Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQIDE9Z)

• DOT Name: Peroxisomal biogenesis factor 19 (PEX19)
• Synonyms: 33 kDa housekeeping protein; Peroxin-19; Peroxisomal farnesylated protein
• Gene Name: PEX19
• Related Disease:
  Glaucoma/ocular hypertension
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 12A (Zellweger)
  Peroxisome biogenesis disorder 1A (Zellweger)
  Angle-closure glaucoma
  Malaria
  Neoplasm
  Non-small-cell lung cancer
  Zellweger spectrum disorders
  Ocular hypertension
• UniProt ID: PEX19_HUMAN
• PDB ID: 2W85; 2WL8; 3AJB; 3MK4; 5LNF
• Pfam ID: PF04614
• Sequence:
  MAAAEEGCSVGAEADRELEELLESALDDFDKAKPSPAPPSTTTAPDASGPQKRSPGDTAK
  DALFASQEKFFQELFDSELASQATAEFEKAMKELAEEEPHLVEQFQKLSEAAGRVGSDMT
  SQQEFTSCLKETLSGLAKNATDLQNSSMSEEELTKAMEGLGMDEGDGEGNILPIMQSIMQ
  NLLSKDVLYPSLKEITEKYPEWLQSHRESLPPEQFEKYQEQHSVMCKICEQFEAETPTDS
  ETTQKARFEMVLDLMQQLQDLGHPPKELAGEMPPGLNFDLDALNLSGPPGASGEQCLIM
• Function: Necessary for early peroxisomal biogenesis. Acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). Binds and stabilizes newly synthesized PMPs in the cytoplasm by interacting with their hydrophobic membrane-spanning domains, and targets them to the peroxisome membrane by binding to the integral membrane protein PEX3. Excludes CDKN2A from the nucleus and prevents its interaction with MDM2, which results in active degradation of TP53.
• Tissue Specificity: Ubiquitously expressed. Isoform 1 is strongly predominant in all tissues except in utero where isoform 2 is the main form.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Class I peroxisomal membrane protein import (R-HSA-9603798)
  ABC transporters in lipid homeostasis (R-HSA-1369062)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Genetic Variation	[1]
Peroxisome biogenesis disorder	DISBQ6QJ	Definitive	Autosomal recessive	[2]
Peroxisome biogenesis disorder 12A (Zellweger)	DISLHJSV	Definitive	Autosomal recessive	[3]
Peroxisome biogenesis disorder 1A (Zellweger)	DISDO833	Definitive	Autosomal recessive	[3]
Angle-closure glaucoma	DISZ95KY	Strong	Biomarker	[4]
Malaria	DISQ9Y50	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[7]
Ocular hypertension	DISC2BT9	Limited	Genetic Variation	[1]

9 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 Peroxisomal biogenesis factor 19 (PEX19).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peroxisomal biogenesis factor 19 (PEX19).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peroxisomal biogenesis factor 19 (PEX19).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peroxisomal biogenesis factor 19 (PEX19).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Peroxisomal biogenesis factor 19 (PEX19).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Peroxisomal biogenesis factor 19 (PEX19).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Peroxisomal biogenesis factor 19 (PEX19).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Peroxisomal biogenesis factor 19 (PEX19).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Peroxisomal biogenesis factor 19 (PEX19).	[19]

4 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 Peroxisomal biogenesis factor 19 (PEX19).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Peroxisomal biogenesis factor 19 (PEX19).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Peroxisomal biogenesis factor 19 (PEX19).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Peroxisomal biogenesis factor 19 (PEX19).	[13]

References

• [1] Clinical spectrum of pseudoexfoliation syndrome-An electronic records audit.PLoS One. 2017 Oct 27;12(10):e0185373. doi: 10.1371/journal.pone.0185373. eCollection 2017.
• [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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Functional Activity of Matrix Metalloproteinases 2 and 9 in Tears of Patients With Glaucoma.Invest Ophthalmol Vis Sci. 2017 May 1;58(6):BIO106-BIO113. doi: 10.1167/iovs.17-21723.
• [5] A neurotoxin that specifically targets Anopheles mosquitoes.Nat Commun. 2019 Jun 28;10(1):2869. doi: 10.1038/s41467-019-10732-w.
• [6] Efficacy of low-dose oral metronomic dosing of the prodrug of gemcitabine, LY2334737, in human tumor xenografts.Mol Cancer Ther. 2013 Apr;12(4):481-90. doi: 10.1158/1535-7163.MCT-12-0654. Epub 2013 Jan 31.
• [7] Zellweger Spectrum Disorder. 2003 Dec 12 [updated 2020 Oct 29]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] 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.
• [17] 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.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.