Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT61XMYC)

• DOT Name: Diphosphoinositol polyphosphate phosphohydrolase 3-alpha (NUDT10)
• Synonyms: DIPP-3-alpha; DIPP3-alpha; hDIPP3alpha; EC 3.6.1.52; Diadenosine 5',5'''-P1,P6-hexaphosphate hydrolase 3-alpha; Diadenosine hexaphosphate hydrolase (AMP-forming); EC 3.6.1.60; Nucleoside diphosphate-linked moiety X motif 10; Nudix motif 10; hAps2
• Gene Name: NUDT10
• Related Disease:
  Autoimmune polyendocrinopathy
  Type-1 diabetes
  Addison disease
  Autoimmune disease
  Autoimmune polyendocrine syndrome type 1
  Graves disease
  Hypothyroidism
  Smith-Magenis syndrome
  Vitiligo
  Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
  Primary adrenal insufficiency
  Sjogren syndrome
  Asthma
• UniProt ID: NUD10_HUMAN
• PDB ID: 3MCF
• EC Number: 3.6.1.52; 3.6.1.60
• Pfam ID: PF00293
• Sequence:
  MKCKPNQTRTYDPEGFKKRAACLCFRSEREDEVLLVSSSRYPDRWIVPGGGMEPEEEPGG
  AAVREVYEEAGVKGKLGRLLGVFEQNQDPKHRTYVYVLTVTELLEDWEDSVSIGRKREWF
  KVEDAIKVLQCHKPVHAEYLEKLKLGGSPTNGNSMAPSSPDSDP
• Function: Cleaves a beta-phosphate from the diphosphate groups in PP-InsP5 (diphosphoinositol pentakisphosphate), suggesting that it may play a role in signal transduction. Also able to catalyze the hydrolysis of dinucleoside oligophosphates, with Ap6A and 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.
• Tissue Specificity: Mainly expressed in testis and, at lower level in brain. According to PubMed:12121577, it is widely expressed.
• Reactome Pathway: Synthesis of pyrophosphates in the cytosol (R-HSA-1855167)
• BioCyc Pathway: MetaCyc:HS04604-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune polyendocrinopathy	DISOLDB2	Definitive	Genetic Variation	[1]
Type-1 diabetes	DIS7HLUB	Definitive	Genetic Variation	[2]
Addison disease	DIS7HNOH	Strong	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Autoimmune polyendocrine syndrome type 1	DISWJP8J	Strong	Biomarker	[4]
Graves disease	DISU4KOQ	Strong	Biomarker	[5]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[6]
Smith-Magenis syndrome	DISG4G6X	Strong	Biomarker	[7]
Vitiligo	DISR05SL	Strong	Biomarker	[5]
Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome	DIST4IL8	moderate	Biomarker	[8]
Primary adrenal insufficiency	DISNMBYU	moderate	Genetic Variation	[1]
Sjogren syndrome	DISUBX7H	moderate	Genetic Variation	[1]
Asthma	DISW9QNS	Limited	Biomarker	[9]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
DIADENOSINE TETRAPHOSPHATE	DMTJOEL	Phase 2	Diphosphoinositol polyphosphate phosphohydrolase 3-alpha (NUDT10) increases the metabolism of DIADENOSINE TETRAPHOSPHATE.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-alpha (NUDT10).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-alpha (NUDT10).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-alpha (NUDT10).	[12]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-alpha (NUDT10).	[13]

References

• [1] A rare case of autoimmune polyglandular syndrome with Sjgren's syndrome and primary hypoparathyroidism.BMJ Case Rep. 2019 May 27;12(5):e228634. doi: 10.1136/bcr-2018-228634.
• [2] HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III.J Clin Endocrinol Metab. 2014 Jan;99(1):E177-82. doi: 10.1210/jc.2013-2852. Epub 2013 Dec 20.
• [3] ATPase4A Autoreactivity and Its Association With Autoimmune Phenotypes in the Type 1 Diabetes Genetics Consortium Study.Diabetes Care. 2015 Oct;38 Suppl 2(Suppl 2):S29-36. doi: 10.2337/dcs15-2006.
• [4] The natural history of autoimmune Addison's disease from the detection of autoantibodies to development of the disease: a long-term follow-up study on 143 patients.Eur J Endocrinol. 2019 Mar;180(3):223-234. doi: 10.1530/EJE-18-0313.
• [5] HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III.Horm Metab Res. 2003 Feb;35(2):120-4. doi: 10.1055/s-2003-39059.
• [6] Jaundice and anaemia as presenting features of an incomplete autoimmune polyglandular syndrome type II.BMJ Case Rep. 2019 Apr 8;12(4):e228490. doi: 10.1136/bcr-2018-228490.
• [7] Comparative analysis of epitope recognition of glutamic acid decarboxylase (GAD) by autoantibodies from different autoimmune disorders.Clin Exp Immunol. 1999 Dec;118(3):349-56. doi: 10.1046/j.1365-2249.1999.01030.x.
• [8] Autoimmune polyglandular syndromes.Nat Rev Endocrinol. 2010 May;6(5):270-7. doi: 10.1038/nrendo.2010.40. Epub 2010 Mar 23.
• [9] Suggestive association between variants in IL1RAPL and asthma symptoms in Latin American children.Eur J Hum Genet. 2017 Apr;25(4):439-445. doi: 10.1038/ejhg.2016.197. Epub 2017 Jan 25.
• [10] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] 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.
• [13] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [14] Cloning and characterisation of hAps1 and hAps2, human diadenosine polyphosphate-metabolising Nudix hydrolases. BMC Biochem. 2002 Jul 16;3:20. doi: 10.1186/1471-2091-3-20.