Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO7O557)

• DOT Name: Histone-arginine methyltransferase METTL23 (METTL23)
• Synonyms: EC 2.1.1.319; Methyltransferase-like protein 23
• Gene Name: METTL23
• Related Disease:
  Intellectual disability, autosomal recessive 44
  Intellectual disability
  Autosomal recessive non-syndromic intellectual disability
• UniProt ID: MET23_HUMAN
• EC Number: 2.1.1.319
• Pfam ID: PF10294
• Sequence:
  MYVWPCAVVLAQYLWFHRRSLPGKAILEIGAGVSLPGILAAKCGAEVILSDSSELPHCLE
  VCRQSCQMNNLPHLQVVGLTWGHISWDLLALPPQDIILASDVFFEPEDFEDILATIYFLM
  HKNPKVQLWSTYQVRSADWSLEALLYKWDMKCVHIPLESFDADKEDIAESTLPGRHTVEM
  LVISFAKDSL
• Function: Histone methyltransferase that dimethylates histone H3 at 'Arg-17', forming asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling. Maternal factor involved in epigenetic chromatin reprogramming of the paternal genome in the zygote: mediates H3R17me2a, promoting histone H3.3 incorporation in the male pronucleus, leading to TET3 recruitment and subsequent DNA demethylation.
• Reactome Pathway:
  Replacement of protamines by nucleosomes in the male pronucleus (R-HSA-9821993)
  Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal recessive 44	DIS0WEIX	Strong	Autosomal recessive	[1]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[2]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Histone-arginine methyltransferase METTL23 (METTL23).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Histone-arginine methyltransferase METTL23 (METTL23).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone-arginine methyltransferase METTL23 (METTL23).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Histone-arginine methyltransferase METTL23 (METTL23).	[6]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Histone-arginine methyltransferase METTL23 (METTL23).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Histone-arginine methyltransferase METTL23 (METTL23).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Histone-arginine methyltransferase METTL23 (METTL23).	[10]

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 affects the methylation of Histone-arginine methyltransferase METTL23 (METTL23).	[8]

References

• [1] METTL23, a transcriptional partner of GABPA, is essential for human cognition. Hum Mol Genet. 2014 Jul 1;23(13):3456-66. doi: 10.1093/hmg/ddu054. Epub 2014 Feb 5.
• [2] Disruption of the methyltransferase-like 23 gene METTL23 causes mild autosomal recessive intellectual disability. Hum Mol Genet. 2014 Aug 1;23(15):4015-23. doi: 10.1093/hmg/ddu115. Epub 2014 Mar 13.
• [3] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] 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.
• [7] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.