Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYB9R6I)

• DOT Name: N-alpha-acetyltransferase 10 (NAA10)
• Synonyms: EC 2.3.1.255; N-terminal acetyltransferase complex ARD1 subunit homolog A; hARD1; NatA catalytic subunit Naa10
• Gene Name: NAA10
• Related Disease:
  Lateral meningocele syndrome
  Limb-mammary syndrome
  Microphthalmia, syndromic 1
  NAA10-related syndrome
  Ogden syndrome
  Ablepharon macrostomia syndrome
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Diabetes insipidus, nephrogenic, X-linked
  Hepatocellular carcinoma
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Obesity
  Microphthalmia, Lenz type
  Isolated congenital microcephaly
  Lung adenocarcinoma
  Advanced cancer
  Bone osteosarcoma
  Breast disorder
  Colitis
  Colorectal carcinoma
  Osteosarcoma
  Thyroid gland papillary carcinoma
• UniProt ID: NAA10_HUMAN
• PDB ID: 6C95; 6C9M; 6PPL; 6PW9
• EC Number: 2.3.1.255
• Pfam ID: PF00583
• Sequence:
  MNIRNARPEDLMNMQHCNLLCLPENYQMKYYFYHGLSWPQLSYIAEDENGKIVGYVLAKM
  EEDPDDVPHGHITSLAVKRSHRRLGLAQKLMDQASRAMIENFNAKYVSLHVRKSNRAALH
  LYSNTLNFQISEVEPKYYADGEDAYAMKRDLTQMADELRRHLELKEKGRHVVLGAIENKV
  ESKGNSPPSSGEACREEKGLAAEDSGGDSKDLSEVSETTESTDVKDSSEASDSAS
• Function: Catalytic subunit of N-terminal acetyltransferase complexes which display alpha (N-terminal) acetyltransferase activity. Acetylates amino termini that are devoid of initiator methionine. The alpha (N-terminal) acetyltransferase activity may be important for vascular, hematopoietic and neuronal growth and development. Without NAA15, displays epsilon (internal) acetyltransferase activity towards HIF1A, thereby promoting its degradation. Represses MYLK kinase activity by acetylation, and thus represses tumor cell migration. Acetylates, and stabilizes TSC2, thereby repressing mTOR activity and suppressing cancer development. Acetylates HSPA1A and HSPA1B at 'Lys-77' which enhances its chaperone activity and leads to preferential binding to co-chaperone HOPX. Acetylates HIST1H4A. Acts as a negative regulator of sister chromatid cohesion during mitosis.
• Tissue Specificity: Ubiquitous.
• BioCyc Pathway: MetaCyc:HS02336-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lateral meningocele syndrome	DISG74RP	Definitive	Genetic Variation	[1]
Limb-mammary syndrome	DIS7H4FP	Definitive	Genetic Variation	[1]
Microphthalmia, syndromic 1	DISA9P0U	Definitive	X-linked	[2]
NAA10-related syndrome	DISVSZYQ	Definitive	X-linked	[3]
Ogden syndrome	DISLI754	Definitive	X-linked recessive	[4]
Ablepharon macrostomia syndrome	DIS1P3YX	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Altered Expression	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Diabetes insipidus, nephrogenic, X-linked	DISHUTO5	Strong	Genetic Variation	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[12]
Obesity	DIS47Y1K	moderate	Altered Expression	[14]
Microphthalmia, Lenz type	DISWYX38	Supportive	X-linked	[1]
Isolated congenital microcephaly	DISUXHZ6	Disputed	Genetic Variation	[10]
Lung adenocarcinoma	DISD51WR	Disputed	Biomarker	[15]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[16]
Breast disorder	DISJTGMA	Limited	Biomarker	[17]
Colitis	DISAF7DD	Limited	Altered Expression	[18]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[18]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[16]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[19]

12 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 10 (NAA10).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of N-alpha-acetyltransferase 10 (NAA10).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of N-alpha-acetyltransferase 10 (NAA10).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of N-alpha-acetyltransferase 10 (NAA10).	[23]
Selenium	DM25CGV	Approved	Selenium increases the expression of N-alpha-acetyltransferase 10 (NAA10).	[24]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of N-alpha-acetyltransferase 10 (NAA10).	[25]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of N-alpha-acetyltransferase 10 (NAA10).	[26]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of N-alpha-acetyltransferase 10 (NAA10).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of N-alpha-acetyltransferase 10 (NAA10).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of N-alpha-acetyltransferase 10 (NAA10).	[30]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of N-alpha-acetyltransferase 10 (NAA10).	[31]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of N-alpha-acetyltransferase 10 (NAA10).	[32]

