Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA96AVN)

• DOT Name: N-acetylaspartate synthetase (NAT8L)
• Synonyms: NAA synthetase; EC 2.3.1.17; Camello-like protein 3; N-acetyltransferase 8-like protein
• Gene Name: NAT8L
• Related Disease:
  Attention deficit hyperactivity disorder
  Canavan disease
  Depression
  Major depressive disorder
  Methamphetamine dependence
  Multiple sclerosis
  Neoplasm
  Psychotic disorder
  Schizophrenia
  N-acetylaspartate deficiency
• UniProt ID: NAT8L_HUMAN
• EC Number: 2.3.1.17
• Pfam ID: PF00583
• Sequence:
  MHCGPPDMVCETKIVAAEDHEALPGAKKDALLAAAGAMWPPLPAAPGPAAAPPAPPPAPV
  AQPHGGAGGAGPPGGRGVCIREFRAAEQEAARRIFYDGIMERIPNTAFRGLRQHPRAQLL
  YALLAALCFAVSRSLLLTCLVPAALLGLRYYYSRKVIRAYLECALHTDMADIEQYYMKPP
  GSCFWVAVLDGNVVGIVAARAHEEDNTVELLRMSVDSRFRGKGIAKALGRKVLEFAVVHN
  YSAVVLGTTAVKVAAHKLYESLGFRHMGASDHYVLPGMTLSLAERLFFQVRYHRYRLQLR
  EE
• Function: Catalyzes the synthesis of N-acetylaspartate acid (NAA) from L-aspartate and acetyl-CoA. Promotes dopamine uptake by regulating TNF-alpha expression. Attenuates methamphetamine-induced inhibition of dopamine uptake.
• Tissue Specificity: Expressed in brain.
• KEGG Pathway:
  Alanine, aspartate and glutamate metabolism (hsa00250)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Aspartate and asparagine metabolism (R-HSA-8963693)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[1]
Canavan disease	DIS7UPG8	Strong	Biomarker	[2]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[3]
Methamphetamine dependence	DIS1UU1B	Strong	Genetic Variation	[1]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
N-acetylaspartate deficiency	DIS3R7SS	Limited	Autosomal recessive	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of N-acetylaspartate synthetase (NAT8L).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of N-acetylaspartate synthetase (NAT8L).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of N-acetylaspartate synthetase (NAT8L).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of N-acetylaspartate synthetase (NAT8L).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of N-acetylaspartate synthetase (NAT8L).	[11]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of N-acetylaspartate synthetase (NAT8L).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N-acetylaspartate synthetase (NAT8L).	[13]
Fenfluramine	DM0762O	Phase 3	Fenfluramine increases the expression of N-acetylaspartate synthetase (NAT8L).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of N-acetylaspartate synthetase (NAT8L).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of N-acetylaspartate synthetase (NAT8L).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of N-acetylaspartate synthetase (NAT8L).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of N-acetylaspartate synthetase (NAT8L).	[18]

References

• [1] Shati/Nat8l knockout mice show behavioral deficits ameliorated by atomoxetine and methylphenidate.Behav Brain Res. 2018 Feb 26;339:207-214. doi: 10.1016/j.bbr.2017.11.040. Epub 2017 Dec 2.
• [2] Brain Nat8l Knockdown Suppresses Spongiform Leukodystrophy in an Aspartoacylase-Deficient Canavan Disease Mouse Model.Mol Ther. 2018 Mar 7;26(3):793-800. doi: 10.1016/j.ymthe.2018.01.002. Epub 2018 Jan 10.
• [3] Vulnerability to depressive behavior induced by overexpression of striatal Shati/Nat8l via the serotonergic neuronal pathway in mice.Behav Brain Res. 2019 Dec 30;376:112227. doi: 10.1016/j.bbr.2019.112227. Epub 2019 Sep 11.
• [4] The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition.Exp Brain Res. 2017 Jan;235(1):279-292. doi: 10.1007/s00221-016-4789-z. Epub 2016 Oct 5.
• [5] N-Acetylaspartate Metabolism Outside the Brain: Lipogenesis, Histone Acetylation, and Cancer.Front Endocrinol (Lausanne). 2017 Sep 20;8:240. doi: 10.3389/fendo.2017.00240. eCollection 2017.
• [6] Decreased DNA Methylation in the Shati/Nat8l Promoter in Both Patients with Schizophrenia and a Methamphetamine-Induced Murine Model of Schizophrenia-Like Phenotype.PLoS One. 2016 Jun 27;11(6):e0157959. doi: 10.1371/journal.pone.0157959. eCollection 2016.
• [7] 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.
• [8] 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.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] 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.
• [12] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. Pulm Circ. 2011 Jul-Sep;1(3):405-18. doi: 10.4103/2045-8932.87310.
• [15] 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.
• [16] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [17] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [18] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.