Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAHW80B)

• DOT Name: DNA-3-methyladenine glycosylase (MPG)
• Synonyms: EC 3.2.2.21; 3-alkyladenine DNA glycosylase; 3-methyladenine DNA glycosidase; ADPG; N-methylpurine-DNA glycosylase
• Gene Name: MPG
• Related Disease:
  Leishmaniasis
  Tuberculosis
  Xeroderma pigmentosum group C
  Adenoma
  Advanced cancer
  Alzheimer disease
  Anemia
  Aortic valve stenosis
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Carcinoma
  Chikungunya virus infection
  Chromosomal disorder
  Colorectal carcinoma
  Colorectal neoplasm
  Depression
  Esophageal adenocarcinoma
  Familial multiple trichoepithelioma
  Glioma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Hyperglycemia
  IgA nephropathy
  Inflammatory bowel disease
  Lung cancer
  Lung carcinoma
  Male infertility
  Neoplasm
  Neuralgia
  Pulmonary fibrosis
  Retinoblastoma
  Rheumatoid arthritis
  Type-1/2 diabetes
  Ulcerative colitis
  Plasma cell myeloma
  Polycystic ovarian syndrome
  Melanoma
  Subarachnoid hemorrhage
  Cervical cancer
  Cervical carcinoma
  Eosinophilic esophagitis
  Gallbladder cancer
  Gallbladder carcinoma
  Glioblastoma multiforme
  Human papillomavirus infection
  Non-small-cell lung cancer
  Schizophrenia
• UniProt ID: 3MG_HUMAN
• PDB ID: 1BNK; 1EWN; 1F4R; 1F6O; 3QI5; 3UBY; 7XFH; 7XFJ; 7XFM
• EC Number: 3.2.2.21
• Pfam ID: PF02245
• Sequence:
  MVTPALQMKKPKQFCRRMGQKKQRPARAGQPHSSSDAAQAPAEQPHSSSDAAQAPCPRER
  CLGPPTTPGPYRSIYFSSPKGHLTRLGLEFFDQPAVPLARAFLGQVLVRRLPNGTELRGR
  IVETEAYLGPEDEAAHSRGGRQTPRNRGMFMKPGTLYVYIIYGMYFCMNISSQGDGACVL
  LRALEPLEGLETMRQLRSTLRKGTASRVLKDRELCSGPSKLCQALAINKSFDQRDLAQDE
  AVWLERGPLEPSEPAVVAAARVGVGHAGEWARKPLRFYVRGSPWVSVVDRVAEQDTQA
• Function: Hydrolysis of the deoxyribose N-glycosidic bond to excise 3-methyladenine, and 7-methylguanine from the damaged DNA polymer formed by alkylation lesions.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway:
  Cleavage of the damaged purine (R-HSA-110331)
  Displacement of DNA glycosylase by APEX1 (R-HSA-110357)
  Recognition and association of DNA glycosylase with site containing an affected purine (R-HSA-110330)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leishmaniasis	DISABTW7	Definitive	Biomarker	[1]
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[2]
Xeroderma pigmentosum group C	DIS8DQXS	Definitive	Altered Expression	[3]
Adenoma	DIS78ZEV	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[6]
Anemia	DISTVL0C	Strong	Biomarker	[7]
Aortic valve stenosis	DISW7AQ9	Strong	Biomarker	[8]
Barrett esophagus	DIS416Y7	Strong	Altered Expression	[9]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[10]
Carcinoma	DISH9F1N	Strong	Altered Expression	[11]
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[12]
Chromosomal disorder	DISM5BB5	Strong	Altered Expression	[13]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[14]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[15]
Depression	DIS3XJ69	Strong	Genetic Variation	[16]
Esophageal adenocarcinoma	DISODWFP	Strong	Altered Expression	[9]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[17]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[18]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[19]
Hyperglycemia	DIS0BZB5	Strong	Genetic Variation	[16]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[20]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[5]
Lung cancer	DISCM4YA	Strong	Biomarker	[21]
Lung carcinoma	DISTR26C	Strong	Biomarker	[21]
Male infertility	DISY3YZZ	Strong	Altered Expression	[11]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[22]
