Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXBK59G)

DOT Name Protein mono-ADP-ribosyltransferase PARP4 (PARP4)
Synonyms
EC 2.4.2.-; 193 kDa vault protein; ADP-ribosyltransferase diphtheria toxin-like 4; ARTD4; PARP-related/IalphaI-related H5/proline-rich; PH5P; Poly polymerase 4; PARP-4; Vault poly(ADP-ribose) polymerase; VPARP
Gene Name PARP4
Related Disease
Breast cancer ( )
Breast carcinoma ( )
Pseudotumor cerebri ( )
Thyroid cancer ( )
Thyroid tumor ( )
Colon cancer ( )
Colonic neoplasm ( )
Esophageal squamous cell carcinoma ( )
leukaemia ( )
Leukemia ( )
Thyroid gland carcinoma ( )
Pancreatic cancer ( )
Lymphoma ( )
UniProt ID
PARP4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
8SWY; 8SWZ; 8SX1; 8SX2
EC Number
2.4.2.-
Pfam ID
PF00533 ; PF00644 ; PF08487 ; PF00092
Sequence
MVMGIFANCIFCLKVKYLPQQQKKKLQTDIKENGGKFSFSLNPQCTHIILDNADVLSQYQ
LNSIQKNHVHIANPDFIWKSIREKRLLDVKNYDPYKPLDITPPPDQKASSSEVKTEGLCP
DSATEEEDTVELTEFGMQNVEIPHLPQDFEVAKYNTLEKVGMEGGQEAVVVELQCSRDSR
DCPFLISSHFLLDDGMETRRQFAIKKTSEDASEYFENYIEELKKQGFLLREHFTPEATQL
ASEQLQALLLEEVMNSSTLSQEVSDLVEMIWAEALGHLEHMLLKPVNRISLNDVSKAEGI
LLLVKAALKNGETAEQLQKMMTEFYRLIPHKGTMPKEVNLGLLAKKADLCQLIRDMVNVC
ETNLSKPNPPSLAKYRALRCKIEHVEQNTEEFLRVRKEVLQNHHSKSPVDVLQIFRVGRV
NETTEFLSKLGNVRPLLHGSPVQNIVGILCRGLLLPKVVEDRGVQRTDVGNLGSGIYFSD
SLSTSIKYSHPGETDGTRLLLICDVALGKCMDLHEKDFSLTEAPPGYDSVHGVSQTASVT
TDFEDDEFVVYKTNQVKMKYIIKFSMPGDQIKDFHPSDHTELEEYRPEFSNFSKVEDYQL
PDAKTSSSTKAGLQDASGNLVPLEDVHIKGRIIDTVAQVIVFQTYTNKSHVPIEAKYIFP
LDDKAAVCGFEAFINGKHIVGEIKEKEEAQQEYLEAVTQGHGAYLMSQDAPDVFTVSVGN
LPPKAKVLIKITYITELSILGTVGVFFMPATVAPWQQDKALNENLQDTVEKICIKEIGTK
QSFSLTMSIEMPYVIEFIFSDTHELKQKRTDCKAVISTMEGSSLDSSGFSLHIGLSAAYL
PRMWVEKHPEKESEACMLVFQPDLDVDLPDLASESEVIICLDCSSSMEGVTFLQAKQIAL
HALSLVGEKQKVNIIQFGTGYKELFSYPKHITSNTMAAEFIMSATPTMGNTDFWKTLRYL
SLLYPARGSRNILLVSDGHLQDESLTLQLVKRSRPHTRLFACGIGSTANRHVLRILSQCG
AGVFEYFNAKSKHSWRKQIEDQMTRLCSPSCHSVSVKWQQLNPDVPEALQAPAQVPSLFL
NDRLLVYGFIPHCTQATLCALIQEKEFRTMVSTTELQKTTGTMIHKLAARALIRDYEDGI
LHENETSHEMKKQTLKSLIIKLSKENSLITQFTSFVAVEKRDENESPFPDIPKVSELIAK
EDVDFLPYMSWQGEPQEAVRNQSLLASSEWPELRLSKRKHRKIPFSKRKMELSQPEVSED
FEEDGLGVLPAFTSNLERGGVEKLLDLSWTESCKPTATEPLFKKVSPWETSTSSFFPILA
PAVGSYLPPTARAHSPASLSFASYRQVASFGSAAPPRQFDASQFSQGPVPGTCADWIPQS
ASCPTGPPQNPPSSPYCGIVFSGSSLSSAQSAPLQHPGGFTTRPSAGTFPELDSPQLHFS
LPTDPDPIRGFGSYHPSASSPFHFQPSAASLTANLRLPMASALPEALCSQSRTTPVDLCL
LEESVGSLEGSRCPVFAFQSSDTESDELSEVLQDSCFLQIKCDTKDDSILCFLEVKEEDE
IVCIQHWQDAVPWTELLSLQTEDGFWKLTPELGLILNLNTNGLHSFLKQKGIQSLGVKGR
ECLLDLIATMLVLQFIRTRLEKEGIVFKSLMKMDDASISRNIPWAFEAIKQASEWVRRTE
GQYPSICPRLELGNDWDSATKQLLGLQPISTVSPLHRVLHYSQG
Function Mono-ADP-ribosyltransferase that mediates mono-ADP-ribosylation of target proteins.
Tissue Specificity Widely expressed; the highest levels are in the kidney; also detected in heart, placenta, lung, liver, skeletal muscle, spleen, leukocytes and pancreas.
KEGG Pathway
Base excision repair (hsa03410 )
Apoptosis (hsa04210 )
Reactome Pathway
Maturation of nucleoprotein (R-HSA-9683610 )
Maturation of nucleoprotein (R-HSA-9694631 )
Nicotinamide salvaging (R-HSA-197264 )

