Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT85JXS5)

• DOT Name: Lysine-specific histone demethylase 1A (KDM1A)
• Synonyms: EC 1.14.99.66; BRAF35-HDAC complex protein BHC110; Flavin-containing amine oxidase domain-containing protein 2; -dimethyl-L-lysine(4) FAD-dependent demethylase 1A
• Gene Name: KDM1A
• Related Disease: Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome
• UniProt ID: KDM1A_HUMAN
• PDB ID: 2COM ; 2DW4 ; 2EJR ; 2H94 ; 2HKO ; 2IW5 ; 2L3D ; 2UXN ; 2UXX ; 2V1D ; 2X0L ; 2XAF ; 2XAG ; 2XAH ; 2XAJ ; 2XAQ ; 2XAS ; 2Y48 ; 2Z3Y ; 2Z5U ; 3ABT ; 3ABU ; 3ZMS ; 3ZMT ; 3ZMU ; 3ZMV ; 3ZMZ ; 3ZN0 ; 3ZN1 ; 4BAY ; 4CZZ ; 4KUM ; 4UV8 ; 4UV9 ; 4UVA ; 4UVB ; 4UVC ; 4UXN ; 4XBF ; 5AFW ; 5H6Q ; 5H6R ; 5IT3 ; 5L3B ; 5L3C ; 5L3D ; 5L3E ; 5L3F ; 5L3G ; 5LBQ ; 5LGN ; 5LGT ; 5LGU ; 5LHG ; 5LHH ; 5LHI ; 5X60 ; 5YJB ; 6E1F ; 6K3E ; 6KGK ; 6KGL ; 6KGM ; 6KGN ; 6KGO ; 6KGP ; 6KGQ ; 6KGR ; 6NQM ; 6NQU ; 6NR5 ; 6S35 ; 6TE1 ; 6TUY ; 6VYP ; 6W4K ; 6WC6 ; 7CDC ; 7CDD ; 7CDE ; 7CDF ; 7CDG ; 7E0G ; 7JJL ; 7JJM ; 7JK7 ; 7VQS ; 7VQT ; 7VQU ; 7W3L ; 7XW8 ; 7ZRY
• EC Number: 1.14.99.66
• Pfam ID: PF01593 ; PF04433
• Sequence:
  MLSGKKAAAAAAAAAAAATGTEAGPGTAGGSENGSEVAAQPAGLSGPAEVGPGAVGERTP
  RKKEPPRASPPGGLAEPPGSAGPQAGPTVVPGSATPMETGIAETPEGRRTSRRKRAKVEY
  REMDESLANLSEDEYYSEEERNAKAEKEKKLPPPPPQAPPEEENESEPEEPSGVEGAAFQ
  SRLPHDRMTSQEAACFPDIISGPQQTQKVFLFIRNRTLQLWLDNPKIQLTFEATLQQLEA
  PYNSDTVLVHRVHSYLERHGLINFGIYKRIKPLPTKKTGKVIIIGSGVSGLAAARQLQSF
  GMDVTLLEARDRVGGRVATFRKGNYVADLGAMVVTGLGGNPMAVVSKQVNMELAKIKQKC
  PLYEANGQAVPKEKDEMVEQEFNRLLEATSYLSHQLDFNVLNNKPVSLGQALEVVIQLQE
  KHVKDEQIEHWKKIVKTQEELKELLNKMVNLKEKIKELHQQYKEASEVKPPRDITAEFLV
  KSKHRDLTALCKEYDELAETQGKLEEKLQELEANPPSDVYLSSRDRQILDWHFANLEFAN
  ATPLSTLSLKHWDQDDDFEFTGSHLTVRNGYSCVPVALAEGLDIKLNTAVRQVRYTASGC
  EVIAVNTRSTSQTFIYKCDAVLCTLPLGVLKQQPPAVQFVPPLPEWKTSAVQRMGFGNLN
  KVVLCFDRVFWDPSVNLFGHVGSTTASRGELFLFWNLYKAPILLALVAGEAAGIMENISD
  DVIVGRCLAILKGIFGSSAVPQPKETVVSRWRADPWARGSYSYVAAGSSGNDYDLMAQPI
  TPGPSIPGAPQPIPRLFFAGEHTIRNYPATVHGALLSGLREAGRIADQFLGAMYTLPRQA
  TPGVPAQQSPSM
• Function: Histone demethylase that can demethylate both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (AR)-dependent transcription, by being recruited to AR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in AR-containing complexes, which mediates phosphorylation of 'Thr-6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Demethylates methylated 'Lys-42' and methylated 'Lys-117' of SOX2. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Effector of SNAI1-mediated transcription repression of E-cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway:
  HDMs demethylate histones (R-HSA-3214842)
  Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 (R-HSA-5625886)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Estrogen-dependent gene expression (R-HSA-9018519)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  Potential therapeutics for SARS (R-HSA-9679191)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  HDACs deacetylate histones (R-HSA-3214815)
• BioCyc Pathway: MetaCyc:ENSG00000004487-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome	DISP1CK5	Strong	Autosomal dominant	[1]

12 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 Lysine-specific histone demethylase 1A (KDM1A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Lysine-specific histone demethylase 1A (KDM1A).	[7]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[8]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide increases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[9]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Lysine-specific histone demethylase 1A (KDM1A).	[16]

3 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 increases the methylation of Lysine-specific histone demethylase 1A (KDM1A).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Lysine-specific histone demethylase 1A (KDM1A).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Lysine-specific histone demethylase 1A (KDM1A).	[15]

References

• [1] De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome. Am J Med Genet A. 2014 Jul;164A(7):1744-9. doi: 10.1002/ajmg.a.36450. Epub 2014 May 16.
• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [3] Differential responses to retinoic acid and endocrine disruptor compounds of subpopulations within human embryonic stem cell lines. Differentiation. 2012 Nov;84(4):330-43. doi: 10.1016/j.diff.2012.07.006. Epub 2012 Aug 18.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] 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.
• [8] Cyclophosphamide perturbs cytosine methylation in Jurkat-T cells through LSD1-mediated stabilization of DNMT1 protein. Chem Res Toxicol. 2011 Nov 21;24(11):2040-3. doi: 10.1021/tx2003849. Epub 2011 Nov 1.
• [9] Nitric oxide modifies global histone methylation by inhibiting Jumonji C domain-containing demethylases. J Biol Chem. 2013 May 31;288(22):16004-15. doi: 10.1074/jbc.M112.432294. Epub 2013 Apr 1.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.