Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLYFX8A)

• DOT Name: Lysine-specific demethylase 5A (KDM5A)
• Synonyms: EC 1.14.11.67; Histone demethylase JARID1A; Jumonji/ARID domain-containing protein 1A; Retinoblastoma-binding protein 2; RBBP-2; -trimethyl-L-lysine(4) demethylase 5A
• Gene Name: KDM5A
• Related Disease: Congenital heart disease
• UniProt ID: KDM5A_HUMAN
• PDB ID: 2JXJ ; 2KGG ; 2KGI ; 3GL6 ; 5C11 ; 5CEH ; 5E6H ; 5ISL ; 5IVB ; 5IVC ; 5IVE ; 5IVF ; 5IVJ ; 5IVV ; 5IVY ; 5IW0 ; 5IWF ; 5K4L ; 5V9P ; 5V9T ; 6BGU ; 6BGV ; 6BGW ; 6BGX ; 6BGY ; 6BGZ ; 6BH0 ; 6BH1 ; 6BH2 ; 6BH3 ; 6BH4 ; 6BH5 ; 6DQ4 ; 6DQ5 ; 6DQ6 ; 6DQ7 ; 6DQ8 ; 6DQ9 ; 6DQA ; 6DQB ; 6DQC ; 6DQD ; 6DQE ; 6DQF ; 7KLO ; 7KLR
• EC Number: 1.14.11.67
• Pfam ID: PF01388 ; PF02373 ; PF02375 ; PF21323 ; PF00628 ; PF08429 ; PF02928
• Sequence:
  MAGVGPGGYAAEFVPPPECPVFEPSWEEFTDPLSFIGRIRPLAEKTGICKIRPPKDWQPP
  FACEVKSFRFTPRVQRLNELEAMTRVRLDFLDQLAKFWELQGSTLKIPVVERKILDLYAL
  SKIVASKGGFEMVTKEKKWSKVGSRLGYLPGKGTGSLLKSHYERILYPYELFQSGVSLMG
  VQMPNLDLKEKVEPEVLSTDTQTSPEPGTRMNILPKRTRRVKTQSESGDVSRNTELKKLQ
  IFGAGPKVVGLAMGTKDKEDEVTRRRKVTNRSDAFNMQMRQRKGTLSVNFVDLYVCMFCG
  RGNNEDKLLLCDGCDDSYHTFCLIPPLPDVPKGDWRCPKCVAEECSKPREAFGFEQAVRE
  YTLQSFGEMADNFKSDYFNMPVHMVPTELVEKEFWRLVSSIEEDVIVEYGADISSKDFGS
  GFPVKDGRRKILPEEEEYALSGWNLNNMPVLEQSVLAHINVDISGMKVPWLYVGMCFSSF
  CWHIEDHWSYSINYLHWGEPKTWYGVPSHAAEQLEEVMRELAPELFESQPDLLHQLVTIM
  NPNVLMEHGVPVYRTNQCAGEFVVTFPRAYHSGFNQGYNFAEAVNFCTADWLPIGRQCVN
  HYRRLRRHCVFSHEELIFKMAADPECLDVGLAAMVCKELTLMTEEETRLRESVVQMGVLM
  SEEEVFELVPDDERQCSACRTTCFLSALTCSCNPERLVCLYHPTDLCPCPMQKKCLRYRY
  PLEDLPSLLYGVKVRAQSYDTWVSRVTEALSANFNHKKDLIELRVMLEDAEDRKYPENDL
  FRKLRDAVKEAETCASVAQLLLSKKQKHRQSPDSGRTRTKLTVEELKAFVQQLFSLPCVI
  SQARQVKNLLDDVEEFHERAQEAMMDETPDSSKLQMLIDMGSSLYVELPELPRLKQELQQ
  ARWLDEVRLTLSDPQQVTLDVMKKLIDSGVGLAPHHAVEKAMAELQELLTVSERWEEKAK
  VCLQARPRHSVASLESIVNEAKNIPAFLPNVLSLKEALQKAREWTAKVEAIQSGSNYAYL
  EQLESLSAKGRPIPVRLEALPQVESQVAAARAWRERTGRTFLKKNSSHTLLQVLSPRTDI
  GVYGSGKNRRKKVKELIEKEKEKDLDLEPLSDLEEGLEETRDTAMVVAVFKEREQKEIEA
  MHSLRAANLAKMTMVDRIEEVKFCICRKTASGFMLQCELCKDWFHNSCVPLPKSSSQKKG
  SSWQAKEVKFLCPLCMRSRRPRLETILSLLVSLQKLPVRLPEGEALQCLTERAMSWQDRA
  RQALATDELSSALAKLSVLSQRMVEQAAREKTEKIISAELQKAAANPDLQGHLPSFQQSA
  FNRVVSSVSSSPRQTMDYDDEETDSDEDIRETYGYDMKDTASVKSSSSLEPNLFCDEEIP
  IKSEEVVTHMWTAPSFCAEHAYSSASKSCSQGSSTPRKQPRKSPLVPRSLEPPVLELSPG
  AKAQLEELMMVGDLLEVSLDETQHIWRILQATHPPSEDRFLHIMEDDSMEEKPLKVKGKD
  SSEKKRKRKLEKVEQLFGEGKQKSKELKKMDKPRKKKLKLGADKSKELNKLAKKLAKEEE
  RKKKKEKAAAAKVELVKESTEKKREKKVLDIPSKYDWSGAEESDDENAVCAAQNCQRPCK
  DKVDWVQCDGGCDEWFHQVCVGVSPEMAENEDYICINCAKKQGPVSPGPAPPPSFIMSYK
  LPMEDLKETS
• Function: Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Regulates specific gene transcription through DNA-binding on 5'-CCGCCC-3' motif. May stimulate transcription mediated by nuclear receptors. Involved in transcriptional regulation of Hox proteins during cell differentiation. May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1. Seems to act as a transcriptional corepressor for some genes such as MT1F and to favor the proliferation of cancer cells.
• Reactome Pathway:
  Chromatin modifications during the maternal to zygotic transition (MZT) (R-HSA-9821002)
  HDMs demethylate histones (R-HSA-3214842)
• BioCyc Pathway: MetaCyc:ENSG00000073614-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
Congenital heart disease	DISQBA23	Limited	Autosomal dominant	[1]