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Breast cancer DIS7DPX1 Definitive Biomarker [1]
Breast carcinoma DIS2UE88 Definitive Genetic Variation [2]
Pseudotumor cerebri DISLLY7S Definitive Genetic Variation [3]
Thyroid cancer DIS3VLDH Definitive Biomarker [1]
Thyroid tumor DISLVKMD Definitive Biomarker [1]
Colon cancer DISVC52G Strong Biomarker [4]
Colonic neoplasm DISSZ04P Strong Biomarker [4]
Esophageal squamous cell carcinoma DIS5N2GV Strong Biomarker [5]
leukaemia DISS7D1V Strong Altered Expression [6]
Leukemia DISNAKFL Strong Altered Expression [6]
Thyroid gland carcinoma DISMNGZ0 Strong Biomarker [1]
Pancreatic cancer DISJC981 moderate Biomarker [7]
Lymphoma DISN6V4S Limited Posttranslational Modification [8]
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⏷ Show the Full List of 13 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
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 Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [9]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [21]
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12 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [10]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [11]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [12]
Estradiol DMUNTE3 Approved Estradiol affects the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [13]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [14]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [15]
Nicotine DMWX5CO Approved Nicotine increases the splicing of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [16]
Liothyronine DM6IR3P Approved Liothyronine decreases the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [17]
Lithium DMZ3OU6 Phase 2 Lithium increases the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [18]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide decreases the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [19]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [20]
Paraoxon DMN4ZKC Investigative Paraoxon increases the expression of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [23]
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⏷ Show the Full List of 12 Drug(s)
1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
PJ34 DMXO6YH Preclinical PJ34 affects the binding of Protein mono-ADP-ribosyltransferase PARP4 (PARP4). [22]
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References

1 Genetic variants of PARP4 gene and PARP4P2 pseudogene in patients with multiple primary tumors including thyroid cancer.Mutat Res. 2019 Nov;816-818:111672. doi: 10.1016/j.mrfmmm.2019.111672. Epub 2019 Jun 1.
2 Assessment of PARP4 as a candidate breast cancer susceptibility gene.Breast Cancer Res Treat. 2019 Aug;177(1):145-153. doi: 10.1007/s10549-019-05286-w. Epub 2019 May 22.
3 Genetic Survey of Adult-Onset Idiopathic Intracranial Hypertension.J Neuroophthalmol. 2019 Mar;39(1):50-55. doi: 10.1097/WNO.0000000000000648.
4 Increased susceptibility of vault poly(ADP-ribose) polymerase-deficient mice to carcinogen-induced tumorigenesis.Cancer Res. 2005 Oct 1;65(19):8846-52. doi: 10.1158/0008-5472.CAN-05-0770.
5 Singlecell intratumoral stemness analysis reveals the involvement of cell cycle and DNA damage repair in two different types of esophageal cancer.Oncol Rep. 2019 Jun;41(6):3201-3208. doi: 10.3892/or.2019.7117. Epub 2019 Apr 15.
6 Fluctuation of gene expression for poly(ADP-ribose) synthetase during hemin-induced erythroid differentiation of human leukemia K562 cells and its reversion process.Biochim Biophys Acta. 1991 Mar 26;1088(3):359-64. doi: 10.1016/0167-4781(91)90125-6.
7 Mutations in Known and Novel cancer Susceptibility Genes in Young Patients with Pancreatic Cancer.Arch Iran Med. 2018 Jun 1;21(6):228-233.
8 Enhanced expression of poly(ADP-ribose) synthetase gene in malignant lymphoma.Am J Hematol. 1991 Aug;37(4):223-7. doi: 10.1002/ajh.2830370402.
9 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.
10 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.
11 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
12 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
13 Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
14 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.
15 Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
16 Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
17 Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
18 Effect of mood stabilizers on gene expression in lymphoblastoid cells. J Neural Transm (Vienna). 2010 Feb;117(2):155-64.
19 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
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 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.
22 Identification of pim kinases as novel targets for PJ34 with confounding effects in PARP biology. ACS Chem Biol. 2012 Dec 21;7(12):1962-7. doi: 10.1021/cb300317y. Epub 2012 Oct 8.
23 Genomic and phenotypic alterations of the neuronal-like cells derived from human embryonal carcinoma stem cells (NT2) caused by exposure to organophosphorus compounds paraoxon and mipafox. Int J Mol Sci. 2014 Jan 9;15(1):905-26. doi: 10.3390/ijms15010905.