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 affects the methylation of N-alpha-acetyltransferase 10 (NAA10).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of N-alpha-acetyltransferase 10 (NAA10).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of N-alpha-acetyltransferase 10 (NAA10).	[29]

References

• [1] A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signalling pathway and causes Lenz microphthalmia syndrome. J Med Genet. 2014 Mar;51(3):185-96. doi: 10.1136/jmedgenet-2013-101660. Epub 2014 Jan 15.
• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] 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.
• [4] Using VAAST to identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency. Am J Hum Genet. 2011 Jul 15;89(1):28-43. doi: 10.1016/j.ajhg.2011.05.017. Epub 2011 Jun 23.
• [5] Understanding molecular mechanisms of Rhodiola rosea for the treatment of acute mountain sickness through computational approaches (a STROBE-compliant article).Medicine (Baltimore). 2018 Sep;97(39):e11886. doi: 10.1097/MD.0000000000011886.
• [6] ARD1 contributes to IKK-mediated breast cancer tumorigenesis.Cell Death Dis. 2018 Aug 28;9(9):860. doi: 10.1038/s41419-018-0921-2.
• [7] Diverse roles of arrest defective 1 in cancer development.Arch Pharm Res. 2019 Dec;42(12):1040-1051. doi: 10.1007/s12272-019-01195-0. Epub 2019 Dec 7.
• [8] Severe combined immunodeficiency associated with nephrogenic diabetes insipidus and a deletion in the Xq28 region.Clin Immunol. 2006 Aug;120(2):147-55. doi: 10.1016/j.clim.2006.05.001. Epub 2006 Jun 15.
• [9] ARD1/NAA10 in hepatocellular carcinoma: pathways and clinical implications.Exp Mol Med. 2018 Jul 27;50(7):1-12. doi: 10.1038/s12276-018-0106-1.
• [10] A novel NAA10 p.(R83H) variant with impaired acetyltransferase activity identified in two boys with ID and microcephaly.BMC Med Genet. 2019 Jun 7;20(1):101. doi: 10.1186/s12881-019-0803-1.
• [11] Correlation of expression of human arrest-defective-1 (hARD1) protein with breast cancer.Cancer Invest. 2009 Dec;27(10):978-83. doi: 10.3109/07357900902769723.
• [12] Inverse correlation between Naa10p and Pirh2 expression and the combined prognostic value in oral squamous cell carcinoma patients.J Oral Pathol Med. 2019 Sep;48(8):686-695. doi: 10.1111/jop.12886. Epub 2019 Jun 9.
• [13] ARD1/NAA10 acetylation in prostate cancer.Exp Mol Med. 2018 Jul 27;50(7):1-8. doi: 10.1038/s12276-018-0107-0.
• [14] Naa10p Inhibits Beige Adipocyte-Mediated Thermogenesis through N--acetylation of Pgc1.Mol Cell. 2019 Nov 7;76(3):500-515.e8. doi: 10.1016/j.molcel.2019.07.026. Epub 2019 Aug 15.
• [15] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [16] N--acetyltransferase 10 protein promotes metastasis by stabilizing matrix metalloproteinase-2 protein in human osteosarcomas.Cancer Lett. 2018 Oct 1;433:86-98. doi: 10.1016/j.canlet.2018.06.033. Epub 2018 Jun 27.
• [17] Up-regulation of human arrest-defective 1 protein is correlated with metastatic phenotype and poor prognosis in breast cancer.Asian Pac J Cancer Prev. 2011;12(8):1973-7.
• [18] Generation of novel monoclonal antibodies and their application for detecting ARD1 expression in colorectal cancer.Cancer Lett. 2008 Jun 8;264(1):83-92. doi: 10.1016/j.canlet.2008.01.028. Epub 2008 Mar 5.
• [19] Expression of N-acetyl transferase human and human Arrest defective 1 proteins in thyroid neoplasms.Thyroid. 2005 Oct;15(10):1131-6. doi: 10.1089/thy.2005.15.1131.
• [20] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [21] 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.
• [22] 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.
• [23] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [24] 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.
• [25] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [26] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [31] Down-regulation of the expression of the FIH-1 and ARD-1 genes at the transcriptional level by nickel and cobalt in the human lung adenocarcinoma A549 cell line. Int J Environ Res Public Health. 2005 Apr;2(1):10-3. doi: 10.3390/ijerph2005010010.
• [32] Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). Toxicol Lett. 2012 Jul 7;212(1):18-28. doi: 10.1016/j.toxlet.2012.04.013. Epub 2012 May 1.