Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCN4IQZ)

• DOT Name: tRNA wybutosine-synthesizing protein 2 homolog (TRMT12)
• Synonyms: tRNA-yW-synthesizing protein 2; EC 2.5.1.114; tRNA(Phe; 4-demethylwyosine(37)-C(7)) aminocarboxypropyltransferase
• Gene Name: TRMT12
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Neoplasm
• UniProt ID: TYW2_HUMAN
• EC Number: 2.5.1.114
• Pfam ID: PF02475
• Sequence:
  MRENVVVSNMERESGKPVAVVAVVTEPWFTQRYREYLQRQKLFDTQHRVEKMPDGSVALP
  VLGETLPEQHLQELRNRVAPGSPCMLTQLPDPVPSKRAQGCSPAQKLCLEVSRWVEGRGV
  KWSAELEADLPRSWQRHGNLLLLSEDCFQAKQWKNLGPELWETVALALGVQRLAKRGRVS
  PDGTRTPAVTLLLGDHGWVEHVDNGIRYKFDVTQCMFSFGNITEKLRVASLSCAGEVLVD
  LYAGIGYFTLPFLVHAGAAFVHACEWNPHAVVALRNNLEINGVADRCQIHFGDNRKLKLS
  NIADRVILGLIPSSEEGWPIACQVLRQDAGGILHIHQNVESFPGKNLQALGVSKVEKEHW
  LYPQQITTNQWKNGATRDSRGKMLSPATKPEWQRWAESAETRIATLLQQVHGKPWKTQIL
  HIQPVKSYAPHVDHIVLDLECCPCPSVG
• Function: S-adenosyl-L-methionine-dependent transferase that acts as a component of the wybutosine biosynthesis pathway. Wybutosine is a hyper modified guanosine with a tricyclic base found at the 3'-position adjacent to the anticodon of eukaryotic phenylalanine tRNA. Catalyzes the transfer of the alpha-amino-alpha-carboxypropyl (acp) group from S-adenosyl-L-methionine to the C-7 position of 4-demethylwyosine (imG-14) to produce wybutosine-86.
• Reactome Pathway: Synthesis of wybutosine at G37 of tRNA(Phe) (R-HSA-6782861)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of tRNA wybutosine-synthesizing protein 2 homolog (TRMT12).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA wybutosine-synthesizing protein 2 homolog (TRMT12).	[3]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of tRNA wybutosine-synthesizing protein 2 homolog (TRMT12).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA wybutosine-synthesizing protein 2 homolog (TRMT12).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of tRNA wybutosine-synthesizing protein 2 homolog (TRMT12).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of tRNA wybutosine-synthesizing protein 2 homolog (TRMT12).	[9]

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 wybutosine-synthesizing protein 2 homolog (TRMT12).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of tRNA wybutosine-synthesizing protein 2 homolog (TRMT12).	[8]

References

• [1] Chromosome 8 BAC array comparative genomic hybridization and expression analysis identify amplification and overexpression of TRMT12 in breast cancer.Genes Chromosomes Cancer. 2007 Jul;46(7):694-707. doi: 10.1002/gcc.20454.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] 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.
• [9] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.