Details of Drug Off-Target (DOT)

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

• DOT Name: Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3)
• Synonyms: DIPP-1; EC 3.6.1.52; Diadenosine hexaphosphate hydrolase; Ap6A hydrolase; EC 3.6.1.61; Endopolyphosphatase; EC 3.6.1.10; Nucleoside diphosphate-linked moiety X motif 3; Nudix motif 3; m7GpppN-mRNA hydrolase; EC 3.6.1.62; m7GpppX diphosphatase; EC 3.6.1.59
• Gene Name: NUDT3
• UniProt ID: NUDT3_HUMAN
• PDB ID: 2FVV; 2Q9P; 6PCK; 6PCL; 6WO7; 6WO8; 6WO9; 6WOA; 6WOB; 6WOC; 6WOD; 6WOE; 6WOF; 6WOG; 6WOH; 6WOI; 7TN4; 8T98; 8T99; 8TF9; 8TFA
• EC Number: 3.6.1.10; 3.6.1.52; 3.6.1.59; 3.6.1.61; 3.6.1.62
• Pfam ID: PF00293
• Sequence:
  MMKLKSNQTRTYDGDGYKKRAACLCFRSESEEEVLLVSSSRHPDRWIVPGGGMEPEEEPS
  VAAVREVCEEAGVKGTLGRLVGIFENQERKHRTYVYVLIVTEVLEDWEDSVNIGRKREWF
  KIEDAIKVLQYHKPVQASYFETLRQGYSANNGTPVVATTYSVSAQSSMSGIR
• Function: Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate) and [PP]2-InsP4 (bisdiphosphoinositol tetrakisphosphate), suggesting that it may play a role in signal transduction. InsP6 (inositol hexakisphosphate) is not a substrate. Acts as a negative regulator of the ERK1/2 pathway. Also able to catalyze the hydrolysis of dinucleoside oligophosphates, with diadenosine 5',5'''-P1,P6-hexaphosphate (Ap6A) and diadenosine 5',5'''- P1,P5-pentaphosphate (Ap5A) being the preferred substrates. The major reaction products are ADP and p4a from Ap6A and ADP and ATP from Ap5A. Also able to hydrolyze 5-phosphoribose 1-diphosphate. Acts as a decapping enzyme that modulates the stability of a subset of mRNAs implicated in cell motility. Hydrolyzes monomethylated capped RNA after both the alpha- and beta-phosphates generating m7GMP + ppRNA and m7GDP + pRNA. Can hydrolyze unmethylated capped RNAs. Divalent cations zinc, magnesium and manganese determine its substrate specificity. Exhibits diphosphoinositol polyphosphate phosphohydrolase in the presence of magnesium ions, diadenosine hexaphosphate hydrolase activity in the presence of manganese ions and endopolyphosphatase activity in the presence of zinc ions. Plays an important role in limiting DNA damage and maintaining cell survival upon oxidative stress via its endopolyphosphatase activity.
• Tissue Specificity: Widely expressed. Expressed at higher level in brain, heart, pancreas and liver. Also expressed in placenta, lung and kidney.
• Reactome Pathway: Synthesis of pyrophosphates in the cytosol (R-HSA-1855167)
• BioCyc Pathway: MetaCyc:HS03602-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 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 Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 1 (NUDT3).	[10]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] 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.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Gene expression profiling in Caco-2 human colon cells exposed to TCDD, benzo[a]pyrene, and natural Ah receptor agonists from cruciferous vegetables and citrus fruits. Toxicol In Vitro. 2008 Mar;22(2):396-410.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.