Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHYCBA6)

• DOT Name: ADP-sugar pyrophosphatase (NUDT5)
• Synonyms: EC 3.6.1.13; 8-oxo-dGDP phosphatase; EC 3.6.1.58; Nuclear ATP-synthesis protein NUDIX5; EC 2.7.7.96; Nucleoside diphosphate-linked moiety X motif 5; Nudix motif 5; hNUDT5; YSA1H
• Gene Name: NUDT5
• Related Disease:
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Neoplasm
  Advanced cancer
• UniProt ID: NUDT5_HUMAN
• PDB ID: 2DSB ; 2DSC ; 2DSD ; 3AC9 ; 3ACA ; 3BM4 ; 3L85 ; 5NQR ; 5NWH ; 5QJ4 ; 5QJ5 ; 5QJ6 ; 5QJ7 ; 5QJ8 ; 5QJ9 ; 5QJA ; 5QJB ; 5QJC ; 5QJD ; 5QJE ; 5QJF ; 5QJG ; 5QJH ; 5QJI ; 5QJJ ; 5QJK ; 5QJL ; 5QJM ; 5QJN ; 5QJO ; 5QJP ; 5QJQ ; 5QJR ; 5QJS ; 5QJT ; 5QJU ; 5QJV ; 5QJW ; 5QJX ; 5QJY ; 5QJZ ; 5QK0 ; 5QK1 ; 5QK2 ; 5QK3 ; 5QK4 ; 5QK5 ; 5QK6 ; 5QK7 ; 5QK8 ; 5QK9 ; 5QKA ; 5QKB ; 5QTL ; 5QTM ; 5QTN ; 5QTO ; 5QTP ; 5QTQ ; 5QTR ; 5QTS ; 6GRU
• EC Number: 2.7.7.96; 3.6.1.13; 3.6.1.58
• Pfam ID: PF00293
• Sequence:
  MESQEPTESSQNGKQYIISEELISEGKWVKLEKTTYMDPTGKTRTWESVKRTTRKEQTAD
  GVAVIPVLQRTLHYECIVLVKQFRPPMGGYCIEFPAGLIDDGETPEAAALRELEEETGYK
  GDIAECSPAVCMDPGLSNCTIHIVTVTINGDDAENARPKPKPGDGEFVEVISLPKNDLLQ
  RLDALVAEEHLTVDARVYSYALALKHANAKPFEVPFLKF
• Function: Enzyme that can either act as an ADP-sugar pyrophosphatase in absence of diphosphate or catalyze the synthesis of ATP in presence of diphosphate. In absence of diphosphate, hydrolyzes with similar activities various modified nucleoside diphosphates such as ADP-ribose, ADP-mannose, ADP-glucose, 8-oxo-GDP and 8-oxo-dGDP. Can also hydrolyze other nucleotide sugars with low activity. In presence of diphosphate, mediates the synthesis of ATP in the nucleus by catalyzing the conversion of ADP-ribose to ATP and ribose 5-phosphate. Nuclear ATP synthesis takes place when dephosphorylated at Thr-45. Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming. Does not play a role in U8 snoRNA decapping activity. Binds U8 snoRNA.
• Tissue Specificity: Widely expressed. Most abundant in liver.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Phosphate bond hydrolysis by NUDT proteins (R-HSA-2393930)
• BioCyc Pathway: MetaCyc:HS09255-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of ADP-sugar pyrophosphatase (NUDT5).	[4]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of ADP-sugar pyrophosphatase (NUDT5).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ADP-sugar pyrophosphatase (NUDT5).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ADP-sugar pyrophosphatase (NUDT5).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ADP-sugar pyrophosphatase (NUDT5).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of ADP-sugar pyrophosphatase (NUDT5).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ADP-sugar pyrophosphatase (NUDT5).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of ADP-sugar pyrophosphatase (NUDT5).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of ADP-sugar pyrophosphatase (NUDT5).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ADP-sugar pyrophosphatase (NUDT5).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ADP-sugar pyrophosphatase (NUDT5).	[14]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of ADP-sugar pyrophosphatase (NUDT5).	[15]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of ADP-sugar pyrophosphatase (NUDT5).	[16]

References

• [1] Expression of Oncogenic Drivers in 3D Cell Culture Depends on Nuclear ATP Synthesis by NUDT5.Cancers (Basel). 2019 Sep 10;11(9):1337. doi: 10.3390/cancers11091337.
• [2] NUDT expression is predictive of prognosis in patients with clear cell renal cell carcinoma.Oncol Lett. 2017 Nov;14(5):6121-6128. doi: 10.3892/ol.2017.6997. Epub 2017 Sep 18.
• [3] MutT-related proteins are novel progression and prognostic markers for colorectal cancer.Oncotarget. 2017 Nov 11;8(62):105714-105726. doi: 10.18632/oncotarget.22393. eCollection 2017 Dec 1.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [13] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [14] 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.
• [15] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [16] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.