Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0THBVA)

• DOT Name: Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT)
• Synonyms: dUTPase; EC 3.6.1.23; dUTP pyrophosphatase
• Gene Name: DUT
• Related Disease: Bone marrow failure and diabetes mellitus syndrome
• UniProt ID: DUT_HUMAN
• PDB ID: 1Q5H; 1Q5U; 2HQU; 3ARA; 3ARN; 3EHW; 4MZ5; 4MZ6; 5H4J; 7PWJ
• EC Number: 3.6.1.23
• Pfam ID: PF00692
• Sequence:
  MTPLCPRPALCYHFLTSLLRSAMQNARGARQRAEAAVLSGPGPPLGRAAQHGIPRPLSSA
  GRLSQGCRGASTVGAAGWKGELPKAGGSPAPGPETPAISPSKRARPAEVGGMQLRFARLS
  EHATAPTRGSARAAGYDLYSAYDYTIPPMEKAVVKTDIQIALPSGCYGRVAPRSGLAAKH
  FIDVGAGVIDEDYRGNVGVVLFNFGKEKFEVKKGDRIAQLICERIFYPEIEEVQALDDTE
  RGSGGFGSTGKN
• Function: Catalyzes the cleavage of 2'-deoxyuridine 5'-triphosphate (dUTP) into 2'-deoxyuridine 5'-monophosphate (dUMP) and inorganic pyrophosphate and through its action efficiently prevents uracil misincorporation into DNA and at the same time provides dUMP, the substrate for de novo thymidylate biosynthesis. Inhibits peroxisome proliferator-activated receptor (PPAR) activity by binding of its N-terminal to PPAR, preventing the latter's dimerization with retinoid X receptor. Essential for embryonic development.
• Tissue Specificity: Found in a variety of tissues. Isoform 3 expression is constitutive, while isoform 2 expression correlates with the onset of DNA replication (at protein level). Isoform 2 degradation coincides with the cessation of nuclear DNA replication (at protein level).
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• BioCyc Pathway: MetaCyc:HS05235-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone marrow failure and diabetes mellitus syndrome	DISP91UZ	Strong	Autosomal recessive	[1]

25 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 Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[13]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[10]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[14]
Acocantherin	DM7JT24	Approved	Acocantherin affects the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[16]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[17]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Deoxyuridine 5'-triphosphate nucleotidohydrolase, mitochondrial (DUT).	[24]

References

• [1] dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure. Diabetes. 2017 Apr;66(4):1086-1096. doi: 10.2337/db16-0839. Epub 2017 Jan 10.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [11] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [12] 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.
• [13] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Proteomics analysis of the proliferative effect of low-dose ouabain on human endothelial cells. Biol Pharm Bull. 2007 Feb;30(2):247-53. doi: 10.1248/bpb.30.247.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Regulation of lipocalin-2 gene by the cancer chemopreventive retinoid 4-HPR. Int J Cancer. 2006 Oct 1;119(7):1599-606.
• [18] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [19] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [20] 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.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.