Details of Drug Off-Target (DOT)

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

• DOT Name: Peroxisome biogenesis factor 10 (PEX10)
• Synonyms: EC 2.3.2.27; Peroxin-10; Peroxisomal biogenesis factor 10; Peroxisome assembly protein 10; RING finger protein 69
• Gene Name: PEX10
• Related Disease:
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 6A (Zellweger)
  Peroxisome biogenesis disorder 6B
  Cerebellar ataxia
  Peroxisomal disorder
  Peroxisome biogenesis disorder 1A (Zellweger)
  Autosomal recessive ataxia due to PEX10 deficiency
  Zellweger spectrum disorders
• UniProt ID: PEX10_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF04757 ; PF13639
• Sequence:
  MAPAAASPPEVIRAAQKDEYYRGGLRSAAGGALHSLAGARKWLEWRKEVELLSDVAYFGL
  TTLAGYQTLGEEYVSIIQVDPSRIHVPSSLRRGVLVTLHAVLPYLLDKALLPLEQELQAD
  PDSGRPLQGSLGPGGRGCSGARRWMRHHTATLTEQQRRALLRAVFVLRQGLACLQRLHVA
  WFYIHGVFYHLAKRLTGITYLRVRSLPGEDLRARVSYRLLGVISLLHLVLSMGLQLYGFR
  QRQRARKEWRLHRGLSHRRASLEERAVSRNPLCTLCLEERRHPTATPCGHLFCWECITAW
  CSSKAECPLCREKFPPQKLIYLRHYR
• 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. PEX10 also regulates PEX5 recycling by acting as a E3 ubiquitin-protein ligase. When PEX5 recycling is compromised, PEX10 catalyzes polyubiquitination of PEX5 during its passage through the retrotranslocation channel, leading to its degradation.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Peroxisome biogenesis disorder	DISBQ6QJ	Definitive	Autosomal recessive	[1]
Peroxisome biogenesis disorder 6A (Zellweger)	DIS8KSDI	Definitive	Autosomal recessive	[1]
Peroxisome biogenesis disorder 6B	DISTI7EA	Definitive	Autosomal recessive	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Peroxisomal disorder	DISV185U	Strong	Genetic Variation	[3]
Peroxisome biogenesis disorder 1A (Zellweger)	DISDO833	Strong	Biomarker	[4]
Autosomal recessive ataxia due to PEX10 deficiency	DIS343P6	Supportive	Autosomal recessive	[5]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[6]

2 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 Peroxisome biogenesis factor 10 (PEX10).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Peroxisome biogenesis factor 10 (PEX10).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peroxisome biogenesis factor 10 (PEX10).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peroxisome biogenesis factor 10 (PEX10).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Peroxisome biogenesis factor 10 (PEX10).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Peroxisome biogenesis factor 10 (PEX10).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Peroxisome biogenesis factor 10 (PEX10).	[13]
Z-Pro-Prolinal	DM43O2U	Investigative	Z-Pro-Prolinal increases the expression of Peroxisome biogenesis factor 10 (PEX10).	[14]

References

• [1] 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.
• [2] 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.
• [3] Ataxia with novel compound heterozygous PEX10 mutations and a literature review of PEX10-related peroxisome biogenesis disorders.Clin Neurol Neurosurg. 2019 Feb;177:92-96. doi: 10.1016/j.clineuro.2019.01.004. Epub 2019 Jan 7.
• [4] Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients. Hum Mutat. 2000;15(6):509-21. doi: 10.1002/1098-1004(200006)15:6<509::AID-HUMU3>3.0.CO;2-#.
• [5] Mutations in PEX10 are a cause of autosomal recessive ataxia. Ann Neurol. 2010 Aug;68(2):259-63. doi: 10.1002/ana.22035.
• [6] 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.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] 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.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Prolyl endopeptidase is involved in cellular signalling in human neuroblastoma SH-SY5Y cells. Neurosignals. 2011;19(2):97-109. doi: 10.1159/000326342. Epub 2011 Apr 10.