Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7E09Y4)

• DOT Name: tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8)
• Synonyms: EC 2.1.1.-; Methyltransferase-like protein 8; mRNA N(3)-methylcytidine methyltransferase METTL8; EC 2.1.1.-
• Gene Name: METTL8
• Related Disease:
  Hepatocellular carcinoma
  Acute otitis media
  Adult teratoma
  Breast neoplasm
  Cystic fibrosis
  Joubert syndrome
  Neoplasm
  Otitis media
  Teratoma
  Advanced cancer
  Acute graft versus host disease
  Graft-versus-host disease
• UniProt ID: METL8_HUMAN
• EC Number: 2.1.1.-
• Pfam ID: PF08242
• Sequence:
  MNMIWRNSISCLRLGKVPHRYQSGYHPVAPLGSRILTDPAKVFEHNMWDHMQWSKEEEAA
  ARKKVKENSAVRVLLEEQVKYEREASKYWDTFYKIHKNKFFKDRNWLLREFPEILPVDQK
  PEEKARESSWDHVKTSATNRFSRMHCPTVPDEKNHYEKSSGSSEGQSKTESDFSNLDSEK
  HKKGPMETGLFPGSNATFRILEVGCGAGNSVFPILNTLENSPESFLYCCDFASGAVELVK
  SHSSYRATQCFAFVHDVCDDGLPYPFPDGILDVILLVFVLSSIHPDRTLFI
• Function: Mitochondrial S-adenosyl-L-methionine-dependent methyltransferase that mediates N(3)-methylcytidine modification of residue 32 of the tRNA anticodon loop of mitochondrial tRNA(Ser)(UCN) and tRNA(Thr). N(3)-methylcytidine methylation modification regulates mitochondrial translation efficiency and is required for activity of the respiratory chain. N(3)-methylcytidine methylation of mitochondrial tRNA(Ser)(UCN) requires the formation of N(6)-dimethylallyladenosine(37) (i6A37) by TRIT1 as prerequisite. May also mediate N(3)-methylcytidine modification of mRNAs. The existence of N(3)-methylcytidine modification on mRNAs is however unclear, and additional evidences are required to confirm the role of the N(3)-methylcytidine-specific mRNA methyltransferase activity of METTL8 in vivo.

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Acute otitis media	DISL8D8G	Strong	Biomarker	[2]
Adult teratoma	DISBY81U	Strong	Genetic Variation	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[5]
Joubert syndrome	DIS7P5CO	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Otitis media	DISGZDUO	Strong	Biomarker	[2]
Teratoma	DIS6ICY4	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Acute graft versus host disease	DIS8KLVM	Limited	Biomarker	[9]
Graft-versus-host disease	DIS0QADF	Limited	Biomarker	[9]

15 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 N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial (METTL8).	[23]

References

• [1] AlkB Homologue 1 Demethylates N(3)-Methylcytidine in mRNA of Mammals.ACS Chem Biol. 2019 Jul 19;14(7):1418-1425. doi: 10.1021/acschembio.8b01001. Epub 2019 Jun 24.
• [2] The "TIP algorithm" for the accurate diagnosis of pediatric otitis media.Int J Pediatr Otorhinolaryngol. 2019 Sep;124:185-189. doi: 10.1016/j.ijporl.2019.05.028. Epub 2019 May 27.
• [3] Surgical Management of Patients with Advanced Germ Cell Tumors Following Salvage Chemotherapy: Memorial Sloan Kettering Cancer Center (MSKCC) Experience.Urology. 2019 Feb;124:174-178. doi: 10.1016/j.urology.2018.09.024. Epub 2018 Oct 6.
• [4] #NAME?
• [5] Economic Evaluation of Tobramycin Inhalation Powder for the Treatment of Chronic Pulmonary Pseudomonas aeruginosa Infection in Patients with Cystic Fibrosis.Clin Drug Investig. 2017 Aug;37(8):795-805. doi: 10.1007/s40261-017-0537-9.
• [6] A CEP104-CSPP1 Complex Is Required for Formation of Primary Cilia Competent in Hedgehog Signaling.Cell Rep. 2019 Aug 13;28(7):1907-1922.e6. doi: 10.1016/j.celrep.2019.07.025.
• [7] TIP: A Web Server for Resolving Tumor Immunophenotype Profiling.Cancer Res. 2018 Dec 1;78(23):6575-6580. doi: 10.1158/0008-5472.CAN-18-0689. Epub 2018 Aug 28.
• [8] Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers.Pathol Oncol Res. 2018 Jul;24(3):617-622. doi: 10.1007/s12253-017-0287-2. Epub 2017 Aug 12.
• [9] TIP, a T-cell factor identified using high-throughput screening increases survival in a graft-versus-host disease model.Nat Biotechnol. 2003 Mar;21(3):302-7. doi: 10.1038/nbt797. Epub 2003 Feb 24.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [17] 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.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [20] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [21] 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.
• [22] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [23] 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.