Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT98BZHE)

• DOT Name: Peroxisomal membrane protein PEX14 (PEX14)
• Synonyms: PTS1 receptor-docking protein; Peroxin-14; Peroxisomal membrane anchor protein PEX14
• Gene Name: PEX14
• Related Disease:
  Neuroblastoma
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 13A (Zellweger)
  Peroxisome biogenesis disorder 1B
  Breast cancer
  Breast carcinoma
  Prostate carcinoma
  Triple negative breast cancer
  Trypanosomiasis
  Neoplasm
  Zellweger spectrum disorders
  Alopecia
  Asthma
  Fetal growth restriction
• UniProt ID: PEX14_HUMAN
• PDB ID: 2W84; 2W85; 4BXU
• Pfam ID: PF04695
• Sequence:
  MASSEQAEQPSQPSSTPGSENVLPREPLIATAVKFLQNSRVRQSPLATRRAFLKKKGLTD
  EEIDMAFQQSGTAADEPSSLGPATQVVPVQPPHLISQPYSPAGSRWRDYGALAIIMAGIA
  FGFHQLYKKYLLPLILGGREDRKQLERMEAGLSELSGSVAQTVTQLQTTLASVQELLIQQ
  QQKIQELAHELAAAKATTSTNWILESQNINELKSEINSLKGLLLNRRQFPPSPSAPKIPS
  WQIPVKSPSPSSPAAVNHHSSSDISPVSNESTSSSPGKEGHSPEGSTVTYHLLGPQEEGE
  GVVDVKGQVRMEVQGEEEKREDKEDEEDEEDDDVSHVDEEDCLGVQREDRRGGDGQINEQ
  VEKLRRPEGASNESERD
• 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. Plays a key role for peroxisome movement through a direct interaction with tubulin.
• 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

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Peroxisome biogenesis disorder	DISBQ6QJ	Definitive	Autosomal recessive	[2]
Peroxisome biogenesis disorder 13A (Zellweger)	DISA88XF	Definitive	Autosomal recessive	[3]
Peroxisome biogenesis disorder 1B	DISCYF3O	Definitive	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[7]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[8]
Trypanosomiasis	DISUBO83	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	moderate	Biomarker	[1]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[10]
Alopecia	DIS37HU4	Limited	Genetic Variation	[11]
Asthma	DISW9QNS	Limited	Genetic Variation	[12]
Fetal growth restriction	DIS5WEJ5	Limited	Altered Expression	[13]

5 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 Peroxisomal membrane protein PEX14 (PEX14).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Peroxisomal membrane protein PEX14 (PEX14).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Peroxisomal membrane protein PEX14 (PEX14).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Peroxisomal membrane protein PEX14 (PEX14).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Peroxisomal membrane protein PEX14 (PEX14).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Peroxisomal membrane protein PEX14 (PEX14).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peroxisomal membrane protein PEX14 (PEX14).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peroxisomal membrane protein PEX14 (PEX14).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peroxisomal membrane protein PEX14 (PEX14).	[18]
Selenium	DM25CGV	Approved	Selenium increases the expression of Peroxisomal membrane protein PEX14 (PEX14).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Peroxisomal membrane protein PEX14 (PEX14).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peroxisomal membrane protein PEX14 (PEX14).	[23]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Peroxisomal membrane protein PEX14 (PEX14).	[24]

References

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• [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] Pharmacological induction of peroxisomes in peroxisome biogenesis disorders.Ann Neurol. 2000 Mar;47(3):286-96.
• [5] Identification of novel susceptibility markers for the risk of overall breast cancer as well as subtypes defined by hormone receptor status in the Chinese population.J Hum Genet. 2016 Dec;61(12):1027-1034. doi: 10.1038/jhg.2016.97. Epub 2016 Sep 8.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [8] An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection.Cancer Immunol Immunother. 2017 Dec;66(12):1529-1544. doi: 10.1007/s00262-017-2047-2. Epub 2017 Aug 2.
• [9] Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites.Science. 2017 Mar 31;355(6332):1416-1420. doi: 10.1126/science.aal1807.
• [10] 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.
• [11] Genetic prediction of male pattern baldness.PLoS Genet. 2017 Feb 14;13(2):e1006594. doi: 10.1371/journal.pgen.1006594. eCollection 2017 Feb.
• [12] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [13] Label-Free Proteomics of the Fetal Pancreas Identifies Deficits in the Peroxisome in Rats with Intrauterine Growth Restriction.Oxid Med Cell Longev. 2019 Nov 3;2019:1520753. doi: 10.1155/2019/1520753. eCollection 2019.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [23] 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.
• [24] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.