Neuralgia	DISWO58J	Strong	Biomarker	[23]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[24]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[25]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[26]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[27]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[5]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[28]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Biomarker	[29]
Melanoma	DIS1RRCY	Disputed	Biomarker	[30]
Subarachnoid hemorrhage	DISI7I8Y	Disputed	Biomarker	[31]
Cervical cancer	DISFSHPF	Limited	Biomarker	[32]
Cervical carcinoma	DIST4S00	Limited	Biomarker	[32]
Eosinophilic esophagitis	DISR8WSB	Limited	Altered Expression	[33]
Gallbladder cancer	DISXJUAF	Limited	Biomarker	[34]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[34]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[35]
Human papillomavirus infection	DISX61LX	Limited	Biomarker	[36]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[22]
Schizophrenia	DISSRV2N	No Known	Unknown	[37]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	DNA-3-methyladenine glycosylase (MPG) decreases the response to substance of Temozolomide.	[47]
DTI-015	DMXZRW0	Approved	DNA-3-methyladenine glycosylase (MPG) decreases the response to substance of DTI-015.	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of DNA-3-methyladenine glycosylase (MPG).	[38]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of DNA-3-methyladenine glycosylase (MPG).	[42]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA-3-methyladenine glycosylase (MPG).	[46]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA-3-methyladenine glycosylase (MPG).	[39]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA-3-methyladenine glycosylase (MPG).	[40]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA-3-methyladenine glycosylase (MPG).	[41]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DNA-3-methyladenine glycosylase (MPG).	[43]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of DNA-3-methyladenine glycosylase (MPG).	[44]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA-3-methyladenine glycosylase (MPG).	[45]

References

• [1] Encapsulation of the HSP-90 Chaperone Inhibitor 17-AAG in Stable Liposome Allow Increasing the Therapeutic Index as Assessed, in vitro, on Leishmania (L) amazonensis Amastigotes-Hosted in Mouse CBA Macrophages.Front Cell Infect Microbiol. 2018 Aug 30;8:303. doi: 10.3389/fcimb.2018.00303. eCollection 2018.
• [2] Will the European Union reach the United Nations Millennium declaration target of a 50% reduction of tuberculosis mortality between 1990 and 2015?.BMC Public Health. 2017 Jul 6;17(1):629. doi: 10.1186/s12889-017-4544-9.
• [3] 17-(Allylamino)-17-Demethoxygeldanamycin Enhances Etoposide-Induced Cytotoxicity via the Downregulation of Xeroderma Pigmentosum Complementation Group C Expression in Human Lung Squamous Cell Carcinoma Cells.Pharmacology. 2018;102(1-2):91-104. doi: 10.1159/000490256. Epub 2018 Jun 28.
• [4] Chemically induced lung and forestomach neoplasias in transgenic mice carry mutant forms of the human c-Ha-ras transgene.Carcinogenesis. 1996 Feb;17(2):341-5. doi: 10.1093/carcin/17.2.341.
• [5] Oral Targeted Delivery by Nanoparticles Enhances Efficacy of an Hsp90 Inhibitor by Reducing Systemic Exposure in Murine Models of Colitis and Colitis-Associated Cancer.J Crohns Colitis. 2020 Jan 1;14(1):130-141. doi: 10.1093/ecco-jcc/jjz113.
• [6] Expression of nucleotide excision repair in Alzheimer's disease is higher in brain tissue than in blood.Neurosci Lett. 2018 Apr 13;672:53-58. doi: 10.1016/j.neulet.2018.02.043. Epub 2018 Feb 21.
