Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ5AKN4)

• DOT Name: tRNA methyltransferase 10 homolog A (TRMT10A)
• Synonyms: EC 2.1.1.221; RNA (guanine-9-)-methyltransferase domain-containing protein 2; tRNA (guanine(9)-N(1))-methyltransferase TRMT10A
• Gene Name: TRMT10A
• Related Disease:
  Intellectual developmental disorder, autosomal recessive 68
  Epilepsy
  Intellectual disability
  Isolated congenital microcephaly
  Microcephaly, short stature, and impaired glucose metabolism 1
  Non-insulin dependent diabetes
  Type-1/2 diabetes
  Primary microcephaly-mild intellectual disability-young-onset diabetes syndrome
• UniProt ID: TM10A_HUMAN
• PDB ID: 4FMW
• EC Number: 2.1.1.221
• Pfam ID: PF01746
• Sequence:
  MSSEMLPAFIETSNVDKKQGINEDQEESQKPRLGEGCEPISKRQMKKLIKQKQWEEQREL
  RKQKRKEKRKRKKLERQCQMEPNSDGHDRKRVRRDVVHSTLRLIIDCSFDHLMVLKDIKK
  LHKQIQRCYAENRRALHPVQFYLTSHGGQLKKNMDENDKGWVNWKDIHIKPEHYSELIKK
  EDLIYLTSDSPNILKELDESKAYVIGGLVDHNHHKGLTYKQASDYGINHAQLPLGNFVKM
  NSRKVLAVNHVFEIILEYLETRDWQEAFFTILPQRKGAVPTDKACESASHDNQSVRMEEG
  GSDSDSSEEEYSRNELDSPHEEKQDKENHTESTVNSLPH
• Function: S-adenosyl-L-methionine-dependent guanine N(1)-methyltransferase that catalyzes the formation of N(1)-methylguanine at position 9 (m1G9) in tRNAs. Probably not able to catalyze formation of N(1)-methyladenine at position 9 (m1A9) in tRNAs.
• Tissue Specificity: Expressed in embryonic and fetal brain. It is expressed throughout the dorsal telencephalon at 8 and 11 weeks of gestation, with highest expression in ventricular zone and marginal zone. Detected in cerebellar cortex and nuclei, but not in dorsal telencephalon, at later stages.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual developmental disorder, autosomal recessive 68	DISGZW9I	Definitive	Autosomal recessive	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[2]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[3]
Microcephaly, short stature, and impaired glucose metabolism 1	DIS2GGUF	Strong	Autosomal recessive	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[2]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[3]
Primary microcephaly-mild intellectual disability-young-onset diabetes syndrome	DISUJDOX	Supportive	Autosomal recessive	[5]

7 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 methyltransferase 10 homolog A (TRMT10A).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of tRNA methyltransferase 10 homolog A (TRMT10A).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA methyltransferase 10 homolog A (TRMT10A).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of tRNA methyltransferase 10 homolog A (TRMT10A).	[10]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of tRNA methyltransferase 10 homolog A (TRMT10A).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of tRNA methyltransferase 10 homolog A (TRMT10A).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of tRNA methyltransferase 10 homolog A (TRMT10A).	[13]

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 increases the methylation of tRNA methyltransferase 10 homolog A (TRMT10A).	[9]

References

• [1] Case Report: Compound heterozygous nonsense mutations in TRMT10A are associated with microcephaly, delayed development, and periventricular white matter hyperintensities. F1000Res. 2015 Sep 28;4:912. doi: 10.12688/f1000research.7106.1. eCollection 2015.
• [2] tRNA methyltransferase homologue gene TRMT10A mutation in young adult-onset diabetes with intellectual disability, microcephaly and epilepsy.Diabet Med. 2016 Sep;33(9):e21-5. doi: 10.1111/dme.13024.
• [3] Pancreatic -cell tRNA hypomethylation and fragmentation link TRMT10A deficiency with diabetes.Nucleic Acids Res. 2018 Nov 2;46(19):10302-10318. doi: 10.1093/nar/gky839.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans. PLoS Genet. 2013 Oct;9(10):e1003888. doi: 10.1371/journal.pgen.1003888. Epub 2013 Oct 31.
• [6] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [7] 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.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] 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.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.