Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ1KXM7)

• DOT Name: Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU)
• Synonyms: EC 2.8.1.14; MTO2 homolog
• Gene Name: TRMU
• Related Disease:
  Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins
  Acute liver failure
  Cardiomyopathy
  Liver cirrhosis
  MELAS syndrome
  Mitochondrial DNA depletion syndrome
  Leigh syndrome
  Mitochondrial myopathy with reversible cytochrome C oxidase deficiency
  Liver failure
• UniProt ID: MTU1_HUMAN
• EC Number: 2.8.1.14
• Pfam ID: PF03054 ; PF20258 ; PF20259
• Sequence:
  MQALRHVVCALSGGVDSAVAALLLRRRGYQVTGVFMKNWDSLDEHGVCTADKDCEDAYRV
  CQILDIPFHQVSYVKEYWNDVFSDFLNEYEKGRTPNPDIVCNKHIKFSCFFHYAVDNLGA
  DAIATGHYARTSLEDEEVFEQKHVKKPEGLFRNRFEVRNAVKLLQAADSFKDQTFFLSQV
  SQDALRRTIFPLGGLTKEFVKKIAAENRLHHVLQKKESMGMCFIGKRNFEHFLLQYLQPR
  PGHFISIEDNKVLGTHKGWFLYTLGQRANIGGLREPWYVVEKDSVKGDVFVAPRTDHPAL
  YRDLLRTSRVHWIAEEPPAALVRDKMMECHFRFRHQMALVPCVLTLNQDGTVWVTAVQAV
  RALATGQFAVFYKGDECLGSGKILRLGPSAYTLQKGQRRAGMATESPSDSPEDGPGLSPL
  L
• Function: Catalyzes the 2-thiolation of uridine at the wobble position (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln). Required for the formation of 5-taurinomethyl-2-thiouridine (tm5s2U) of mitochondrial tRNA(Lys), tRNA(Glu), and tRNA(Gln) at the wobble position. ATP is required to activate the C2 atom of the wobble base.
• Tissue Specificity: Ubiquitous. Abundantly expressed in tissues with high metabolic rates including heart, liver, kidney, and brain.
• Reactome Pathway: tRNA modification in the mitochondrion (R-HSA-6787450)
• BioCyc Pathway: MetaCyc:ENSG00000100416-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	DISRYQ0I	Strong	Autosomal recessive	[1]
Acute liver failure	DIS5EZKX	Strong	Genetic Variation	[2]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[3]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[2]
MELAS syndrome	DIS81Z3S	Strong	Altered Expression	[4]
Mitochondrial DNA depletion syndrome	DISIGZSM	Strong	Biomarker	[5]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[6]
Mitochondrial myopathy with reversible cytochrome C oxidase deficiency	DISW3XTC	Supportive	Mitochondrial	[7]
Liver failure	DISLGEL6	Limited	Genetic Variation	[4]

2 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 Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[14]

8 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 Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[16]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Mitochondrial tRNA-specific 2-thiouridylase 1 (TRMU).	[17]

References

• [1] 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.
• [2] Acute liver failure with subsequent cirrhosis as the primary manifestation of TRMU mutations.J Inherit Metab Dis. 2011 Feb;34(1):197-201. doi: 10.1007/s10545-010-9250-z. Epub 2010 Dec 10.
• [3] Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA. 2014 Jul 2;312(1):68-77. doi: 10.1001/jama.2014.7184.
• [4] The 2-thiouridylase function of the human MTU1 (TRMU) enzyme is dispensable for mitochondrial translation.Hum Mol Genet. 2011 Dec 1;20(23):4634-43. doi: 10.1093/hmg/ddr397. Epub 2011 Sep 1.
• [5] L-Cysteine supplementation prevents liver transplantation in a patient with TRMU deficiency.Mol Genet Metab Rep. 2019 Jan 25;19:100453. doi: 10.1016/j.ymgmr.2019.100453. eCollection 2019 Jun.
• [6] 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.
• [7] Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease. J Med Genet. 2011 Oct;48(10):660-668. doi: 10.1136/jmg.2011.089995.
• [8] 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.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] 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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.