Details of Drug Off-Target (DOT)

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

• DOT Name: Bifunctional polynucleotide phosphatase/kinase (PNKP)
• Synonyms: DNA 5'-kinase/3'-phosphatase; Polynucleotide kinase-3'-phosphatase
• Gene Name: PNKP
• Related Disease:
  Ataxia - oculomotor apraxia type 4
  Microcephaly, seizures, and developmental delay
  Charcot-Marie-Tooth disease type 2B2
  Infantile spasm
• UniProt ID: PNKP_HUMAN
• PDB ID: 2BRF; 2W3O
• EC Number: 2.7.1.78; 3.1.3.32
• Pfam ID: PF13671 ; PF17913 ; PF08645
• Sequence:
  MGEVEAPGRLWLESPPGGAPPIFLPSDGQALVLGRGPLTQVTDRKCSRTQVELVADPETR
  TVAVKQLGVNPSTTGTQELKPGLEGSLGVGDTLYLVNGLHPLTLRWEETRTPESQPDTPP
  GTPLVSQDEKRDAELPKKRMRKSNPGWENLEKLLVFTAAGVKPQGKVAGFDLDGTLITTR
  SGKVFPTGPSDWRILYPEIPRKLRELEAEGYKLVIFTNQMSIGRGKLPAEEFKAKVEAVV
  EKLGVPFQVLVATHAGLYRKPVTGMWDHLQEQANDGTPISIGDSIFVGDAAGRPANWAPG
  RKKKDFSCADRLFALNLGLPFATPEEFFLKWPAAGFELPAFDPRTVSRSGPLCLPESRAL
  LSASPEVVVAVGFPGAGKSTFLKKHLVSAGYVHVNRDTLGSWQRCVTTCETALKQGKRVA
  IDNTNPDAASRARYVQCARAAGVPCRCFLFTATLEQARHNNRFREMTDSSHIPVSDMVMY
  GYRKQFEAPTLAEGFSAILEIPFRLWVEPRLGRLYCQFSEG
• Function: Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways. Through its two catalytic activities, PNK ensures that DNA termini are compatible with extension and ligation by either removing 3'-phosphates from, or by phosphorylating 5'-hydroxyl groups on, the ribose sugar of the DNA backbone.
• Tissue Specificity: Expressed in many tissues with highest expression in spleen and testis, and lowest expression in small intestine . Expressed in higher amount in pancreas, heart and kidney and at lower levels in brain, lung and liver .
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway: APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway (R-HSA-5649702)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ataxia - oculomotor apraxia type 4	DISIRQ3E	Definitive	Autosomal recessive	[1]
Microcephaly, seizures, and developmental delay	DIS7CVVV	Definitive	Autosomal recessive	[2]
Charcot-Marie-Tooth disease type 2B2	DISNPA2O	Strong	Autosomal recessive	[3]
Infantile spasm	DISZSKDG	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[13]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[18]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[17]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Bifunctional polynucleotide phosphatase/kinase (PNKP).	[19]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. Neurogenetics. 2018 Dec;19(4):215-225. doi: 10.1007/s10048-018-0555-7. Epub 2018 Jul 24.
• [4] Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet. 2010 Mar;42(3):245-9. doi: 10.1038/ng.526. Epub 2010 Jan 31.
• [5] 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.
• [6] 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.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] 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.
• [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] Pro-oxidant induced DNA damage in human lymphoblastoid cells: homeostatic mechanisms of genotoxic tolerance. Toxicol Sci. 2012 Aug;128(2):387-97. doi: 10.1093/toxsci/kfs152. Epub 2012 Apr 26.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Role of DNA Repair Pathways in Response to Zidovudine-induced DNA Damage in Immortalized Human Liver THLE2 Cells. Int J Biomed Sci. 2013 Mar;9(1):18-25.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] 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.
• [18] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [19] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [20] Imbalance in the antioxidant defence system and pro-genotoxic status induced by high glucose concentrations: In vitro testing in human liver cells. Toxicol In Vitro. 2020 Dec;69:105001. doi: 10.1016/j.tiv.2020.105001. Epub 2020 Sep 15.