Details of Drug Off-Target (DOT)

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

• DOT Name: Dimethyladenosine transferase 1, mitochondrial (TFB1M)
• Synonyms: EC 2.1.1.-; Mitochondrial 12S rRNA dimethylase 1; Mitochondrial transcription factor B1; h-mtTFB; h-mtTFB1; hTFB1M; mtTFB1; S-adenosylmethionine-6-N', N'-adenosyl(rRNA) dimethyltransferase 1
• Gene Name: TFB1M
• Related Disease:
  Astrocytoma
  Non-insulin dependent diabetes
  Type-1/2 diabetes
• UniProt ID: TFB1M_HUMAN
• PDB ID: 6AAX; 6AJK; 8CSP; 8CSQ; 8CSR; 8CSU
• EC Number: 2.1.1.-
• Pfam ID: PF00398
• Sequence:
  MAASGKLSTCRLPPLPTIREIIKLLRLQAAKQLSQNFLLDLRLTDKIVRKAGNLTNAYVY
  EVGPGPGGITRSILNADVAELLVVEKDTRFIPGLQMLSDAAPGKLRIVHGDVLTFKVEKA
  FSESLKRPWEDDPPNVHIIGNLPFSVSTPLIIKWLENISCRDGPFVYGRTQMTLTFQKEV
  AERLAANTGSKQRSRLSVMAQYLCNVRHIFTIPGQAFVPKPEVDVGVVHFTPLIQPKIEQ
  PFKLVEKVVQNVFQFRRKYCHRGLRMLFPEAQRLESTGRLLELADIDPTLRPRQLSISHF
  KSLCDVYRKMCDEDPQLFAYNFREELKRRKSKNEEKEEDDAENYRL
• Function: S-adenosyl-L-methionine-dependent methyltransferase which specifically dimethylates mitochondrial 12S rRNA at the conserved stem loop. Also required for basal transcription of mitochondrial DNA, probably via its interaction with POLRMT and TFAM. Stimulates transcription independently of the methyltransferase activity.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway:
  rRNA modification in the mitochondrion (R-HSA-6793080)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Astrocytoma	DISL3V18	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[2]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Dimethyladenosine transferase 1, mitochondrial (TFB1M) affects the response to substance of Cisplatin.	[18]

3 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 Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[15]

11 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 Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[11]
Teriflunomide	DMQ2FKJ	Approved	Teriflunomide decreases the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[16]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Dimethyladenosine transferase 1, mitochondrial (TFB1M).	[17]

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] Transcribing -cell mitochondria in health and disease.Mol Metab. 2017 May 31;6(9):1040-1051. doi: 10.1016/j.molmet.2017.05.014. eCollection 2017 Sep.
• [3] Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes.Hum Mol Genet. 2014 Nov 1;23(21):5733-49. doi: 10.1093/hmg/ddu288. Epub 2014 Jun 10.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] 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.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] 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.
• [12] Mitochondrial dysfunction induced by leflunomide and its active metabolite. Toxicology. 2018 Mar 1;396-397:33-45.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [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] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.