Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGJH9XH)

• DOT Name: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1)
• Synonyms: NMN/NaMN adenylyltransferase 1; EC 2.7.7.1; EC 2.7.7.18; Nicotinamide-nucleotide adenylyltransferase 1; NMN adenylyltransferase 1; Nicotinate-nucleotide adenylyltransferase 1; NaMN adenylyltransferase 1
• Gene Name: NMNAT1
• Related Disease:
  Leber congenital amaurosis 9
  NMNAT1-related retinopathy
  Cone-rod dystrophy
  Leber congenital amaurosis
  Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis
• UniProt ID: NMNA1_HUMAN
• PDB ID: 1GZU; 1KKU; 1KQN; 1KQO; 1KR2
• EC Number: 2.7.7.1; 2.7.7.18
• Pfam ID: PF01467
• Sequence:
  MENSEKTEVVLLACGSFNPITNMHLRLFELAKDYMNGTGRYTVVKGIISPVGDAYKKKGL
  IPAYHRVIMAELATKNSKWVEVDTWESLQKEWKETLKVLRHHQEKLEASDCDHQQNSPTL
  ERPGRKRKWTETQDSSQKKSLEPKTKAVPKVKLLCGADLLESFAVPNLWKSEDITQIVAN
  YGLICVTRAGNDAQKFIYESDVLWKHRSNIHVVNEWIANDISSTKIRRALRRGQSIRYLV
  PDLVQEYIEKHNLYSSESEDRNAGVILAPLQRNTAEAKT
• Function: Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP. Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate with the same efficiency. Can use triazofurin monophosphate (TrMP) as substrate. Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+). For the pyrophosphorolytic activity, prefers NAD(+) and NaAD as substrates and degrades NADH, nicotinic acid adenine dinucleotide phosphate (NHD) and nicotinamide guanine dinucleotide (NGD) less effectively. Involved in the synthesis of ATP in the nucleus, together with PARP1, PARG and NUDT5. Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming. Also acts as a cofactor for glutamate and aspartate ADP-ribosylation by directing PARP1 catalytic activity to glutamate and aspartate residues on histones. Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+). Protects against axonal degeneration following mechanical or toxic insults.
• Tissue Specificity: Widely expressed with highest levels in skeletal muscle, heart and kidney. Also expressed in the liver pancreas and placenta. Widely expressed throughout the brain.
• KEGG Pathway:
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Nicotinate metabolism (R-HSA-196807)
• BioCyc Pathway: MetaCyc:HS10701-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leber congenital amaurosis 9	DIS35YGW	Definitive	Autosomal recessive	[1]
NMNAT1-related retinopathy	DISA5PVY	Definitive	Autosomal recessive	[2]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[3]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[4]
Spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis	DISUYEZI	Limited	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1).	[13]
OXYRESVERATROL	DMN7S4L	Investigative	OXYRESVERATROL increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1).	[14]

2 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 increases the methylation of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1 (NMNAT1).	[11]

References

• [1] Nonpenetrance of the most frequent autosomal recessive leber congenital amaurosis mutation in NMNAT1. JAMA Ophthalmol. 2014 Aug;132(8):1002-4. doi: 10.1001/jamaophthalmol.2014.983.
• [2] 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.
• [3] Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype. Clin Genet. 2018 Jan;93(1):149-154. doi: 10.1111/cge.13022. Epub 2017 May 9.
• [4] NMNAT1 mutations cause Leber congenital amaurosis. Nat Genet. 2012 Sep;44(9):1040-5. doi: 10.1038/ng.2361. Epub 2012 Jul 29.
• [5] An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs. Hum Mol Genet. 2020 Aug 3;29(13):2250-2260. doi: 10.1093/hmg/ddaa112.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [14] Oxyresveratrol stimulates mucin production in an NAD+-dependent manner in human intestinal goblet cells. Food Chem Toxicol. 2018 Aug;118:880-888.