Details of Drug Off-Target (DOT)

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

• DOT Name: Peroxisome biogenesis factor 2 (PEX2)
• Synonyms: EC 2.3.2.27; EC 2.3.2.36; 35 kDa peroxisomal membrane protein; Peroxin-2; Peroxisomal membrane protein 3; Peroxisome assembly factor 1; PAF-1; RING finger protein 72
• Gene Name: PEX2
• Related Disease:
  Intellectual disability
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 5A (Zellweger)
  Peroxisome biogenesis disorder 5B
  Attention deficit hyperactivity disorder
  Lysosomal lipid storage disorder
  Peroxisomal disorder
  Peroxisome biogenesis disorder 1B
  Trichohepatoenteric syndrome
  Zellweger spectrum disorders
• UniProt ID: PEX2_HUMAN
• EC Number: 2.3.2.27; 2.3.2.36
• Pfam ID: PF04757
• Sequence:
  MASRKENAKSANRVLRISQLDALELNKALEQLVWSQFTQCFHGFKPGLLARFEPEVKACL
  WVFLWRFTIYSKNATVGQSVLNIKYKNDFSPNLRYQPPSKNQKIWYAVCTIGGRWLEERC
  YDLFRNHHLASFGKVKQCVNFVIGLLKLGGLINFLIFLQRGKFATLTERLLGIHSVFCKP
  QNICEVGFEYMNRELLWHGFAEFLIFLLPLINVQKLKAKLSSWCIPLTGAPNSDNTLATS
  GKECALCGEWPTMPHTIGCEHIFCYFCAKSSFLFDVYFTCPKCGTEVHSLQPLKSGIEMS
  EVNAL
• Function: E3 ubiquitin-protein ligase component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling. The retrotranslocation channel is composed of PEX2, PEX10 and PEX12; each subunit contributing transmembrane segments that coassemble into an open channel that specifically allows the passage of PEX5 through the peroxisomal membrane. PEX2 also regulates peroxisome organization by acting as a E3 ubiquitin-protein ligase. PEX2 ubiquitinates PEX5 during its passage through the retrotranslocation channel: catalyzes monoubiquitination of PEX5 at 'Cys-11', a modification that acts as a signal for PEX5 extraction into the cytosol. Required for pexophagy in response to starvation by mediating ubiquitination of peroxisomal proteins, such as PEX5 and ABCD3/PMP70. Also involved in the response to reactive oxygen species (ROS) by mediating 'Lys-48'-linked polyubiquitination and subsequent degradation of PNPLA2/ATGL, thereby regulating lipolysis.
• 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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Peroxisome biogenesis disorder	DISBQ6QJ	Definitive	Autosomal recessive	[2]
Peroxisome biogenesis disorder 5A (Zellweger)	DIS8H0DD	Definitive	Autosomal recessive	[2]
Peroxisome biogenesis disorder 5B	DIS9E8J7	Definitive	Autosomal recessive	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[1]
Lysosomal lipid storage disorder	DISXQRTX	Strong	Genetic Variation	[4]
Peroxisomal disorder	DISV185U	Strong	Biomarker	[5]
Peroxisome biogenesis disorder 1B	DISCYF3O	Strong	Genetic Variation	[6]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[7]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Peroxisome biogenesis factor 2 (PEX2).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Peroxisome biogenesis factor 2 (PEX2).	[15]
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Peroxisome biogenesis factor 2 (PEX2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisome biogenesis factor 2 (PEX2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peroxisome biogenesis factor 2 (PEX2).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Peroxisome biogenesis factor 2 (PEX2).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peroxisome biogenesis factor 2 (PEX2).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Peroxisome biogenesis factor 2 (PEX2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Peroxisome biogenesis factor 2 (PEX2).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Peroxisome biogenesis factor 2 (PEX2).	[17]

References

• [1] Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study.Mol Psychiatry. 2017 Feb;22(2):250-256. doi: 10.1038/mp.2016.85. Epub 2016 May 24.
• [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] The peroxisome deficient PEX2 Zellweger mouse: pathologic and biochemical correlates of lipid dysfunction.J Mol Neurosci. 2001 Apr-Jun;16(2-3):289-97; discussion 317-21. doi: 10.1385/JMN:16:2-3:289.
• [5] The Pichia pastoris PER6 gene product is a peroxisomal integral membrane protein essential for peroxisome biogenesis and has sequence similarity to the Zellweger syndrome protein PAF-1.Mol Cell Biol. 1996 May;16(5):2527-36. doi: 10.1128/MCB.16.5.2527.
• [6] Defective PEX gene products correlate with the protein import, biochemical abnormalities, and phenotypic heterogeneity in peroxisome biogenesis disorders. J Med Genet. 1999 Oct;36(10):779-81. doi: 10.1136/jmg.36.10.779.
• [7] A human gene responsible for Zellweger syndrome that affects peroxisome assembly.Science. 1992 Feb 28;255(5048):1132-4. doi: 10.1126/science.1546315.
• [8] 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.
• [9] 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.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] 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.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. Sci Rep. 2018 Jul 12;8(1):10497. doi: 10.1038/s41598-018-28813-z.