Details of Drug Off-Target (DOT)

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

• DOT Name: Peroxisomal membrane protein PEX13 (PEX13)
• Synonyms: Peroxin-13
• Gene Name: PEX13
• Related Disease:
  Cataract
  Glaucoma/ocular hypertension
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 11A (Zellweger)
  Peroxisome biogenesis disorder 11B
  Adrenoleukodystrophy
  Adrenomyeloneuropathy
  Zellweger spectrum disorders
  Timothy syndrome
  Tourette syndrome
  Tuberous sclerosis
• UniProt ID: PEX13_HUMAN
• PDB ID: 7Z0I; 7Z0J; 7Z0K
• Pfam ID: PF04088 ; PF14604
• Sequence:
  MASQPPPPPKPWETRRIPGAGPGPGPGPTFQSADLGPTLMTRPGQPALTRVPPPILPRPS
  QQTGSSSVNTFRPAYSSFSSGYGAYGNSFYGGYSPYSYGYNGLGYNRLRVDDLPPSRFVQ
  QAEESSRGAFQSIESIVHAFASVSMMMDATFSAVYNSFRAVLDVANHFSRLKIHFTKVFS
  AFALVRTIRYLYRRLQRMLGLRRGSENEDLWAESEGTVACLGAEDRAATSAKSWPIFLFF
  AVILGGPYLIWKLLSTHSDEVTDSINWASGEDDHVVARAEYDFAAVSEEEISFRAGDMLN
  LALKEQQPKVRGWLLASLDGQTTGLIPANYVKILGKRKGRKTVESSKVSKQQQSFTNPTL
  TKGATVADSLDEQEAAFESVFVETNKVPVAPDSIGKDGEKQDL
• Function: Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor. The PEX13-PEX14 docking complex forms a large import pore which can be opened to a diameter of about 9 nm. Mechanistically, PEX5 receptor along with cargo proteins associates with the PEX14 subunit of the PEX13-PEX14 docking complex in the cytosol, leading to the insertion of the receptor into the organelle membrane with the concomitant translocation of the cargo into the peroxisome matrix. Involved in the import of PTS1- and PTS2-type containing proteins.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Class I peroxisomal membrane protein import (R-HSA-9603798)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract	DISUD7SL	Definitive	Biomarker	[1]
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Genetic Variation	[1]
Peroxisome biogenesis disorder	DISBQ6QJ	Definitive	Autosomal recessive	[2]
Peroxisome biogenesis disorder 11A (Zellweger)	DISKULS3	Definitive	Autosomal recessive	[3]
Peroxisome biogenesis disorder 11B	DISV9CQE	Definitive	Autosomal recessive	[3]
Adrenoleukodystrophy	DISTUD1F	Strong	Biomarker	[4]
Adrenomyeloneuropathy	DISPTS3P	Strong	Biomarker	[4]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[5]
Timothy syndrome	DISBXBZP	Limited	Genetic Variation	[6]
Tourette syndrome	DISX9D54	Limited	Genetic Variation	[6]
Tuberous sclerosis	DISEMUGZ	Limited	Genetic Variation	[6]

14 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 membrane protein PEX13 (PEX13).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Peroxisomal membrane protein PEX13 (PEX13).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Peroxisomal membrane protein PEX13 (PEX13).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[7]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Peroxisomal membrane protein PEX13 (PEX13).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Peroxisomal membrane protein PEX13 (PEX13).	[17]

References

• [1] Loss of heterozygosity in pseudoexfoliation syndrome.Invest Ophthalmol Vis Sci. 1999 May;40(6):1255-60.
• [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] PEX13 is mutated in complementation group 13 of the peroxisome-biogenesis disorders.Am J Hum Genet. 1999 Sep;65(3):621-34. doi: 10.1086/302534.
• [5] 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.
• [6] Molecular mechanism of a temperature-sensitive phenotype in peroxisomal biogenesis disorder.Pediatr Res. 2005 Aug;58(2):263-9. doi: 10.1203/01.PDR.0000169984.89199.69. Epub 2005 Jul 8.
• [7] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] 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.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] 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.