Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3YR9B2)

• DOT Name: Protein-L-histidine N-pros-methyltransferase (METTL9)
• Synonyms: EC 2.1.1.-; DORA reverse strand protein; DREV; DREV1; Methyltransferase-like protein 9; hMETTL9
• Gene Name: METTL9
• Related Disease:
  Advanced cancer
  Carcinoma
  Cervical Intraepithelial neoplasia
  Colitis
  Dysplasia of cervix
  Human papillomavirus infection
  Lipodystrophy
  Major depressive disorder
  Neuralgia
  Non-insulin dependent diabetes
  Retinitis pigmentosa 9
  Type-1/2 diabetes
  Neoplasm
• UniProt ID: METL9_HUMAN
• PDB ID: 7Y9C; 7YF2; 7YF3; 7YF4; 8GZE; 8GZF
• EC Number: 2.1.1.-
• Pfam ID: PF05219
• Sequence:
  MRLLAGWLCLSLASVWLARRMWTLRSPLTRSLYVNMTSGPGGPAAAAGGRKENHQWYVCN
  REKLCESLQAVFVQSYLDQGTQIFLNNSIEKSGWLFIQLYHSFVSSVFSLFMSRTSINGL
  LGRGSMFVFSPDQFQRLLKINPDWKTHRLLDLGAGDGEVTKIMSPHFEEIYATELSETMI
  WQLQKKKYRVLGINEWQNTGFQYDVISCLNLLDRCDQPLTLLKDIRSVLEPTRGRVILAL
  VLPFHPYVENVGGKWEKPSEILEIKGQNWEEQVNSLPEVFRKAGFVIEAFTRLPYLCEGD
  MYNDYYVLDDAVFVLKPV
• Function: Protein-histidine N-methyltransferase that specifically catalyzes 1-methylhistidine (pros-methylhistidine) methylation of target proteins. Mediates methylation of proteins with a His-x-His (HxH) motif (where 'x' is preferably a small amino acid). Catalyzes methylation of target proteins such as S100A9, NDUFB3, SLC39A5, SLC39A7, ARMC6 and DNAJB12; 1-methylhistidine modification may affect the binding of zinc and other metals to its target proteins. Constitutes the main methyltransferase for the 1-methylhistidine modification in cell.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Altered Expression	[3]
Colitis	DISAF7DD	Strong	Altered Expression	[4]
Dysplasia of cervix	DISOAROS	Strong	Altered Expression	[3]
Human papillomavirus infection	DISX61LX	Strong	Biomarker	[2]
Lipodystrophy	DIS3SGVD	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Neuralgia	DISWO58J	Strong	Biomarker	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[8]
Retinitis pigmentosa 9	DISHLM3S	moderate	Genetic Variation	[9]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]

8 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 Protein-L-histidine N-pros-methyltransferase (METTL9).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein-L-histidine N-pros-methyltransferase (METTL9).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein-L-histidine N-pros-methyltransferase (METTL9).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein-L-histidine N-pros-methyltransferase (METTL9).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein-L-histidine N-pros-methyltransferase (METTL9).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein-L-histidine N-pros-methyltransferase (METTL9).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein-L-histidine N-pros-methyltransferase (METTL9).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Protein-L-histidine N-pros-methyltransferase (METTL9).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein-L-histidine N-pros-methyltransferase (METTL9).	[17]

References

• [1] Inhibitors of mitochondrial Kv1.3 channels induce Bax/Bak-independent death of cancer cells.EMBO Mol Med. 2012 Jul;4(7):577-93. doi: 10.1002/emmm.201200235. Epub 2012 Apr 11.
• [2] Detection of human papillomavirus DNA by the hybrid capture assay.Braz J Infect Dis. 2003 Apr;7(2):121-5. doi: 10.1590/s1413-86702003000200004. Epub 2003 Nov 19.
• [3] PCR-based high-risk HPV test in cervical cancer screening gives objective risk assessment of women with cytomorphologically normal cervical smears.Int J Cancer. 1996 Dec 11;68(6):766-9. doi: 10.1002/(SICI)1097-0215(19961211)68:6<766::AID-IJC13>3.0.CO;2-Z.
• [4] PAP-1 ameliorates DSS-induced colitis with involvement of NLRP3 inflammasome pathway.Int Immunopharmacol. 2019 Oct;75:105776. doi: 10.1016/j.intimp.2019.105776. Epub 2019 Jul 24.
• [5] Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns.J Biol Chem. 2007 Feb 9;282(6):3450-7. doi: 10.1074/jbc.M610745200. Epub 2006 Dec 7.
• [6] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [7] Nerve Injury-Induced Neuronal PAP-I Maintains Neuropathic Pain by Activating Spinal Microglia.J Neurosci. 2020 Jan 8;40(2):297-310. doi: 10.1523/JNEUROSCI.1414-19.2019. Epub 2019 Nov 19.
• [8] Redundant roles of the phosphatidate phosphatase family in triacylglycerol synthesis in human adipocytes.Diabetologia. 2016 Sep;59(9):1985-94. doi: 10.1007/s00125-016-4018-0. Epub 2016 Jun 25.
• [9] PAP-1, the mutated gene underlying the RP9 form of dominant retinitis pigmentosa, is a splicing factor.Exp Cell Res. 2004 Nov 1;300(2):283-96. doi: 10.1016/j.yexcr.2004.07.029.
• [10] Suppression of cardiac phosphatidate phosphohydrolase 1 activity and lipin mRNA expression in Zucker diabetic fatty rats and humans with type 2 diabetes mellitus.Biochem Biophys Res Commun. 2009 Dec 4;390(1):165-70. doi: 10.1016/j.bbrc.2009.09.108. Epub 2009 Sep 30.
• [11] Regulation of Proliferation by a Mitochondrial Potassium Channel in Pancreatic Ductal Adenocarcinoma Cells.Front Oncol. 2017 Sep 29;7:239. doi: 10.3389/fonc.2017.00239. eCollection 2017.
• [12] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [15] 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.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.