Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFJ8S47)

• DOT Name: N-alpha-acetyltransferase 50 (NAA50)
• Synonyms: hNaa50p; EC 2.3.1.258; N-acetyltransferase 13; N-acetyltransferase 5; hNAT5; N-acetyltransferase san homolog; hSAN; N-epsilon-acetyltransferase 50; EC 2.3.1.-; NatE catalytic subunit
• Gene Name: NAA50
• Related Disease:
  Intellectual disability
  Sinoatrial node disorder
  Acute myocardial infarction
  Autosomal dominant cerebellar ataxia, deafness and narcolepsy
  Channelopathy-associated congenital insensitivity to pain, autosomal recessive
  Dementia
  Hereditary sensory and autonomic neuropathy
  Narcolepsy
  Neuroblastoma
  Non-small-cell lung cancer
  Ogden syndrome
  Polyneuropathy
  Anhidrosis
  Neoplasm
• UniProt ID: NAA50_HUMAN
• PDB ID: 2OB0; 2PSW; 3TFY; 4X5K; 6PPL; 6PW9; 6WF3; 6WF5; 6WFG; 6WFK; 6WFN; 6WFO
• EC Number: 2.3.1.-; 2.3.1.258
• Pfam ID: PF00583
• Sequence:
  MKGSRIELGDVTPHNIKQLKRLNQVIFPVSYNDKFYKDVLEVGELAKLAYFNDIAVGAVC
  CRVDHSQNQKRLYIMTLGCLAPYRRLGIGTKMLNHVLNICEKDGTFDNIYLHVQISNESA
  IDFYRKFGFEIIETKKNYYKRIEPADAHVLQKNLKVPSGQNADVQKTDN
• Function: N-alpha-acetyltransferase that acetylates the N-terminus of proteins that retain their initiating methionine. Has a broad substrate specificity: able to acetylate the initiator methionine of most peptides, except for those with a proline in second position. Also displays N-epsilon-acetyltransferase activity by mediating acetylation of the side chain of specific lysines on proteins. Autoacetylates in vivo. The relevance of N-epsilon-acetyltransferase activity is however unclear: able to acetylate H4 in vitro, but this result has not been confirmed in vivo. Component of N-alpha-acetyltransferase complexes containing NAA10 and NAA15, which has N-alpha-acetyltransferase activity. Does not influence the acetyltransferase activity of NAA10. However, it negatively regulates the N-alpha-acetyltransferase activity of the N-terminal acetyltransferase A complex (also called the NatA complex). The multiprotein complexes probably constitute the major contributor for N-terminal acetylation at the ribosome exit tunnel, with NAA10 acetylating all amino termini that are devoid of methionine and NAA50 acetylating other peptides. Required for sister chromatid cohesion during mitosis by promoting binding of CDCA5/sororin to cohesin: may act by counteracting the function of NAA10.
• BioCyc Pathway: MetaCyc:ENSG00000121579-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Sinoatrial node disorder	DISYJI6J	Definitive	Biomarker	[2]
Acute myocardial infarction	DISE3HTG	Strong	Genetic Variation	[3]
Autosomal dominant cerebellar ataxia, deafness and narcolepsy	DISUGGCJ	Strong	Biomarker	[4]
Channelopathy-associated congenital insensitivity to pain, autosomal recessive	DISJ1NV4	Strong	Biomarker	[5]
Dementia	DISXL1WY	Strong	Genetic Variation	[4]
Hereditary sensory and autonomic neuropathy	DIS2VOAM	Strong	Genetic Variation	[6]
Narcolepsy	DISLCNLI	Strong	Biomarker	[4]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Ogden syndrome	DISLI754	Strong	Biomarker	[9]
Polyneuropathy	DISB9G3W	Strong	Genetic Variation	[4]
Anhidrosis	DISYLSTC	Disputed	Biomarker	[1]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[10]

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 50 (NAA50).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of N-alpha-acetyltransferase 50 (NAA50).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of N-alpha-acetyltransferase 50 (NAA50).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of N-alpha-acetyltransferase 50 (NAA50).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of N-alpha-acetyltransferase 50 (NAA50).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of N-alpha-acetyltransferase 50 (NAA50).	[16]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of N-alpha-acetyltransferase 50 (NAA50).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of N-alpha-acetyltransferase 50 (NAA50).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of N-alpha-acetyltransferase 50 (NAA50).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of N-alpha-acetyltransferase 50 (NAA50).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of N-alpha-acetyltransferase 50 (NAA50).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of N-alpha-acetyltransferase 50 (NAA50).	[20]

References

• [1] Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype.Am J Med Genet A. 2017 Apr;173(4):1009-1016. doi: 10.1002/ajmg.a.38120.
• [2] Oxidized CaMKII causes cardiac sinus node dysfunction in mice.J Clin Invest. 2011 Aug;121(8):3277-88. doi: 10.1172/JCI57833. Epub 2011 Jul 25.
• [3] Detection of Acute Myocardial Infarction in a Pig Model Using the SAN-Atrial-AVN-His (SAAH) Electrocardiogram (ECG), Model PHS-A10, an Automated and Integrated Signals Recognition System.Med Sci Monit. 2018 Mar 4;24:1303-1309. doi: 10.12659/msm.905961.
• [4] Narcolepsy is a common phenotype in HSAN IE and ADCA-DN.Brain. 2014 Jun;137(Pt 6):1643-55. doi: 10.1093/brain/awu069. Epub 2014 Apr 10.
• [5] Midface toddler excoriation syndrome (MiTES) can be caused by autosomal recessive biallelic mutations in a gene for congenital insensitivity to pain, PRDM12.Br J Dermatol. 2018 Nov;179(5):1135-1140. doi: 10.1111/bjd.16893. Epub 2018 Sep 16.
• [6] RETREG1 (FAM134B): A new player in human diseases: 15 years after the discovery in cancer.J Cell Physiol. 2018 Jun;233(6):4479-4489. doi: 10.1002/jcp.26384. Epub 2018 Jan 15.
• [7] Prolonged N-myc protein half-life in a neuroblastoma cell line lacking N-myc amplification.Oncogene. 1990 Dec;5(12):1821-7.
• [8] Sanguinarine exhibits antitumor activity via up-regulation of Fas-associated factor 1 in non-small cell lung cancer.J Biochem Mol Toxicol. 2017 Aug;31(8). doi: 10.1002/jbt.21914. Epub 2017 Mar 14.
• [9] 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.
• [10] Implication of human N-alpha-acetyltransferase 5 in cellular proliferation and carcinogenesis.Oncogene. 2008 Dec 11;27(58):7296-306. doi: 10.1038/onc.2008.332. Epub 2008 Sep 15.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [15] 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.
• [16] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [17] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] 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.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.