Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT51TIMY)

• DOT Name: Ribosome-releasing factor 2, mitochondrial (GFM2)
• Synonyms: RRF2mt; EC 3.6.5.-; Elongation factor G 2, mitochondrial; EF-G2mt; mEF-G 2; Elongation factor G2; hEFG2
• Gene Name: GFM2
• Related Disease:
  Mitochondrial disease
  Cytochrome-c oxidase deficiency disease
  MELAS syndrome
  Mitochondrial trifunctional protein deficiency
  Myopathy
  Combined oxidative phosphorylation deficiency 39
  Leigh syndrome
  Arthrogryposis
• UniProt ID: RRF2M_HUMAN
• PDB ID: 7L20; 7NSH
• EC Number: 3.6.5.-
• Pfam ID: PF00679 ; PF14492 ; PF03764 ; PF00009 ; PF03144
• Sequence:
  MLTNLRIFAMSHQTIPSVYINNICCYKIRASLKRLKPHVPLGRNCSSLPGLIGNDIKSLH
  SIINPPIAKIRNIGIMAHIDAGKTTTTERILYYSGYTRSLGDVDDGDTVTDFMAQERERG
  ITIQSAAVTFDWKGYRVNLIDTPGHVDFTLEVERCLRVLDGAVAVFDASAGVEAQTLTVW
  RQADKHNIPRICFLNKMDKTGASFKYAVESIREKLKAKPLLLQLPIGEAKTFKGVVDVVM
  KEKLLWNCNSNDGKDFERKPLLEMNDPELLKETTEARNALIEQVADLDDEFADLVLEEFS
  ENFDLLPAEKLQTAIHRVTLAQTAVPVLCGSALKNKGIQPLLDAVTMYLPSPEERNYEFL
  QWYKDDLCALAFKVLHDKQRGPLVFMRIYSGTIKPQLAIHNINGNCTERISRLLLPFADQ
  HVEIPSLTAGNIALTVGLKHTATGDTIVSSKSSALAAARRAEREGEKKHRQNNEAERLLL
  AGVEIPEPVFFCTIEPPSLSKQPDLEHALKCLQREDPSLKVRLDPDSGQTVLCGMGELHI
  EIIHDRIKREYGLETYLGPLQVAYRETILNSVRATDTLDRTLGDKRHLVTVEVEARPIET
  SSVMPVIEFEYAESINEGLLKVSQEAIENGIHSACLQGPLLGSPIQDVAITLHSLTIHPG
  TSTTMISACVSRCVQKALKKADKQVLEPLMNLEVTVARDYLSPVLADLAQRRGNIQEIQT
  RQDNKVVIGFVPLAEIMGYSTVLRTLTSGSATFALELSTYQAMNPQDQNTLLNRRSGLT
• Function: Mitochondrial GTPase that mediates the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis. Acts in collaboration with MRRF. Promotes mitochondrial ribosome recycling by dissolution of intersubunit contacts. GTP hydrolysis follows the ribosome disassembly and probably occurs on the ribosome large subunit. Not involved in the GTP-dependent ribosomal translocation step during translation elongation.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: Mitochondrial translation termination (R-HSA-5419276)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Genetic Variation	[1]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Biomarker	[2]
MELAS syndrome	DIS81Z3S	Strong	Genetic Variation	[3]
Mitochondrial trifunctional protein deficiency	DIS2MYYR	Strong	Altered Expression	[4]
Myopathy	DISOWG27	Strong	Altered Expression	[5]
Combined oxidative phosphorylation deficiency 39	DIS4OJ40	Moderate	Autosomal recessive	[6]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[7]
Arthrogryposis	DISC81CM	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	Ribosome-releasing factor 2, mitochondrial (GFM2) affects the response to substance of Josamycin.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ribosome-releasing factor 2, mitochondrial (GFM2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribosome-releasing factor 2, mitochondrial (GFM2).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Ribosome-releasing factor 2, mitochondrial (GFM2).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Ribosome-releasing factor 2, mitochondrial (GFM2).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Ribosome-releasing factor 2, mitochondrial (GFM2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ribosome-releasing factor 2, mitochondrial (GFM2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ribosome-releasing factor 2, mitochondrial (GFM2).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ribosome-releasing factor 2, mitochondrial (GFM2).	[16]

References

• [1] Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits.Neurogenetics. 2017 Dec;18(4):227-235. doi: 10.1007/s10048-017-0526-4. Epub 2017 Oct 26.
• [2] Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene.Neuromuscul Disord. 2008 Jun;18(6):453-9. doi: 10.1016/j.nmd.2008.04.006. Epub 2008 May 27.
• [3] The A3243G tRNALeu(UUR) MELAS mutation causes amino acid misincorporation and a combined respiratory chain assembly defect partially suppressed by overexpression of EFTu and EFG2.Hum Mol Genet. 2008 Dec 1;17(23):3697-707. doi: 10.1093/hmg/ddn265. Epub 2008 Aug 27.
• [4] A diagnostic algorithm for metabolic myopathies.Curr Neurol Neurosci Rep. 2010 Mar;10(2):118-26. doi: 10.1007/s11910-010-0096-4.
• [5] Abnormal levels of human mitochondrial transcription factor A in skeletal muscle in mitochondrial encephalomyopathies.Neurol Sci. 2000;21(5 Suppl):S985-7. doi: 10.1007/s100720070017.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] 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.
• [8] Compound heterozygous GFM2 mutations with Leigh syndrome complicated by arthrogryposis multiplex congenita.J Hum Genet. 2015 Sep;60(9):509-13. doi: 10.1038/jhg.2015.57. Epub 2015 May 28.
• [9] 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.
• [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] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.