause a slowly progressive multisystem disease with childhood-onset hypertrophic cardiomyopathy.Neurogenetics. 2015 Oct;16(4):319-23. doi: 10.1007/s10048-015-0444-2. Epub 2015 Mar 24.
• [5] A metabolic phenotype based on mitochondrial ribosomal protein expression as a predictor of lymph node metastasis in papillary thyroid carcinoma.Medicine (Baltimore). 2015 Jan;94(2):e380. doi: 10.1097/MD.0000000000000380.
• [6] 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.
• [7] 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.
• [8] 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.
• [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] 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.
• [11] 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.
• [12] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.