Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5AM0BM)

• DOT Name: Peroxisome assembly protein 26 (PEX26)
• Synonyms: Peroxin-26
• Gene Name: PEX26
• Related Disease:
  Adrenoleukodystrophy
  Adrenomyeloneuropathy
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 1A (Zellweger)
  Peroxisome biogenesis disorder 7B
  Atrial fibrillation
  Peroxisome biogenesis disorder 1B
  Peroxisome biogenesis disorder 7A (Zellweger)
  Amelogenesis imperfecta
  Dental enamel hypoplasia
  Zellweger spectrum disorders
• UniProt ID: PEX26_HUMAN
• Pfam ID: PF07163
• Sequence:
  MKSDSSTSAAPLRGLGGPLRSSEPVRAVPARAPAVDLLEEAADLLVVHLDFRAALETCER
  AWQSLANHAVAEEPAGTSLEVKCSLCVVGIQALAEMDRWQEVLSWVLQYYQVPEKLPPKV
  LELCILLYSKMQEPGAVLDVVGAWLQDPANQNLPEYGALAEFHVQRVLLPLGCLSEAEEL
  VVGSAAFGEERRLDVLQAIHTARQQQKQEHSGSEEAQKPNLEGSVSHKFLSLPMLVRQLW
  DSAVSHFFSLPFKKSLLAALILCLLVVRFDPASPSSLHFLYKLAQLFRWIRKAAFSRLYQ
  LRIRD
• Function: Peroxisomal docking factor that anchors PEX1 and PEX6 to peroxisome membranes. PEX26 is therefore required for the formation of the PEX1-PEX6 AAA ATPase complex, a complex that mediates the extraction of the PEX5 receptor from peroxisomal membrane.
• Tissue Specificity: Widely expressed . Highly expressed in kidney, liver, brain and skeletal muscles . Expressed at intermediate level in pancreas, placenta and heart . Weakly expressed in lung .
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Class I peroxisomal membrane protein import (R-HSA-9603798)
  Peroxisomal protein import (R-HSA-9033241)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adrenoleukodystrophy	DISTUD1F	Definitive	Biomarker	[1]
Adrenomyeloneuropathy	DISPTS3P	Definitive	Biomarker	[1]
Peroxisome biogenesis disorder	DISBQ6QJ	Definitive	Autosomal recessive	[2]
Peroxisome biogenesis disorder 1A (Zellweger)	DISDO833	Definitive	Autosomal recessive	[1]
Peroxisome biogenesis disorder 7B	DISKM7VC	Definitive	Autosomal recessive	[3]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[4]
Peroxisome biogenesis disorder 1B	DISCYF3O	Strong	Genetic Variation	[5]
Peroxisome biogenesis disorder 7A (Zellweger)	DISM5CI9	Strong	Autosomal recessive	[1]
Amelogenesis imperfecta	DISGYR9E	moderate	Biomarker	[6]
Dental enamel hypoplasia	DISN6ZMR	moderate	Biomarker	[6]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[7]

5 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 Peroxisome assembly protein 26 (PEX26).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peroxisome assembly protein 26 (PEX26).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peroxisome assembly protein 26 (PEX26).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Peroxisome assembly protein 26 (PEX26).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Peroxisome assembly protein 26 (PEX26).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Peroxisome assembly protein 26 (PEX26).	[10]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of Peroxisome assembly protein 26 (PEX26).	[14]

References

• [1] Mutations in novel peroxin gene PEX26 that cause peroxisome-biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation. Am J Hum Genet. 2003 Aug;73(2):233-46. doi: 10.1086/377004. Epub 2003 Jul 8.
• [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] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [5] Mutations in the peroxin Pex26p responsible for peroxisome biogenesis disorders of complementation group 8 impair its stability, peroxisomal localization, and interaction with the Pex1p x Pex6p complex.J Biol Chem. 2006 Jan 20;281(3):1317-23. doi: 10.1074/jbc.M510044200. Epub 2005 Oct 27.
• [6] Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, and PEX26 mutated in Heimler syndrome.Mol Genet Genomic Med. 2017 Jul 6;5(5):531-552. doi: 10.1002/mgg3.312. eCollection 2017 Sep.
• [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] 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.
• [10] 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.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women. Environ Health Perspect. 2022 Apr;130(4):47001. doi: 10.1289/EHP10174. Epub 2022 Apr 4.