Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG9DUU1)

• DOT Name: Dimethyladenosine transferase 2, mitochondrial (TFB2M)
• Synonyms: EC 2.1.1.-; Hepatitis C virus NS5A-transactivated protein 5; HCV NS5A-transactivated protein 5; Mitochondrial 12S rRNA dimethylase 2; Mitochondrial transcription factor B2; h-mtTFB; h-mtTFB2; hTFB2M; mtTFB2; S-adenosylmethionine-6-N', N'-adenosyl(rRNA) dimethyltransferase 2
• Gene Name: TFB2M
• Related Disease:
  Astrocytoma
  Autism spectrum disorder
  Autosomal dominant optic atrophy, classic form
  Pervasive developmental disorder
• UniProt ID: TFB2M_HUMAN
• PDB ID: 6ERO; 6ERP; 6ERQ
• EC Number: 2.1.1.-
• Pfam ID: PF00398
• Sequence:
  MWIPVVGLPRRLRLSALAGAGRFCILGSEAATRKHLPARNHCGLSDSSPQLWPEPDFRNP
  PRKASKASLDFKRYVTDRRLAETLAQIYLGKPSRPPHLLLECNPGPGILTQALLEAGAKV
  VALESDKTFIPHLESLGKNLDGKLRVIHCDFFKLDPRSGGVIKPPAMSSRGLFKNLGIEA
  VPWTADIPLKVVGMFPSRGEKRALWKLAYDLYSCTSIYKFGRIEVNMFIGEKEFQKLMAD
  PGNPDLYHVLSVIWQLACEIKVLHMEPWSSFDIYTRKGPLENPKRRELLDQLQQKLYLIQ
  MIPRQNLFTKNLTPMNYNIFFHLLKHCFGRRSATVIDHLRSLTPLDARDILMQIGKQEDE
  KVVNMHPQDFKTLFETIERSKDCAYKWLYDETLEDR
• Function: S-adenosyl-L-methionine-dependent rRNA methyltransferase which may methylate two specific adjacent adenosines in the loop of a conserved hairpin near the 3'-end of 12S mitochondrial rRNA (Probable). Component of the mitochondrial transcription initiation complex, composed at least of TFB2M, TFAM and POLRMT that is required for basal transcription of mitochondrial DNA. In this complex, TFAM recruits POLRMT to a specific promoter whereas TFB2M induces structural changes in POLRMT to enable promoter opening and trapping of the DNA non-template strand. Stimulates transcription independently of the methyltransferase activity.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway:
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Mitochondrial transcription initiation (R-HSA-163282)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Astrocytoma	DISL3V18	Strong	Biomarker	[1]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[2]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Biomarker	[3]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[2]

12 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 Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[12]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Dimethyladenosine transferase 2, mitochondrial (TFB2M).	[14]

References

• [1] Mitochondrial DNA depletion and its correlation with TFAM, TFB1M, TFB2M and POLG in human diffusely infiltrating astrocytomas.Mitochondrion. 2011 Jan;11(1):48-53. doi: 10.1016/j.mito.2010.07.001. Epub 2010 Jul 17.
• [2] Identification of a rare homozygous c.790C>T variation in the TFB2M gene in Korean patients with autism spectrum disorder.Biochem Biophys Res Commun. 2018 Dec 9;507(1-4):148-154. doi: 10.1016/j.bbrc.2018.10.194. Epub 2018 Nov 7.
• [3] Testosterone induces up-regulation of mitochondrial gene expression in murine C2C12 skeletal muscle cells accompanied by an increase of nuclear respiratory factor-1 and its downstream effectors.Mol Cell Endocrinol. 2020 Jan 15;500:110631. doi: 10.1016/j.mce.2019.110631. Epub 2019 Oct 30.
• [4] 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.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] 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.
• [13] Plasmatic concentration of organochlorine lindane acts as metabolic disruptors in HepG2 liver cell line by inducing mitochondrial disorder. Toxicol Appl Pharmacol. 2013 Oct 15;272(2):325-34.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.