Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTITB7DO)

• DOT Name: N-acetylglutamate synthase, mitochondrial (NAGS)
• Synonyms: EC 2.3.1.1; Amino-acid acetyltransferase
• Gene Name: NAGS
• Related Disease: Hyperammonemia due to N-acetylglutamate synthase deficiency
• UniProt ID: NAGS_HUMAN
• PDB ID: 4K30
• EC Number: 2.3.1.1
• Pfam ID: PF00696 ; PF04768
• Sequence:
  MATALMAVVLRAAAVAPRLRGRGGTGGARRLSCGARRRAARGTSPGRRLSTAWSQPQPPP
  EEYAGADDVSQSPVAEEPSWVPSPRPPVPHESPEPPSGRSLVQRDIQAFLNQCGASPGEA
  RHWLTQFQTCHHSADKPFAVIEVDEEVLKCQQGVSSLAFALAFLQRMDMKPLVVLGLPAP
  TAPSGCLSFWEAKAQLAKSCKVLVDALRHNAAAAVPFFGGGSVLRAAEPAPHASYGGIVS
  VETDLLQWCLESGSIPILCPIGETAARRSVLLDSLEVTASLAKALRPTKIIFLNNTGGLR
  DSSHKVLSNVNLPADLDLVCNAEWVSTKERQQMRLIVDVLSRLPHHSSAVITAASTLLTE
  LFSNKGSGTLFKNAERMLRVRSLDKLDQGRLVDLVNASFGKKLRDDYLASLRPRLHSIYV
  SEGYNAAAILTMEPVLGGTPYLDKFVVSSSRQGQGSGQMLWECLRRDLQTLFWRSRVTNP
  INPWYFKHSDGSFSNKQWIFFWFGLADIRDSYELVNHAKGLPDSFHKPASDPGS
• Function: Plays a role in the regulation of ureagenesis by producing the essential cofactor N-acetylglutamate (NAG), thus modulating carbamoylphosphate synthase I (CPS1) activity.
• Tissue Specificity: Highly expressed in the adult liver, kidney and small intestine. Weakly expressed in the fetal liver, lung, pancreas, placenta, heart and brain tissue.
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Metabolic pathways (hsa01100)
  2-Oxocarboxylic acid metabolism (hsa01210)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway: Urea cycle (R-HSA-70635)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperammonemia due to N-acetylglutamate synthase deficiency	DISL14D6	Definitive	Autosomal recessive	[1]

16 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-acetylglutamate synthase, mitochondrial (NAGS).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[11]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[12]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of N-acetylglutamate synthase, mitochondrial (NAGS).	[15]

References

• [1] 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.
• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] 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.
• [9] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [13] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [14] 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.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.