Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCPOQ6W)

• DOT Name: Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7)
• Synonyms: EC 3.6.1.-; Nucleoside diphosphate-linked moiety X motif 7; Nudix motif 7
• Gene Name: NUDT7
• Related Disease:
  Cranio-osteoarthropathy
  Liver cancer
  Osteoarthritis
• UniProt ID: NUDT7_HUMAN
• PDB ID: 5QGG ; 5QGH ; 5QGI ; 5QGJ ; 5QGK ; 5QGL ; 5QGM ; 5QGN ; 5QGO ; 5QGP ; 5QGQ ; 5QGR ; 5QGS ; 5QGT ; 5QGU ; 5QGV ; 5QGW ; 5QGX ; 5QGY ; 5QGZ ; 5QH0 ; 5QH1 ; 5QH2 ; 5QH3 ; 5QH4 ; 5QH5 ; 5QH6 ; 5QH7 ; 5QH8 ; 5QH9 ; 5QHA ; 5QHB ; 5QHC ; 5QHE ; 5QHF ; 5QHG ; 5QHH ; 5T3P
• EC Number: 3.6.1.-
• Pfam ID: PF00293
• Sequence:
  MSRLGLPEEPVRNSLLDDAKARLRKYDIGGKYSHLPYNKYSVLLPLVAKEGKLHLLFTVR
  SEKLRRAPGEVCFPGGKRDPTDMDDAATALREAQEEVGLRPHQVEVVCCLVPCLIDTDTL
  ITPFVGLIDHNFQAQPNPAEVKDVFLVPLAYFLHPQVHDQHYVTRLGHRFINHIFEYTNP
  EDGVTYQIKGMTANLAVLVAFIILEKKPTFEVQFNLNDVLASSEELFLKVHKKATSRL
• Function: Fatty acyl-coenzyme A (CoA) diphosphatase that hydrolyzes fatty acyl-CoA to yield acyl-4'-phosphopantetheine and adenosine 3',5'-bisphosphate. Cleaves CoA, CoA esters and oxidized CoA with similar efficiencies. Preferentially hydrolyzes medium-chain acyl-CoAs and bile acid-CoAs. Has no activity toward NDP-sugars, CDP-alcohols, (deoxy)nucleoside 5'-triphosphates, nucleoside 5'-di or monophosphates, diadenosine polyphosphates, NAD, NADH, NADP, NADPH or thymidine-5'-monophospho-p-nitrophenyl ester. May be required to eliminate oxidized CoA from peroxisomes, or regulate CoA and acyl-CoA levels in this organelle in response to metabolic demand. Does not play a role in U8 snoRNA decapping activity. Binds U8 snoRNA. Exhibits decapping activity towards dpCoA-capped RNAs in vitro.
• Tissue Specificity: Expressed in liver, kidney, pancreas, pituitary, small intestine, spleen, heart and placenta. Weakly expressed in brain.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Peroxisomal lipid metabolism (R-HSA-390918)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cranio-osteoarthropathy	DISJ5ZZB	Strong	Biomarker	[1]
Liver cancer	DISDE4BI	Strong	Biomarker	[2]
Osteoarthritis	DIS05URM	moderate	Biomarker	[3]

19 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 Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[9]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[17]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Peroxisomal coenzyme A diphosphatase NUDT7 (NUDT7).	[19]

References

• [1] Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform.J Biol Chem. 2018 Mar 16;293(11):4134-4148. doi: 10.1074/jbc.RA117.001358. Epub 2018 Jan 29.
• [2] Genomic models of short-term exposure accurately predict long-term chemical carcinogenicity and identify putative mechanisms of action.PLoS One. 2014 Jul 24;9(7):e102579. doi: 10.1371/journal.pone.0102579. eCollection 2014.
• [3] Dysregulation of the NUDT7-PGAM1 axis is responsible for chondrocyte death during osteoarthritis pathogenesis.Nat Commun. 2018 Aug 24;9(1):3427. doi: 10.1038/s41467-018-05787-0.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] 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.
• [12] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [13] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] 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.
• [19] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.