Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL7257A)

• DOT Name: Histone acetyltransferase KAT5 (KAT5)
• Synonyms: EC 2.3.1.48; 60 kDa Tat-interactive protein; Tip60; Histone acetyltransferase HTATIP; HIV-1 Tat interactive protein; Lysine acetyltransferase 5; Protein 2-hydroxyisobutyryltransferase KAT5; EC 2.3.1.-; Protein acetyltransferase KAT5; EC 2.3.1.-; Protein crotonyltransferase KAT5; EC 2.3.1.-; cPLA(2)-interacting protein
• Gene Name: KAT5
• Related Disease:
  Multiple sclerosis
  Arteriosclerosis
  Ataxia-telangiectasia
  Atherosclerosis
  Autoimmune disease
  Bipolar disorder
  Bone osteosarcoma
  Brain neoplasm
  Breast neoplasm
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gastric cancer
  Gout
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Leukemia
  Liver cancer
  Lung cancer
  Lung carcinoma
  Lymphoma
  Metabolic disorder
  Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities
  Non-small-cell lung cancer
  Obesity
  Osteosarcoma
  Prostate neoplasm
  Schizophrenia
  Stomach cancer
  Triple negative breast cancer
  Adult glioblastoma
  Asthma
  Breast carcinoma
  Glioblastoma multiforme
  Melanoma
  Rheumatoid arthritis
  Acute myelogenous leukaemia
  Advanced cancer
  Breast cancer
  Colorectal carcinoma
  Crohn disease
  Nasopharyngeal carcinoma
  Nervous system disease
  Squamous cell carcinoma
• UniProt ID: KAT5_HUMAN
• PDB ID: 2EKO; 2OU2; 4QQG
• EC Number: 2.3.1.-; 2.3.1.48
• Pfam ID: PF01853 ; PF11717 ; PF17772
• Sequence:
  MAEVGEIIEGCRLPVLRRNQDNEDEWPLAEILSVKDISGRKLFYVHYIDFNKRLDEWVTH
  ERLDLKKIQFPKKEAKTPTKNGLPGSRPGSPEREVPASAQASGKTLPIPVQITLRFNLPK
  EREAIPGGEPDQPLSSSSCLQPNHRSTKRKVEVVSPATPVPSETAPASVFPQNGAARRAV
  AAQPGRKRKSNCLGTDEDSQDSSDGIPSAPRMTGSLVSDRSHDDIVTRMKNIECIELGRH
  RLKPWYFSPYPQELTTLPVLYLCEFCLKYGRSLKCLQRHLTKCDLRHPPGNEIYRKGTIS
  FFEIDGRKNKSYSQNLCLLAKCFLDHKTLYYDTDPFLFYVMTEYDCKGFHIVGYFSKEKE
  STEDYNVACILTLPPYQRRGYGKLLIEFSYELSKVEGKTGTPEKPLSDLGLLSYRSYWSQ
  TILEILMGLKSESGERPQITINEISEITSIKKEDVISTLQYLNLINYYKGQYILTLSEDI
  VDGHERAMLKRLLRIDSKCLHFTPKDWSKRGKW
• Function: Catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H2A and H4. Histone acetylation alters nucleosome-DNA interactions and promotes interaction of the modified histones with other proteins which positively regulate transcription. The NuA4 histone acetyltransferase complex is required for the activation of transcriptional programs associated with proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR): the complex inhibits TP53BP1 binding to chromatin via MBTD1, which recognizes and binds histone H4 trimethylated at 'Lys-20' (H4K20me), and KAT5 that catalyzes acetylation of 'Lys-15' of histone H2A (H2AK15ac), thereby blocking the ubiquitination mark required for TP53BP1 localization at DNA breaks. Also involved in DSB repair by mediating acetylation of 'Lys-5' of histone H2AX (H2AXK5ac), promoting NBN/NBS1 assembly at the sites of DNA damage. The NuA4 complex plays a key role in hematopoietic stem cell maintenance and is required to maintain acetylated H2A.Z/H2AZ1 at MYC target genes. The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone hyperacetylation is required for histone replacement during the transition from round to elongating spermatids. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome. Also acetylates non-histone proteins, such as BMAL1, ATM, AURKB, CHKA, CGAS, ERCC4/XPF, LPIN1, NDC80/HEC1, NR1D2, RAN, SOX4, FOXP3, SQSTM1, ULK1 and RUBCNL/Pacer. Directly acetylates and activates ATM. Promotes nucleotide excision repair (NER) by mediating acetylation of ERCC4/XPF, thereby promoting formation of the ERCC4-ERCC1 complex. Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2. Acts as a regulator of regulatory T-cells (Treg) by catalyzing FOXP3 acetylation, thereby promoting FOXP3 transcriptional repressor activity. Involved in skeletal myoblast differentiation by mediating acetylation of SOX4. Catalyzes acetylation of APBB1/FE65, increasing its transcription activator activity. Promotes transcription elongation during the activation phase of the circadian cycle by catalyzing acetylation of BMAL1, promoting elongation of circadian transcripts. Together with GSK3 (GSK3A or GSK3B), acts as a regulator of autophagy: phosphorylated at Ser-86 by GSK3 under starvation conditions, leading to activate acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. Acts as a regulator of the cGAS-STING innate antiviral response by catalyzing acetylation the N-terminus of CGAS, thereby promoting CGAS DNA-binding and activation. Also regulates lipid metabolism by mediating acetylation of CHKA or LPIN1. Promotes lipolysis of lipid droplets following glucose deprivation by mediating acetylation of isoform 1 of CHKA, thereby promoting monomerization of CHKA and its conversion into a tyrosine-protein kinase. Acts as a regulator of fatty-acid-induced triacylglycerol synthesis by catalyzing acetylation of LPIN1, thereby promoting the synthesis of diacylglycerol. In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA) and 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), and is able to mediate protein crotonylation and 2-hydroxyisobutyrylation, respectively. Acts as a key regulator of chromosome segregation and kinetochore-microtubule attachment during mitosis by mediating acetylation or crotonylation of target proteins. Catalyzes acetylation of AURKB at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis. Acetylates RAN during mitosis, promoting microtubule assembly at mitotic chromosomes. Acetylates NDC80/HEC1 during mitosis, promoting robust kinetochore-microtubule attachment. Catalyzes crotonylation of MAPRE1/EB1, thereby ensuring accurate spindle positioning in mitosis.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Spinocerebellar ataxia (hsa05017)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)
  HATs acetylate histones (R-HSA-3214847)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Sensing of DNA Double Strand Breaks (R-HSA-5693548)
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  Cardiogenesis (R-HSA-9733709)
  Formation of the beta-catenin (R-HSA-201722)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[7]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Carcinoma	DISH9F1N	Strong	Biomarker	[9]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[10]
Cervical cancer	DISFSHPF	Strong	Biomarker	[11]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[11]
Colon cancer	DISVC52G	Strong	Altered Expression	[12]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[12]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[13]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[13]
Gastric cancer	DISXGOUK	Strong	Biomarker	[14]
Gout	DISHC0U7	Strong	Genetic Variation	[15]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[17]
Leukemia	DISNAKFL	Strong	Genetic Variation	[18]
Liver cancer	DISDE4BI	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[19]
Lung carcinoma	DISTR26C	Strong	Biomarker	[19]
Lymphoma	DISN6V4S	Strong	Biomarker	[9]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[20]
Neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities	DIS266RW	Strong	Autosomal dominant	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[22]
Obesity	DIS47Y1K	Strong	Biomarker	[2]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[23]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[24]
Stomach cancer	DISKIJSX	Strong	Biomarker	[14]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[25]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[26]
Asthma	DISW9QNS	moderate	Biomarker	[27]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[28]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[26]
Melanoma	DIS1RRCY	moderate	Biomarker	[29]
Rheumatoid arthritis	DISTSB4J	moderate	Biomarker	[30]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[31]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Breast cancer	DIS7DPX1	Limited	Biomarker	[28]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[32]
Crohn disease	DIS2C5Q8	Limited	Altered Expression	[33]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[34]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[35]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[36]