• [7] Methoxy Polyethylene Glycol-Epoetin Beta as a Novel Erythropoiesis Stimulating Agent with Possible Nephroprotective and Cardiovascular Protective Effects in Non-Dialysis Chronic Kidney Disease Patients.Curr Pharm Biotechnol. 2017;18(4):303-308. doi: 10.2174/1389201018666170127104801.
• [8] Impact of Significant Mitral Regurgitation on Assessing the Severity of Aortic Stenosis.J Am Soc Echocardiogr. 2018 Jan;31(1):26-33. doi: 10.1016/j.echo.2017.09.012. Epub 2017 Nov 20.
• [9] Diagnostic correlation between the expression of the DNA repair enzyme N-methylpurine DNA glycosylase and esophageal adenocarcinoma onset: a retrospective pilot study.Dis Esophagus. 2013 Aug;26(6):644-50. doi: 10.1111/dote.12003. Epub 2012 Nov 8.
• [10] Imbalancing the DNA base excision repair pathway in the mitochondria; targeting and overexpressing N-methylpurine DNA glycosylase in mitochondria leads to enhanced cell killing.Cancer Res. 2003 Feb 1;63(3):608-15.
• [11] Altered expression of the DNA repair protein, N-methylpurine-DNA glycosylase (MPG) in human gonads.Anticancer Res. 2002 Mar-Apr;22(2A):793-8.
• [12] Regulation of Viral Replication, Apoptosis and Pro-Inflammatory Responses by 17-AAG during Chikungunya Virus Infection in Macrophages.Viruses. 2017 Jan 6;9(1):3. doi: 10.3390/v9010003.
• [13] DNA breaks and chromosomal aberrations arise when replication meets base excision repair.J Cell Biol. 2014 Jul 7;206(1):29-43. doi: 10.1083/jcb.201312078. Epub 2014 Jun 30.
• [14] Prognostic impact of changes in base excision repair machinery in sporadic colorectal cancer.Pathol Res Pract. 2018 Jan;214(1):64-71. doi: 10.1016/j.prp.2017.11.012. Epub 2017 Nov 15.
• [15] Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition. BMC Cancer. 2006 Oct 9;6:243. doi: 10.1186/1471-2407-6-243.
• [16] CLOCK gene polymorphisms and quality of aging in a cohort of nonagenarians - The MUGELLO Study.Sci Rep. 2019 Feb 6;9(1):1472. doi: 10.1038/s41598-018-37992-8.
• [17] N-methylpurine DNA glycosylase and DNA polymerase beta modulate BER inhibitor potentiation of glioma cells to temozolomide.Neuro Oncol. 2011 May;13(5):471-86. doi: 10.1093/neuonc/nor011. Epub 2011 Mar 3.
• [18] The structural HCV genes delivered by MPG cell penetrating peptide are directed to enhance immune responses in mice model.Drug Deliv. 2016 Oct;23(8):2852-2859. doi: 10.3109/10717544.2015.1108375. Epub 2015 Nov 11.
• [19] PIG11 over-expression predicts good prognosis and induces HepG2 cell apoptosis via reactive oxygen species-dependent mitochondrial pathway.Biomed Pharmacother. 2018 Dec;108:435-442. doi: 10.1016/j.biopha.2018.09.062. Epub 2018 Sep 18.
• [20] Genetic polymorphisms in HLA-DP and STAT4 are associated with IgA nephropathy in a Southwest Chinese population.Oncotarget. 2018 Jan 2;9(6):7066-7074. doi: 10.18632/oncotarget.23829. eCollection 2018 Jan 23.
• [21] Enzymatic MPG DNA repair assays for two different oxidative DNA lesions reveal associations with increased lung cancer risk.Carcinogenesis. 2014 Dec;35(12):2763-70. doi: 10.1093/carcin/bgu214. Epub 2014 Oct 29.
• [22] A PET imaging approach for determining EGFR mutation status for improved lung cancer patient management.Sci Transl Med. 2018 Mar 7;10(431):eaan8840. doi: 10.1126/scitranslmed.aan8840.
