Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW2A5YY)

• DOT Name: N-lysine methyltransferase KMT5A (KMT5A)
• Synonyms: EC 2.1.1.-; H4-K20-HMTase KMT5A; Histone-lysine N-methyltransferase KMT5A; EC 2.1.1.361; Lysine N-methyltransferase 5A; Lysine-specific methylase 5A; PR/SET domain-containing protein 07; PR-Set7; PR/SET07; SET domain-containing protein 8
• Gene Name: KMT5A
• UniProt ID: KMT5A_HUMAN
• PDB ID: 1ZKK; 2BQZ; 3F9W; 3F9X; 3F9Y; 3F9Z; 4IJ8; 5HQ2; 5T5G; 5TEG; 5TH7; 5V2N; 5W1Y; 6BOZ; 7D1Z; 7D20; 7XPX
• EC Number: 2.1.1.-; 2.1.1.361
• Pfam ID: PF00856
• Sequence:
  MGEGGAAAALVAAAAAAAAAAAAVVAGQRRRRLGRRARCHGPGRAAGGKMSKPCAVEAAA
  AAVAATAPGPEMVERRGPGRPRTDGENVFTGQSKIYSYMSPNKCSGMRFPLQEENSVTHH
  EVKCQGKPLAGIYRKREEKRNAGNAVRSAMKSEEQKIKDARKGPLVPFPNQKSEAAEPPK
  TPPSSCDSTNAAIAKQALKKPIKGKQAPRKKAQGKTQQNRKLTDFYPVRRSSRKSKAELQ
  SEERKRIDELIESGKEEGMKIDLIDGKGRGVIATKQFSRGDFVVEYHGDLIEITDAKKRE
  ALYAQDPSTGCYMYYFQYLSKTYCVDATRETNRLGRLINHSKCGNCQTKLHDIDGVPHLI
  LIASRDIAAGEELLYDYGDRSKASIEAHPWLKH
• Function: Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins. Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1). H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. Required for cell proliferation, probably by contributing to the maintenance of proper higher-order structure of DNA during mitosis. Involved in chromosome condensation and proper cytokinesis. Nucleosomes are preferred as substrate compared to free histones. Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes. Plays a negative role in TGF-beta response regulation and a positive role in cell migration.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  PKMTs methylate histone lysines (R-HSA-3214841)
  Regulation of TP53 Activity through Methylation (R-HSA-6804760)
  Condensation of Prophase Chromosomes (R-HSA-2299718)
• BioCyc Pathway: MetaCyc:HS11381-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 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 N-lysine methyltransferase KMT5A (KMT5A).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[6]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[7]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[8]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[9]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of N-lysine methyltransferase KMT5A (KMT5A).	[6]

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 N-lysine methyltransferase KMT5A (KMT5A).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Differential Effects of Estradiol and Bisphenol A on SET8 and SIRT1 Expression in Ovarian Cancer Cells. Dose Response. 2016 Apr 7;14(2):1559325816640682. doi: 10.1177/1559325816640682. eCollection 2016 Apr-Jun.
• [7] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [8] Alcohol triggered bile acid disequilibrium by suppressing BSEP to sustain hepatocellular carcinoma progression. Chem Biol Interact. 2022 Apr 1;356:109847. doi: 10.1016/j.cbi.2022.109847. Epub 2022 Feb 9.
• [9] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [10] Curcumin inhibits cell growth and invasion through up-regulation of miR-7 in pancreatic cancer cells. Toxicol Lett. 2014 Nov 18;231(1):82-91. doi: 10.1016/j.toxlet.2014.09.014. Epub 2014 Sep 23.
• [11] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.