Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT53SIZG)

• DOT Name: N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15)
• Synonyms: Gastric cancer antigen Ga19; N-terminal acetyltransferase; NMDA receptor-regulated protein 1; Protein tubedown-1; Tbdn100
• Gene Name: NAA15
• Related Disease:
  Intellectual disability, autosomal dominant 50
  Syndromic intellectual disability
  Advanced cancer
  Autism spectrum disorder
  Intellectual disability
  Neoplasm
  Ogden syndrome
  Pervasive developmental disorder
  Burkitt lymphoma
  Neurodevelopmental disorder
  Thyroid gland papillary carcinoma
• UniProt ID: NAA15_HUMAN
• PDB ID: 6C95; 6C9M; 6PPL; 6PW9
• Pfam ID: PF12569 ; PF13181
• Sequence:
  MPAVSLPPKENALFKRILRCYEHKQYRNGLKFCKQILSNPKFAEHGETLAMKGLTLNCLG
  KKEEAYELVRRGLRNDLKSHVCWHVYGLLQRSDKKYDEAIKCYRNALKWDKDNLQILRDL
  SLLQIQMRDLEGYRETRYQLLQLRPAQRASWIGYAIAYHLLEDYEMAAKILEEFRKTQQT
  SPDKVDYEYSELLLYQNQVLREAGLYREALEHLCTYEKQICDKLAVEETKGELLLQLCRL
  EDAADVYRGLQERNPENWAYYKGLEKALKPANMLERLKIYEEAWTKYPRGLVPRRLPLNF
  LSGEKFKECLDKFLRMNFSKGCPPVFNTLRSLYKDKEKVAIIEELVVGYETSLKSCRLFN
  PNDDGKEEPPTTLLWVQYYLAQHYDKIGQPSIALEYINTAIESTPTLIELFLVKAKIYKH
  AGNIKEAARWMDEAQALDTADRFINSKCAKYMLKANLIKEAEEMCSKFTREGTSAVENLN
  EMQCMWFQTECAQAYKAMNKFGEALKKCHEIERHFIEITDDQFDFHTYCMRKITLRSYVD
  LLKLEDVLRQHPFYFKAARIAIEIYLKLHDNPLTDENKEHEADTANMSDKELKKLRNKQR
  RAQKKAQIEEEKKNAEKEKQQRNQKKKKDDDDEEIGGPKEELIPEKLAKVETPLEEAIKF
  LTPLKNLVKNKIETHLFAFEIYFRKEKFLLMLQSVKRAFAIDSSHPWLHECMIRLFNTAV
  CESKDLSDTVRTVLKQEMNRLFGATNPKNFNETFLKRNSDSLPHRLSAAKMVYYLDPSSQ
  KRAIELATTLDESLTNRNLQTCMEVLEALYDGSLGDCKEAAEIYRANCHKLFPYALAFMP
  PGYEEDMKITVNGDSSAEAEELANEI
• Function: Auxillary subunit of N-terminal acetyltransferase complexes which display alpha (N-terminal) acetyltransferase (NAT) activity. The NAT activity may be important for vascular, hematopoietic and neuronal growth and development. Required to control retinal neovascularization in adult ocular endothelial cells. In complex with XRCC6 and XRCC5 (Ku80), up-regulates transcription from the osteocalcin promoter.
• Tissue Specificity: Expressed at high levels in testis and in ocular endothelial cells. Also found in brain (corpus callosum), heart, colon, bone marrow and at lower levels in most adult tissues, including thyroid, liver, pancreas, mammary and salivary glands, lung, ovary, urogenital system and upper gastrointestinal tract. Overexpressed in gastric cancer, in papillary thyroid carcinomas and in a Burkitt lymphoma cell line (Daudi). Specifically suppressed in abnormal proliferating blood vessels in eyes of patients with proliferative diabetic retinopathy.
• BioCyc Pathway: MetaCyc:ENSG00000164134-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 50	DIS3T8AT	Definitive	Autosomal dominant	[1]
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal dominant	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Ogden syndrome	DISLI754	Strong	Genetic Variation	[6]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[4]
Burkitt lymphoma	DIS9D5XU	Limited	Altered Expression	[7]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[8]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[7]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Panobinostat	DM58WKG	Approved	N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15) increases the Cerebrovascular disorder ADR of Panobinostat.	[28]
Framycetin	DMF8DNE	Approved	N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15) increases the Agitation ADR of Framycetin.	[28]

19 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-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[18]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[19]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[22]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[26]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of N-alpha-acetyltransferase 15, NatA auxiliary subunit (NAA15).	[27]

References

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• [3] Depletion of the human N-terminal acetyltransferase A induces p53-dependent apoptosis and p53-independent growth inhibition.Int J Cancer. 2010 Dec 15;127(12):2777-89. doi: 10.1002/ijc.25275.
• [4] Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.Am J Hum Genet. 2018 May 3;102(5):985-994. doi: 10.1016/j.ajhg.2018.03.004. Epub 2018 Apr 12.
• [5] Design, synthesis and invitro evaluation of heterobivalent peptidic radioligands targeting both GRP- and VPAC(1)-Receptors concomitantly overexpressed on various malignancies - Is the concept feasible?.Eur J Med Chem. 2018 Jul 15;155:84-95. doi: 10.1016/j.ejmech.2018.05.047. Epub 2018 May 29.
• [6] Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects.Hum Mol Genet. 2015 Apr 1;24(7):1956-76. doi: 10.1093/hmg/ddu611. Epub 2014 Dec 8.
• [7] NATH, a novel gene overexpressed in papillary thyroid carcinomas.Oncogene. 2002 Aug 1;21(33):5056-68. doi: 10.1038/sj.onc.1205687.
• [8] Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability.Am J Med Genet B Neuropsychiatr Genet. 2018 Jan;177(1):10-20. doi: 10.1002/ajmg.b.32574. Epub 2017 Oct 9.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [16] 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.
• [17] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [18] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [19] 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.
• [20] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [23] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [24] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [27] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [28] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.