Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKOZXN3)

• DOT Name: Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3)
• Synonyms: NMN/NaMN adenylyltransferase 3; Nicotinamide-nucleotide adenylyltransferase 3; NMN adenylyltransferase 3; Nicotinate-nucleotide adenylyltransferase 3; NaMN adenylyltransferase 3; EC 2.7.7.18; Pyridine nucleotide adenylyltransferase 3; PNAT-3; EC 2.7.7.1
• Gene Name: NMNAT3
• UniProt ID: NMNA3_HUMAN
• PDB ID: 1NUP; 1NUQ; 1NUR; 1NUS; 1NUT; 1NUU
• EC Number: 2.7.7.1; 2.7.7.18
• Pfam ID: PF01467
• Sequence:
  MKSRIPVVLLACGSFNPITNMHLRMFEVARDHLHQTGMYQVIQGIISPVNDTYGKKDLAA
  SHHRVAMARLALQTSDWIRVDPWESEQAQWMETVKVLRHHHSKLLRSPPQMEGPDHGKAL
  FSTPAAVPELKLLCGADVLKTFQTPNLWKDAHIQEIVEKFGLVCVGRVGHDPKGYIAESP
  ILRMHQHNIHLAKEPVQNEISATYIRRALGQGQSVKYLIPDAVITYIKDHGLYTKGSTWK
  GKSTQSTEGKTS
• 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. Can also use GTP and ITP as nucleotide donors. Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+). For the pyrophosphorolytic activity, can use NAD(+), NADH, NaAD, nicotinic acid adenine dinucleotide phosphate (NHD), nicotinamide guanine dinucleotide (NGD) as substrates. Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+). Protects against axonal degeneration following injury.
• Tissue Specificity: Expressed in lung and spleen with lower levels in placenta and kidney.
• 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:HS08953-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 increases the methylation of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[3]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3).	[8]

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] 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.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [5] 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.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.