• [23] Heat-shock protein 90 (Hsp90) promotes opioid-induced anti-nociception by an ERK mitogen-activated protein kinase (MAPK) mechanism in mouse brain.J Biol Chem. 2017 Jun 23;292(25):10414-10428. doi: 10.1074/jbc.M116.769489. Epub 2017 Apr 27.
• [24] Amplified canonical transforming growth factor- signalling via heat shock protein 90 in pulmonary fibrosis.Eur Respir J. 2017 Feb 23;49(2):1501941. doi: 10.1183/13993003.01941-2015. Print 2017 Feb.
• [25] Surface-Modified Melphalan Nanoparticles for Intravitreal Chemotherapy of Retinoblastoma.Invest Ophthalmol Vis Sci. 2019 Apr 1;60(5):1696-1705. doi: 10.1167/iovs.18-26251.
• [26] The possible role of heat shock protein-70 induction in collagen-induced arthritis in rats.Physiol Int. 2019 Jun 1;106(2):128-139. doi: 10.1556/2060.106.2019.17. Epub 2019 Jul 2.
• [27] Anti--Glucosidase Activity by a Protease from Bacillus licheniformis.Molecules. 2019 Feb 15;24(4):691. doi: 10.3390/molecules24040691.
• [28] Synergistic effects of rmhTRAIL and 17-AAG on the proliferation and apoptosis of multiple myeloma cells.Hematology. 2018 Oct;23(9):620-625. doi: 10.1080/10245332.2018.1449338. Epub 2018 Mar 22.
• [29] HSP90 as a novel therapeutic target for posterior capsule opacification.Exp Eye Res. 2019 Dec;189:107821. doi: 10.1016/j.exer.2019.107821. Epub 2019 Oct 4.
• [30] A targeted therapy for melanoma by graphene oxide composite with microRNA carrier.Drug Des Devel Ther. 2018 Sep 21;12:3095-3106. doi: 10.2147/DDDT.S160088. eCollection 2018.
• [31] Inhibition of Heat Shock Protein 90 by 17-AAG Reduces Inflammation via P2X7 Receptor/NLRP3 Inflammasome Pathway and Increases Neurogenesis After Subarachnoid Hemorrhage in Mice.Front Mol Neurosci. 2018 Nov 6;11:401. doi: 10.3389/fnmol.2018.00401. eCollection 2018.
• [32] Gene amplification and expression of the DNA repair enzyme, N-methylpurine-DNA glycosylase (MPG) in HPV-infected cervical neoplasias.Anticancer Res. 2001 Jul-Aug;21(4A):2405-11.
• [33] TRAIL deficiency and PP2A activation with salmeterol ameliorates egg allergen-driven eosinophilic esophagitis.Am J Physiol Gastrointest Liver Physiol. 2016 Dec 1;311(6):G998-G1008. doi: 10.1152/ajpgi.00151.2016. Epub 2016 Oct 13.
• [34] Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer.Oncotarget. 2017 Apr 18;8(16):26169-26184. doi: 10.18632/oncotarget.15410.
• [35] C1q/TNF-related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma.Mol Oncol. 2018 Sep;12(9):1464-1479. doi: 10.1002/1878-0261.12349. Epub 2018 Aug 2.
• [36] Comparison of hybrid capture II, linear array, and a bead-based multiplex genotyping assay for detection of human papillomavirus in women with negative pap test results and atypical squamous cells of undetermined significance.J Clin Microbiol. 2012 Dec;50(12):4041-6. doi: 10.1128/JCM.02105-12. Epub 2012 Oct 3.
• [37] 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.
• [38] 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.
• [39] 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.
• [40] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [41] 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.
• [42] 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.
• [43] 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.
• [44] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [45] 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.
• [46] 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.
• [47] Sensitization of human carcinoma cells to alkylating agents by small interfering RNA suppression of 3-alkyladenine-DNA glycosylase. Cancer Res. 2005 Nov 15;65(22):10472-7. doi: 10.1158/0008-5472.CAN-05-1495.