15 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 acetyltransferase KAT5 (KAT5).	[37]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Histone acetyltransferase KAT5 (KAT5).	[38]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Histone acetyltransferase KAT5 (KAT5).	[39]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone acetyltransferase KAT5 (KAT5).	[40]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Histone acetyltransferase KAT5 (KAT5).	[41]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Histone acetyltransferase KAT5 (KAT5).	[37]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Histone acetyltransferase KAT5 (KAT5).	[42]
Pentamidine	DMHZJCG	Approved	Pentamidine decreases the activity of Histone acetyltransferase KAT5 (KAT5).	[43]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Histone acetyltransferase KAT5 (KAT5).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone acetyltransferase KAT5 (KAT5).	[47]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Histone acetyltransferase KAT5 (KAT5).	[48]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Histone acetyltransferase KAT5 (KAT5).	[49]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone acetyltransferase KAT5 (KAT5).	[50]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of Histone acetyltransferase KAT5 (KAT5).	[52]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid increases the expression of Histone acetyltransferase KAT5 (KAT5).	[53]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the acetylation of Histone acetyltransferase KAT5 (KAT5).	[44]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Histone acetyltransferase KAT5 (KAT5).	[45]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Histone acetyltransferase KAT5 (KAT5).	[46]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Histone acetyltransferase KAT5 (KAT5).	[51]

References

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