Details of Drug Off-Target (DOT)

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

• DOT Name: tRNA (TRMT5)
• Synonyms: guanine(37)-N1)-methyltransferase (EC 2.1.1.228; M1G-methyltransferase; tRNA methyltransferase; tRNA methyltransferase 5 homolog
• Gene Name: TRMT5
• Related Disease:
  Mitochondrial disease
  Combined oxidative phosphorylation defect type 26
  Tuberculosis
• UniProt ID: TRM5_HUMAN
• EC Number: 2.1.1.228
• Pfam ID: PF02475
• Sequence:
  MVLWILWRPFGFSGRFLKLESHSITESKSLIPVAWTSLTQMLLEAPGIFLLGQRKRFSTM
  PETETHERETELFSPPSDVRGMTKLDRTAFKKTVNIPVLKVRKEIVSKLMRSLKRAALQR
  PGIRRVIEDPEDKESRLIMLDPYKIFTHDSFEKAELSVLEQLNVSPQISKYNLELTYEHF
  KSEEILRAVLPEGQDVTSGFSRIGHIAHLNLRDHQLPFKHLIGQVMIDKNPGITSAVNKI
  NNIDNMYRNFQMEVLSGEQNMMTKVRENNYTYEFDFSKVYWNPRLSTEHSRITELLKPGD
  VLFDVFAGVGPFAIPVAKKNCTVFANDLNPESHKWLLYNCKLNKVDQKVKVFNLDGKDFL
  QGPVKEELMQLLGLSKERKPSVHVVMNLPAKAIEFLSAFKWLLDGQPCSSEFLPIVHCYS
  FSKDANPAEDVRQRAGAVLGISLEACSSVHLVRNVAPNKEMLCITFQIPASVLYKNQTRN
  PENHEDPPLKRQRTAEAFSDEKTQIVSNT
• Function: Involved in mitochondrial tRNA methylation. Specifically methylates the N1 position of guanosine-37 in various tRNAs. Methylation is not dependent on the nature of the nucleoside 5' of the target nucleoside. This is the first step in the biosynthesis of wybutosine (yW), a modified base adjacent to the anticodon of tRNAs and required for accurate decoding.
• Reactome Pathway: Synthesis of wybutosine at G37 of tRNA(Phe) (R-HSA-6782861)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Combined oxidative phosphorylation defect type 26	DIS6RJZV	Strong	Autosomal recessive	[2]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	tRNA (TRMT5) increases the response to substance of Arsenic trioxide.	[11]
Vinblastine	DM5TVS3	Approved	tRNA (TRMT5) affects the response to substance of Vinblastine.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of tRNA (TRMT5).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of tRNA (TRMT5).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA (TRMT5).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of tRNA (TRMT5).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of tRNA (TRMT5).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of tRNA (TRMT5).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of tRNA (TRMT5).	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of tRNA (TRMT5).	[10]

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] TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies. Am J Hum Genet. 2015 Aug 6;97(2):319-28. doi: 10.1016/j.ajhg.2015.06.011. Epub 2015 Jul 16.
• [3] Discovery and validation of a prognostic proteomic signature for tuberculosis progression: A prospective cohort study.PLoS Med. 2019 Apr 16;16(4):e1002781. doi: 10.1371/journal.pmed.1002781. eCollection 2019 Apr.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] 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.
• [9] 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.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [12] 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.