Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6QC8GK)

• DOT Name: Histone-lysine N-methyltransferase EHMT1 (EHMT1)
• Synonyms: EC 2.1.1.-; EC 2.1.1.367; Euchromatic histone-lysine N-methyltransferase 1; Eu-HMTase1; G9a-like protein 1; GLP; GLP1; Histone H3-K9 methyltransferase 5; H3-K9-HMTase 5; Lysine N-methyltransferase 1D
• Gene Name: EHMT1
• Related Disease:
  Kleefstra syndrome
  Kleefstra syndrome 1
• UniProt ID: EHMT1_HUMAN
• PDB ID: 2IGQ; 2RFI; 3B7B; 3B95; 3FPD; 3HNA; 3MO0; 3MO2; 3MO5; 3SW9; 3SWC; 4I51; 5TTG; 5TUZ; 5V9J; 5VSD; 5VSF; 6BY9; 6MBO; 6MBP; 7T7M
• EC Number: 2.1.1.-; 2.1.1.367
• Pfam ID: PF12796 ; PF13637 ; PF21533 ; PF05033 ; PF00856
• Sequence:
  MAAADAEAVPARGEPQQDCCVKTELLGEETPMAADEGSAEKQAGEAHMAADGETNGSCEN
  SDASSHANAAKHTQDSARVNPQDGTNTLTRIAENGVSERDSEAAKQNHVTADDFVQTSVI
  GSNGYILNKPALQAQPLRTTSTLASSLPGHAAKTLPGGAGKGRTPSAFPQTPAAPPATLG
  EGSADTEDRKLPAPGADVKVHRARKTMPKSVVGLHAASKDPREVREARDHKEPKEEINKN
  ISDFGRQQLLPPFPSLHQSLPQNQCYMATTKSQTACLPFVLAAAVSRKKKRRMGTYSLVP
  KKKTKVLKQRTVIEMFKSITHSTVGSKGEKDLGASSLHVNGESLEMDSDEDDSEELEEDD
  GHGAEQAAAFPTEDSRTSKESMSEADRAQKMDGESEEEQESVDTGEEEEGGDESDLSSES
  SIKKKFLKRKGKTDSPWIKPARKRRRRSRKKPSGALGSESYKSSAGSAEQTAPGDSTGYM
  EVSLDSLDLRVKGILSSQAEGLANGPDVLETDGLQEVPLCSCRMETPKSREITTLANNQC
  MATESVDHELGRCTNSVVKYELMRPSNKAPLLVLCEDHRGRMVKHQCCPGCGYFCTAGNF
  MECQPESSISHRFHKDCASRVNNASYCPHCGEESSKAKEVTIAKADTTSTVTPVPGQEKG
  SALEGRADTTTGSAAGPPLSEDDKLQGAASHVPEGFDPTGPAGLGRPTPGLSQGPGKETL
  ESALIALDSEKPKKLRFHPKQLYFSARQGELQKVLLMLVDGIDPNFKMEHQNKRSPLHAA
  AEAGHVDICHMLVQAGANIDTCSEDQRTPLMEAAENNHLEAVKYLIKAGALVDPKDAEGS
  TCLHLAAKKGHYEVVQYLLSNGQMDVNCQDDGGWTPMIWATEYKHVDLVKLLLSKGSDIN
  IRDNEENICLHWAAFSGCVDIAEILLAAKCDLHAVNIHGDSPLHIAARENRYDCVVLFLS
  RDSDVTLKNKEGETPLQCASLNSQVWSALQMSKALQDSAPDRPSPVERIVSRDIARGYER
  IPIPCVNAVDSEPCPSNYKYVSQNCVTSPMNIDRNITHLQYCVCIDDCSSSNCMCGQLSM
  RCWYDKDGRLLPEFNMAEPPLIFECNHACSCWRNCRNRVVQNGLRARLQLYRTRDMGWGV
  RSLQDIPPGTFVCEYVGELISDSEADVREEDSYLFDLDNKDGEVYCIDARFYGNVSRFIN
  HHCEPNLVPVRVFMAHQDLRFPRIAFFSTRLIEAGEQLGFDYGERFWDIKGKLFSCRCGS
  PKCRHSSAALAQRQASAAQEAQEDGLPDTSSAAAADPL
• Function: Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. During G0 phase, it probably contributes to silencing of MYC- and E2F-responsive genes, suggesting a role in G0/G1 transition in cell cycle. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Represses the expression of mitochondrial function-related genes, perhaps by occupying their promoter regions, working in concert with probable chromatin reader BAZ2B.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
  Longevity regulating pathway (hsa04211)
• Reactome Pathway:
  PKMTs methylate histone lysines (R-HSA-3214841)
  Regulation of TP53 Activity through Methylation (R-HSA-6804760)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
• BioCyc Pathway: MetaCyc:HS17627-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Kleefstra syndrome	DISHH9SN	Definitive	Autosomal dominant	[1]
Kleefstra syndrome 1	DISNODDM	Strong	Autosomal dominant	[2]

14 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 Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[11]
Ym155	DM5Q1W4	Phase 2	Ym155 decreases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[18]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[4]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Histone-lysine N-methyltransferase EHMT1 (EHMT1).	[16]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Effects of chronic exposure to arsenic and estrogen on epigenetic regulatory genes expression and epigenetic code in human prostate epithelial cells. PLoS One. 2012;7(8):e43880. doi: 10.1371/journal.pone.0043880. Epub 2012 Aug 27.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Oxidative stress-induced epigenetic changes associated with malignant transformation of human kidney epithelial cells. Oncotarget. 2017 Feb 14;8(7):11127-11143. doi: 10.18632/oncotarget.12091.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [12] YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells. PLoS One. 2017 Aug 7;12(8):e0182149. doi: 10.1371/journal.pone.0182149. eCollection 2017.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [15] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [17] 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.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.