Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5JLP2H)

• DOT Name: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2)
• Synonyms: NMN/NaMN adenylyltransferase 2; EC 2.7.7.1; EC 2.7.7.18; Nicotinamide mononucleotide adenylyltransferase 2; NMN adenylyltransferase 2; Nicotinate-nucleotide adenylyltransferase 2; NaMN adenylyltransferase 2
• Gene Name: NMNAT2
• UniProt ID: NMNA2_HUMAN
• EC Number: 2.7.7.1; 2.7.7.18
• Pfam ID: PF01467
• Sequence:
  MTETTKTHVILLACGSFNPITKGHIQMFERARDYLHKTGRFIVIGGIVSPVHDSYGKQGL
  VSSRHRLIMCQLAVQNSDWIRVDPWECYQDTWQTTCSVLEHHRDLMKRVTGCILSNVNTP
  SMTPVIGQPQNETPQPIYQNSNVATKPTAAKILGKVGESLSRICCVRPPVERFTFVDENA
  NLGTVMRYEEIELRILLLCGSDLLESFCIPGLWNEADMEVIVGDFGIVVVPRDAADTDRI
  MNHSSILRKYKNNIMVVKDDINHPMSVVSSTKSRLALQHGDGHVVDYLSQPVIDYILKSQ
  LYINASG
• Function: Nicotinamide/nicotinate-nucleotide adenylyltransferase that acts as an axon maintenance factor. Axon survival factor required for the maintenance of healthy axons: acts by delaying Wallerian axon degeneration, an evolutionarily conserved process that drives the loss of damaged axons. Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP. Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate but with a lower efficiency. Cannot use triazofurin monophosphate (TrMP) as substrate. Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+). For the pyrophosphorolytic activity prefers NAD(+), NADH and NaAD as substrates and degrades nicotinic acid adenine dinucleotide phosphate (NHD) less effectively. Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+). Also acts as an activator of ADP-ribosylation by supporting the catalytic activity of PARP16 and promoting mono-ADP-ribosylation of ribosomes by PARP16.
• Tissue Specificity: Highly expressed in brain, in particular in cerebrum, cerebellum, occipital lobe, frontal lobe, temporal lobe and putamen. Also found in the heart, skeletal muscle, pancreas and islets of Langerhans.
• 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:HS08173-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[3]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[2]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[3]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[6]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (NMNAT2).	[11]

References

• [1] 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.
• [2] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [3] 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.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [8] 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.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [10] 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.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.