Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7HCZ1D)

• DOT Name: Protein MTO1 homolog, mitochondrial (MTO1)
• Gene Name: MTO1
• Related Disease:
  Mitochondrial disease
  Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
  Advanced cancer
  Cardiac failure
  Cardiomyopathy
  Cerebellar ataxia
  Congestive heart failure
  Deafness
  Hypertrophic cardiomyopathy
  Lactic acidosis
  Leigh syndrome
  Lung adenocarcinoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Lung cancer
  Lung carcinoma
• UniProt ID: MTO1_HUMAN
• Pfam ID: PF01134 ; PF13932 ; PF21680
• Sequence:
  MFYFRGCGRWVAVSFTKQQFPLARLSSDSAAPRTPHFDVIVIGGGHAGTEAATAAARCGS
  RTLLLTHRVDTIGQMSCNPSFGGIGKGHLMREVDALDGLCSRICDQSGVHYKVLNRRKGP
  AVWGLRAQIDRKLYKQNMQKEILNTPLLTVQEGAVEDLILTEPEPEHTGKCRVSGVVLVD
  GSTVYAESVILTTGTFLRGMIVIGLETHPAGRLGDQPSIGLAQTLEKLGFVVGRLKTGTP
  PRIAKESINFSILNKHIPDNPSIPFSFTNETVWIKPEDQLPCYLTHTNPRVDEIVLKNLH
  LNSHVKETTRGPRYCPSIESKVLRFPNRLHQVWLEPEGMDSDLIYPQGLSMTLPAELQEK
  MITCIRGLEKAKVIQPDGVLLLLPRMECNGAISAHHNLPLPGYGVQYDYLDPRQITPSLE
  THLVQRLFFAGQINGTTGYEEAAAQGVIAGINASLRVSRKPPFVVSRTEGYIGVLIDDLT
  TLGTSEPYRMFTSRVEFRLSLRPDNADSRLTLRGYKDAGCVSQQRYERACWMKSSLEEGI
  SVLKSIEFLSSKWKKLIPEASISTSRSLPVRALDVLKYEEVDMDSLAKAVPEPLKKYTKC
  RELAERLKIEATYESVLFHQLQEIKGVQQDEALQLPKDLDYLTIRDVSLSHEVREKLHFS
  RPQTIGAASRIPGVTPAAIINLLRFVKTTQRRQSAMNESSKTDQYLCDADRLQEREL
• Function: Involved in the 5-carboxymethylaminomethyl modification (mnm(5)s(2)U34) of the wobble uridine base in mitochondrial tRNAs.
• Tissue Specificity: Ubiquitously expressed in various tissues, but with a markedly elevated expression in tissues of high metabolic rates including cochlea.
• Reactome Pathway: tRNA modification in the mitochondrion (R-HSA-6787450)
• BioCyc Pathway: MetaCyc:ENSG00000135297-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency	DISOHOUN	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Cardiac failure	DISDC067	Strong	Genetic Variation	[4]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[5]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[6]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[4]
Deafness	DISKCLH4	Strong	Altered Expression	[7]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[6]
Lactic acidosis	DISZI1ZK	Strong	Biomarker	[6]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[8]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Prostate cancer	DISF190Y	Strong	Altered Expression	[10]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[10]
Breast cancer	DIS7DPX1	Limited	Biomarker	[11]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[12]
Esophageal squamous cell carcinoma	DIS5N2GV	Limited	Biomarker	[12]
Lung cancer	DISCM4YA	Limited	Biomarker	[12]
Lung carcinoma	DISTR26C	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein MTO1 homolog, mitochondrial (MTO1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein MTO1 homolog, mitochondrial (MTO1).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein MTO1 homolog, mitochondrial (MTO1).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Protein MTO1 homolog, mitochondrial (MTO1).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Protein MTO1 homolog, mitochondrial (MTO1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein MTO1 homolog, mitochondrial (MTO1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein MTO1 homolog, mitochondrial (MTO1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein MTO1 homolog, mitochondrial (MTO1).	[18]

References

• [1] 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.
• [2] Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. Am J Hum Genet. 2012 Jun 8;90(6):1079-87. doi: 10.1016/j.ajhg.2012.04.011. Epub 2012 May 17.
• [3] Nuclear-encoded mitochondrial MTO1 and MRPL41 are regulated in an opposite epigenetic mode based on estrogen receptor status in breast cancer.BMC Cancer. 2013 Oct 27;13:502. doi: 10.1186/1471-2407-13-502.
• [4] Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses.PLoS Genet. 2017 Jul 21;13(7):e1006921. doi: 10.1371/journal.pgen.1006921. eCollection 2017 Jul.
• [5] MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy.PLoS One. 2014 Dec 15;9(12):e114918. doi: 10.1371/journal.pone.0114918. eCollection 2014.
• [6] The genotypic and phenotypic spectrum of MTO1 deficiency.Mol Genet Metab. 2018 Jan;123(1):28-42. doi: 10.1016/j.ymgme.2017.11.003. Epub 2017 Nov 15.
• [7] Lack of a modulative factor in locus 8p23 in a Finnish family with nonsyndromic sensorineural hearing loss associated with the 1555A>G mitochondrial DNA mutation.Eur J Hum Genet. 2003 Sep;11(9):652-8. doi: 10.1038/sj.ejhg.5201017.
• [8] Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. Am J Hum Genet. 2014 Dec 4;95(6):708-20. doi: 10.1016/j.ajhg.2014.10.017. Epub 2014 Nov 26.
• [9] A regulatory circuit of circ-MTO1/miR-17/QKI-5 inhibits the proliferation of lung adenocarcinoma.Cancer Biol Ther. 2019;20(8):1127-1135. doi: 10.1080/15384047.2019.1598762. Epub 2019 Apr 12.
• [10] Circ-MTO1 correlates with favorable prognosis and inhibits cell proliferation, invasion as well as miR-17-5p expression in prostate cancer.J Clin Lab Anal. 2020 Mar;34(3):e23086. doi: 10.1002/jcla.23086. Epub 2019 Nov 11.
• [11] Circular RNAMTO1 suppresses breast cancer cell viability and reverses monastrol resistance through regulating the TRAF4/Eg5 axis.Int J Oncol. 2018 Oct;53(4):1752-1762. doi: 10.3892/ijo.2018.4485. Epub 2018 Jul 17.
• [12] The biogenesis and biological functions of circular RNAs and their molecular diagnostic values in cancers.J Clin Lab Anal. 2020 Jan;34(1):e23049. doi: 10.1002/jcla.23049. Epub 2019 Sep 25.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] 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.
• [15] 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.
• [16] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [17] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [18] 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.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.