Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4TSQLG)

• DOT Name: Histone acetyltransferase KAT6A (KAT6A)
• Synonyms: EC 2.3.1.48; MOZ, YBF2/SAS3, SAS2 and TIP60 protein 3; MYST-3; Monocytic leukemia zinc finger protein; Runt-related transcription factor-binding protein 2; Zinc finger protein 220
• Gene Name: KAT6A
• Related Disease:
  Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome
  Syndromic intellectual disability
• UniProt ID: KAT6A_HUMAN
• PDB ID: 1M36; 2LN0; 2OZU; 2RC4; 3V43; 4LJN; 4LK9; 4LKA; 4LLB; 5B75; 5B76; 5B77; 5B78; 6LSB; 7Y43; 8DD5; 8H7A
• EC Number: 2.3.1.48
• Pfam ID: PF01853 ; PF00628 ; PF21524 ; PF17772
• Sequence:
  MVKLANPLYTEWILEAIKKVKKQKQRPSEERICNAVSSSHGLDRKTVLEQLELSVKDGTI
  LKVSNKGLNSYKDPDNPGRIALPKPRNHGKLDNKQNVDWNKLIKRAVEGLAESGGSTLKS
  IERFLKGQKDVSALFGGSAASGFHQQLRLAIKRAIGHGRLLKDGPLYRLNTKATNVDGKE
  SCESLSCLPPVSLLPHEKDKPVAEPIPICSFCLGTKEQNREKKPEELISCADCGNSGHPS
  CLKFSPELTVRVKALRWQCIECKTCSSCRDQGKNADNMLFCDSCDRGFHMECCDPPLTRM
  PKGMWICQICRPRKKGRKLLQKKAAQIKRRYTNPIGRPKNRLKKQNTVSKGPFSKVRTGP
  GRGRKRKITLSSQSASSSSEEGYLERIDGLDFCRDSNVSLKFNKKTKGLIDGLTKFFTPS
  PDGRKARGEVVDYSEQYRIRKRGNRKSSTSDWPTDNQDGWDGKQENEERLFGSQEIMTEK
  DMELFRDIQEQALQKVGVTGPPDPQVRCPSVIEFGKYEIHTWYSSPYPQEYSRLPKLYLC
  EFCLKYMKSRTILQQHMKKCGWFHPPANEIYRKNNISVFEVDGNVSTIYCQNLCLLAKLF
  LDHKTLYYDVEPFLFYVLTQNDVKGCHLVGYFSKEKHCQQKYNVSCIMILPQYQRKGYGR
  FLIDFSYLLSKREGQAGSPEKPLSDLGRLSYMAYWKSVILECLYHQNDKQISIKKLSKLT
  GICPQDITSTLHHLRMLDFRSDQFVIIRREKLIQDHMAKLQLNLRPVDVDPECLRWTPVI
  VSNSVVSEEEEEEAEEGENEEPQCQERELEISVGKSVSHENKEQDSYSVESEKKPEVMAP
  VSSTRLSKQVLPHDSLPANSQPSRRGRWGRKNRKTQERFGDKDSKLLLEETSSAPQEQYG
  ECGEKSEATQEQYTESEEQLVASEEQPSQDGKPDLPKRRLSEGVEPWRGQLKKSPEALKC
  RLTEGSERLPRRYSEGDRAVLRGFSESSEEEEEPESPRSSSPPILTKPTLKRKKPFLHRR
  RRVRKRKHHNSSVVTETISETTEVLDEPFEDSDSERPMPRLEPTFEIDEEEEEEDENELF
  PREYFRRLSSQDVLRCQSSSKRKSKDEEEDEESDDADDTPILKPVSLLRKRDVKNSPLEP
  DTSTPLKKKKGWPKGKSRKPIHWKKRPGRKPGFKLSREIMPVSTQACVIEPIVSIPKAGR
  KPKIQESEETVEPKEDMPLPEERKEEEEMQAEAEEAEEGEEEDAASSEVPAASPADSSNS
  PETETKEPEVEEEEEKPRVSEEQRQSEEEQQELEEPEPEEEEDAAAETAQNDDHDADDED
  DGHLESTKKKELEEQPTREDVKEEPGVQESFLDANMQKSREKIKDKEETELDSEEEQPSH
  DTSVVSEQMAGSEDDHEEDSHTKEELIELKEEEEIPHSELDLETVQAVQSLTQEESSEHE
  GAYQDCEETLAACQTLQSYTQADEDPQMSMVEDCHASEHNSPISSVQSHPSQSVRSVSSP
  NVPALESGYTQISPEQGSLSAPSMQNMETSPMMDVPSVSDHSQQVVDSGFSDLGSIESTT
  ENYENPSSYDSTMGGSICGNSSSQSSCSYGGLSSSSSLTQSSCVVTQQMASMGSSCSMMQ
  QSSVQPAANCSIKSPQSCVVERPPSNQQQQPPPPPPQQPQPPPPQPQPAPQPPPPQQQPQ
  QQPQPQPQQPPPPPPPQQQPPLSQCSMNNSFTPAPMIMEIPESGSTGNISIYERIPGDFG
  AGSYSQPSATFSLAKLQQLTNTIMDPHAMPYSHSPAVTSYATSVSLSNTGLAQLAPSHPL
  AGTPQAQATMTPPPNLASTTMNLTSPLLQCNMSATNIGIPHTQRLQGQMPVKGHISIRSK
  SAPLPSAAAHQQQLYGRSPSAVAMQAGPRALAVQRGMNMGVNLMPTPAYNVNSMNMNTLN
  AMNSYRMTQPMMNSSYHSNPAYMNQTAQYPMQMQMGMMGSQAYTQQPMQPNPHGNMMYTG
  PSHHSYMNAAGVPKQSLNGPYMRR
• Function: Histone acetyltransferase that acetylates lysine residues in histone H3 and histone H4 (in vitro). Component of the MOZ/MORF complex which has a histone H3 acetyltransferase activity. May act as a transcriptional coactivator for RUNX1 and RUNX2. Acetylates p53/TP53 at 'Lys-120' and 'Lys-382' and controls its transcriptional activity via association with PML.
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway:
  Regulation of TP53 Activity through Acetylation (R-HSA-6804758)
  HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome	DIS2QHVZ	Definitive	Autosomal dominant	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Histone acetyltransferase KAT6A (KAT6A).	[3]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Histone acetyltransferase KAT6A (KAT6A).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Histone acetyltransferase KAT6A (KAT6A).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Histone acetyltransferase KAT6A (KAT6A).	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Histone acetyltransferase KAT6A (KAT6A).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Histone acetyltransferase KAT6A (KAT6A).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone acetyltransferase KAT6A (KAT6A).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Histone acetyltransferase KAT6A (KAT6A).	[7]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Histone acetyltransferase KAT6A (KAT6A).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone acetyltransferase KAT6A (KAT6A).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Histone acetyltransferase KAT6A (KAT6A).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Histone acetyltransferase KAT6A (KAT6A).	[12]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Histone acetyltransferase KAT6A (KAT6A).	[13]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Histone acetyltransferase KAT6A (KAT6A).	[14]

References

• [1] De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay. Am J Hum Genet. 2015 Mar 5;96(3):498-506. doi: 10.1016/j.ajhg.2015.01.017. Epub 2015 Feb 26.
• [2] 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.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [14] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.