Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFDXJA1)

• DOT Name: Diphosphoinositol polyphosphate phosphohydrolase 3-beta (NUDT11)
• Synonyms: DIPP-3-beta; DIPP3-beta; hDIPP3beta; EC 3.6.1.52; Diadenosine 5',5'''-P1,P6-hexaphosphate hydrolase 3-beta; Diadenosine hexaphosphate hydrolase (AMP-forming); EC 3.6.1.60; Nucleoside diphosphate-linked moiety X motif 11; Nudix motif 11; hAps1
• Gene Name: NUDT11
• Related Disease:
  Autoimmune hypoparathyroidism
  Adrenocortical insufficiency
  Aicardi-Goutieres syndrome
  Alzheimer disease
  Autoimmune disease
  Autoimmune polyendocrinopathy
  Candidiasis
  Chronic mucocutaneous candidiasis
  Fatty liver disease
  Female hypogonadism
  Hypoparathyroidism
  Non-alcoholic fatty liver disease
  Obesity
  Autoimmune polyendocrine syndrome type 1
  Keratitis
  Addison disease
  Capillary malformation
  Influenza
  Methicillin-resistant staphylococci infection
• UniProt ID: NUD11_HUMAN
• EC Number: 3.6.1.52; 3.6.1.60
• Pfam ID: PF00293
• Sequence:
  MKCKPNQTRTYDPEGFKKRAACLCFRSEREDEVLLVSSSRYPDRWIVPGGGMEPEEEPGG
  AAVREVYEEAGVKGKLGRLLGVFEQNQDRKHRTYVYVLTVTELLEDWEDSVSIGRKREWF
  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 also expressed in pancreas and weakly expressed in thymus, prostate, ovary, lung, small intestine and heart.
• Reactome Pathway: Synthesis of pyrophosphates in the cytosol (R-HSA-1855167)
• BioCyc Pathway: MetaCyc:HS05381-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune hypoparathyroidism	DISPBPEO	Definitive	Biomarker	[1]
Adrenocortical insufficiency	DISZ0CPT	Strong	Biomarker	[2]
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Autoimmune polyendocrinopathy	DISOLDB2	Strong	Biomarker	[5]
Candidiasis	DISIRYMU	Strong	Biomarker	[6]
Chronic mucocutaneous candidiasis	DISPSGYF	Strong	Biomarker	[2]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[7]
Female hypogonadism	DISWASB4	Strong	Genetic Variation	[8]
Hypoparathyroidism	DISICS0V	Strong	Genetic Variation	[2]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[7]
Obesity	DIS47Y1K	Strong	Biomarker	[9]
Autoimmune polyendocrine syndrome type 1	DISWJP8J	moderate	Biomarker	[10]
Keratitis	DISMFOEI	moderate	Biomarker	[11]
Addison disease	DIS7HNOH	Limited	Biomarker	[12]
Capillary malformation	DISR6ZSG	Limited	Biomarker	[13]
Influenza	DIS3PNU3	Limited	Biomarker	[14]
Methicillin-resistant staphylococci infection	DIS6DRDZ	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-beta (NUDT11).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-beta (NUDT11).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-beta (NUDT11).	[18]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-beta (NUDT11).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-beta (NUDT11).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-beta (NUDT11).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-beta (NUDT11).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Diphosphoinositol polyphosphate phosphohydrolase 3-beta (NUDT11).	[23]

References

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• [2] A new mutation site in the AIRE gene causes autoimmune polyendocrine syndrome type 1.Immunogenetics. 2017 Oct;69(10):643-651. doi: 10.1007/s00251-017-0995-5. Epub 2017 May 24.
• [3] Nonallelism for the audiogenic seizure prone (Asp1) and the aryl hydrocarbon receptor (Ahr) loci in mice.J Neurogenet. 1998 Nov;12(4):191-203. doi: 10.3109/01677069809108558.
• [4] Effects of Zn2+ binding on the structural and dynamic properties of amyloid peptide associated with Alzheimer's disease: Asp1 or Glu11?.ACS Chem Neurosci. 2013 Nov 20;4(11):1458-68. doi: 10.1021/cn4001445. Epub 2013 Sep 13.
• [5] AIRE is not essential for the induction of human tolerogenic dendritic cells.Autoimmunity. 2016 Jun;49(4):211-8. doi: 10.3109/08916934.2016.1148692. Epub 2016 Feb 25.
• [6] Persistent Candida albicans colonization and molecular mechanisms of azole resistance in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients.J Antimicrob Chemother. 2010 Dec;65(12):2505-13. doi: 10.1093/jac/dkq354. Epub 2010 Sep 28.
• [7] Sugary Kefir Strain Lactobacillus mali APS1 Ameliorated Hepatic Steatosis by Regulation of SIRT-1/Nrf-2 and Gut Microbiota in Rats.Mol Nutr Food Res. 2018 Apr;62(8):e1700903. doi: 10.1002/mnfr.201700903. Epub 2018 Apr 3.
• [8] Autoimmune oophoritis with multiple molecular targets mitigated by transgenic expression of mater.Endocrinology. 2011 Jun;152(6):2465-73. doi: 10.1210/en.2011-0022. Epub 2011 Mar 29.
• [9] A combination of Lactobacillus mali APS1 and dieting improved the efficacy of obesity treatment via manipulating gut microbiome in mice.Sci Rep. 2018 Apr 18;8(1):6153. doi: 10.1038/s41598-018-23844-y.
• [10] Development and Validation of an Ultrasensitive Single Molecule Array Digital Enzyme-linked Immunosorbent Assay for Human Interferon-.J Vis Exp. 2018 Jun 14;(136):57421. doi: 10.3791/57421.
• [11] Topical tacrolimus solution in autoimmune polyglandular syndrome-1-associated keratitis.Br J Ophthalmol. 2017 Sep;101(9):1230-1233. doi: 10.1136/bjophthalmol-2016-309808. Epub 2017 Jan 30.
• [12] Addison's disease: a survey on 633 patients in Padova.Eur J Endocrinol. 2013 Oct 21;169(6):773-84. doi: 10.1530/EJE-13-0528. Print 2013 Dec.
• [13] The Evolving View of IL-17-Mediated Immunity in Defense Against Mucocutaneous Candidiasis in Humans.Int Rev Immunol. 2015;34(4):348-63. doi: 10.3109/08830185.2015.1049345.
• [14] The parasite-derived rOv-ASP-1 is an effective antigen-sparing CD4(+) T cell-dependent adjuvant for the trivalent inactivated influenza vaccine, and functions in the absence of MyD88 pathway.Vaccine. 2018 Jun 14;36(25):3650-3665. doi: 10.1016/j.vaccine.2018.05.029.
• [15] Purification and characterisation of a novel antistaphylococcal peptide (ASP-1) from Bacillus sp. URID 12.1.Int J Antimicrob Agents. 2018 Jan;51(1):89-97. doi: 10.1016/j.ijantimicag.2017.08.030. Epub 2017 Sep 5.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] 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.
• [18] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [19] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [20] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [21] 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.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.