Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLBKU22)

• DOT Name: tRNA (NSUN3)
• Synonyms: cytosine(34)-C(5))-methyltransferase, mitochondrial (EC 2.1.1.-; NOL1/NOP2/Sun domain family member 3
• Gene Name: NSUN3
• Related Disease:
  Lung adenocarcinoma
  Combined oxidative phosphorylation deficiency 48
• UniProt ID: NSUN3_HUMAN
• EC Number: 2.1.1.-
• Pfam ID: PF01189
• Sequence:
  MLTQLKAKSEGKLAKQICKVVLDHFEKQYSKELGDAWNTVREILTSPSCWQYAVLLNRFN
  YPFELEKDLHLKGYHTLSQGSLPNYPKSVKCYLSRTPGRIPSERHQIGNLKKYYLLNAAS
  LLPVLALELRDGEKVLDLCAAPGGKSIALLQCACPGYLHCNEYDSLRLRWLRQTLESFIP
  QPLINVIKVSELDGRKMGDAQPEMFDKVLVDAPCSNDRSWLFSSDSQKASCRISQRRNLP
  LLQIELLRSAIKALRPGGILVYSTCTLSKAENQDVISEILNSHGNIMPMDIKGIARTCSH
  DFTFAPTGQECGLLVIPDKGKAWGPMYVAKLKKSWSTGKW
• Function: Mitochondrial tRNA methyltransferase that mediates methylation of cytosine to 5-methylcytosine (m5C) at position 34 of mt-tRNA(Met). mt-tRNA(Met) methylation at cytosine(34) takes place at the wobble position of the anticodon and initiates the formation of 5-formylcytosine (f(5)c) at this position. mt-tRNA(Met) containing the f(5)c modification at the wobble position enables recognition of the AUA codon in addition to the AUG codon, expanding codon recognition in mitochondrial translation.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[1]
Combined oxidative phosphorylation deficiency 48	DISMZY3E	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of tRNA (NSUN3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of tRNA (NSUN3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA (NSUN3).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of tRNA (NSUN3).	[7]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of tRNA (NSUN3).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of tRNA (NSUN3).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of tRNA (NSUN3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of tRNA (NSUN3).	[12]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of tRNA (NSUN3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of tRNA (NSUN3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of tRNA (NSUN3).	[10]

References

• [1] Genomic aberrations in lung adenocarcinoma in never smokers.PLoS One. 2010 Dec 6;5(12):e15145. doi: 10.1371/journal.pone.0015145.
• [2] Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a patient carrying mutations in NSUN3. Nat Commun. 2016 Jun 30;7:12039. doi: 10.1038/ncomms12039.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] 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.
• [6] 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.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.