Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMHM1DH)

• DOT Name: Bis(5'-nucleosyl)-tetraphosphatase (NUDT2)
• Synonyms: EC 3.6.1.17; Diadenosine 5',5'''-P1,P4-tetraphosphate asymmetrical hydrolase; Ap4A hydrolase; Ap4Aase; Diadenosine tetraphosphatase; Nucleoside diphosphate-linked moiety X motif 2; Nudix motif 2
• Gene Name: NUDT2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Dilated cardiomyopathy 1A
  Ductal breast carcinoma in situ
  Intellectual developmental disorder with or without peripheral neuropathy
  Invasive ductal breast carcinoma
  Malaria
  Intellectual disability
  Neurodevelopmental disorder
  Advanced cancer
• UniProt ID: AP4A_HUMAN
• PDB ID: 1XSA; 1XSB; 1XSC; 3U53; 4ICK; 4IJX
• EC Number: 3.6.1.17
• Pfam ID: PF00293
• Sequence:
  MALRACGLIIFRRCLIPKVDNNAIEFLLLQASDGIHHWTPPKGHVEPGEDDLETALRETQ
  EEAGIEAGQLTIIEGFKRELNYVARNKPKTVIYWLAEVKDYDVEIRLSHEHQAYRWLGLE
  EACQLAQFKEMKAALQEGHQFLCSIEA
• Function: Catalyzes the asymmetric hydrolysis of diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) to yield AMP and ATP. Exhibits decapping activity towards FAD-capped RNAs and dpCoA-capped RNAs in vitro.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Detoxification of Reactive Oxygen Species (R-HSA-3299685)

Molecular Interaction Atlas (MIA) of This DOT

11 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]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[1]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Biomarker	[1]
Intellectual developmental disorder with or without peripheral neuropathy	DISRA4KS	Strong	Autosomal recessive	[2]
Invasive ductal breast carcinoma	DIS43J58	Strong	Biomarker	[1]
Malaria	DISQ9Y50	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	moderate	Biomarker	[4]
Neurodevelopmental disorder	DIS372XH	moderate	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[5]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DIADENOSINE TETRAPHOSPHATE	DMTJOEL	Phase 2	Bis(5'-nucleosyl)-tetraphosphatase (NUDT2) increases the hydrolysis of DIADENOSINE TETRAPHOSPHATE.	[1]

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 Bis(5'-nucleosyl)-tetraphosphatase (NUDT2).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Bis(5'-nucleosyl)-tetraphosphatase (NUDT2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bis(5'-nucleosyl)-tetraphosphatase (NUDT2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bis(5'-nucleosyl)-tetraphosphatase (NUDT2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Bis(5'-nucleosyl)-tetraphosphatase (NUDT2).	[1]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Bis(5'-nucleosyl)-tetraphosphatase (NUDT2).	[10]

References

• [1] Nudix-type motif 2 in human breast carcinoma: a potent prognostic factor associated with cell proliferation. Int J Cancer. 2011 Apr 15;128(8):1770-82. doi: 10.1002/ijc.25505.
• [2] Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry. 2017 Apr;22(4):615-624. doi: 10.1038/mp.2016.113. Epub 2016 Jul 19.
• [3] Functional genetic evaluation of DNA house-cleaning enzymes in the malaria parasite: dUTPase and Ap4AH are essential in Plasmodium berghei but ITPase and NDH are dispensable.Expert Opin Ther Targets. 2019 Mar;23(3):251-261. doi: 10.1080/14728222.2019.1575810. Epub 2019 Feb 13.
• [4] A founder nonsense variant in NUDT2 causes a recessive neurodevelopmental disorder in Saudi Arab children.Clin Genet. 2018 Oct;94(3-4):393-395. doi: 10.1111/cge.13386. Epub 2018 Jul 30.
• [5] NUDT2 Disruption Elevates Diadenosine Tetraphosphate (Ap4A) and Down-Regulates Immune Response and Cancer Promotion Genes.PLoS One. 2016 May 4;11(5):e0154674. doi: 10.1371/journal.pone.0154674. eCollection 2016.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Nudix-type motif 2 in human breast carcinoma: a potent prognostic factor associated with cell proliferation. Int J Cancer. 2011 Apr 15;128(8):1770-82. doi: 10.1002/ijc.25505.
• [10] 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.
• [11] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [12] Nudix-type motif 2 in human breast carcinoma: a potent prognostic factor associated with cell proliferation. Int J Cancer. 2011 Apr 15;128(8):1770-82. doi: 10.1002/ijc.25505.