16 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 demethylase 5A (KDM5A).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysine-specific demethylase 5A (KDM5A).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lysine-specific demethylase 5A (KDM5A).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Lysine-specific demethylase 5A (KDM5A).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Lysine-specific demethylase 5A (KDM5A).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Lysine-specific demethylase 5A (KDM5A).	[7]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Lysine-specific demethylase 5A (KDM5A).	[9]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Lysine-specific demethylase 5A (KDM5A).	[10]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Lysine-specific demethylase 5A (KDM5A).	[11]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Lysine-specific demethylase 5A (KDM5A).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Lysine-specific demethylase 5A (KDM5A).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Lysine-specific demethylase 5A (KDM5A).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Lysine-specific demethylase 5A (KDM5A).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lysine-specific demethylase 5A (KDM5A).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Lysine-specific demethylase 5A (KDM5A).	[17]
aconitine	DMFOZ60	Investigative	aconitine increases the expression of Lysine-specific demethylase 5A (KDM5A).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Lysine-specific demethylase 5A (KDM5A).	[8]

References

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• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
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• [8] 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.
• [9] 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.
• [10] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [11] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [12] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [18] Notch1-mediated histone demethylation of HCN4 contributes to aconitine-induced ventricular myocardial dysrhythmia. Toxicol Lett. 2020 Jul 1;327:19-31. doi: 10.1016/j.toxlet.2020.03.017. Epub 2020 Mar 28.