Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBUY58C)

• DOT Name: NAD-capped RNA hydrolase NUDT12 (NUDT12)
• Synonyms: DeNADding enzyme NUDT12; EC 3.6.1.-; NADH pyrophosphatase NUDT12; EC 3.6.1.22; Nucleoside diphosphate-linked moiety X motif 12; Nudix motif 12
• Gene Name: NUDT12
• UniProt ID: NUD12_HUMAN
• PDB ID: 6SCX
• EC Number: 3.6.1.-; 3.6.1.22
• Pfam ID: PF12796 ; PF00293 ; PF09296 ; PF09297
• Sequence:
  MSSVKRSLKQEIVTQFHCSAAEGDIAKLTGILSHSPSLLNETSENGWTALMYAARNGHPE
  IVQFLLEKGCDRSIVNKSRQTALDIAVFWGYKHIANLLATAKGGKKPWFLTNEVEECENY
  FSKTLLDRKSEKRNNSDWLLAKESHPATVFILFSDLNPLVTLGGNKESFQQPEVRLCQLN
  YTDIKDYLAQPEKITLIFLGVELEIKDKLLNYAGEVPREEEDGLVAWFALGIDPIAAEEF
  KQRHENCYFLHPPMPALLQLKEKEAGVVAQARSVLAWHSRYKFCPTCGNATKIEEGGYKR
  LCLKEDCPSLNGVHNTSYPRVDPVVIMQVIHPDGTKCLLGRQKRFPPGMFTCLAGFIEPG
  ETIEDAVRREVEEESGVKVGHVQYVACQPWPMPSSLMIGCLALAVSTEIKVDKNEIEDAR
  WFTREQVLDVLTKGKQQAFFVPPSRAIAHQLIKHWIRINPNL
• Function: mRNA decapping enzyme that specifically removes the nicotinamide adenine dinucleotide (NAD) cap from a subset of mRNAs by hydrolyzing the diphosphate linkage to produce nicotinamide mononucleotide (NMN) and 5' monophosphate mRNA. The NAD-cap is present at the 5'-end of some RNAs; in contrast to the canonical N7 methylguanosine (m7G) cap, the NAD cap promotes mRNA decay. Preferentially acts on NAD-capped transcripts in response to nutrient stress. Also acts on free nicotinamide adenine dinucleotide molecules: hydrolyzes NAD(H) into NMN(H) and AMP, and NADPH into NMNH and 2',5'-ADP. May act to regulate the concentration of peroxisomal nicotinamide nucleotide cofactors required for oxidative metabolism in this organelle. Regulates the levels of circadian clock components PER1, PER2, PER3 and CRY2 in the liver.
• KEGG Pathway:
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)
  Peroxisome (hsa04146)
• Reactome Pathway: Nicotinamide salvaging (R-HSA-197264)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorothiazide	DMLHESP	Approved	NAD-capped RNA hydrolase NUDT12 (NUDT12) increases the Metabolic disorder ADR of Chlorothiazide.	[11]

9 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 NAD-capped RNA hydrolase NUDT12 (NUDT12).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of NAD-capped RNA hydrolase NUDT12 (NUDT12).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of NAD-capped RNA hydrolase NUDT12 (NUDT12).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NAD-capped RNA hydrolase NUDT12 (NUDT12).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of NAD-capped RNA hydrolase NUDT12 (NUDT12).	[5]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of NAD-capped RNA hydrolase NUDT12 (NUDT12).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NAD-capped RNA hydrolase NUDT12 (NUDT12).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of NAD-capped RNA hydrolase NUDT12 (NUDT12).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of NAD-capped RNA hydrolase NUDT12 (NUDT12).	[10]

1 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 decreases the methylation of NAD-capped RNA hydrolase NUDT12 (NUDT12).	[7]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.