Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGZ7ME2)

• DOT Name: Peroxisomal biogenesis factor 3 (PEX3)
• Synonyms: Peroxin-3; Peroxisomal assembly protein PEX3
• Gene Name: PEX3
• Related Disease:
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 10A (Zellweger)
  Peroxisome biogenesis disorder 10B
  Respiratory papillomatosis
  Trypanosomiasis
  Hydrops fetalis
  Peroxisomal disorder
  Zellweger spectrum disorders
  Intellectual disability
  Melanoma
• UniProt ID: PEX3_HUMAN
• PDB ID: 3AJB; 3MK4
• Pfam ID: PF04882
• Sequence:
  MLRSVWNFLKRHKKKCIFLGTVLGGVYILGKYGQKKIREIQEREAAEYIAQARRQYHFES
  NQRTCNMTVLSMLPTLREALMQQLNSESLTALLKNRPSNKLEIWEDLKIISFTRSTVAVY
  STCMLVVLLRVQLNIIGGYIYLDNAAVGKNGTTILAPPDVQQQYLSSIQHLLGDGLTELI
  TVIKQAVQKVLGSVSLKHSLSLLDLEQKLKEIRNLVEQHKSSSWINKDGSKPLLCHYMMP
  DEETPLAVQACGLSPRDITTIKLLNETRDMLESPDFSTVLNTCLNRGFSRLLDNMAEFFR
  PTEQDLQHGNSMNSLSSVSLPLAKIIPIVNGQIHSVCSETPSHFVQDLLTMEQVKDFAAN
  VYEAFSTPQQLEK
• Function: Involved in peroxisome biosynthesis and integrity. Assembles membrane vesicles before the matrix proteins are translocated. As a docking factor for PEX19, is necessary for the import of peroxisomal membrane proteins in the peroxisomes.
• Tissue Specificity: Found in all examined tissues.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Class I peroxisomal membrane protein import (R-HSA-9603798)
  ABC transporters in lipid homeostasis (R-HSA-1369062)

Molecular Interaction Atlas (MIA) of This DOT

10 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 10A (Zellweger)	DISUT5TZ	Definitive	Autosomal recessive	[2]
Peroxisome biogenesis disorder 10B	DIS51ZSU	Strong	Mitochondrial	[3]
Respiratory papillomatosis	DISXL96I	Strong	Biomarker	[4]
Trypanosomiasis	DISUBO83	Strong	Biomarker	[5]
Hydrops fetalis	DISD9BBF	moderate	Biomarker	[6]
Peroxisomal disorder	DISV185U	moderate	Biomarker	[6]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[7]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[8]
Melanoma	DIS1RRCY	Disputed	Altered Expression	[9]

1 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 biogenesis factor 3 (PEX3).	[10]

15 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 Peroxisomal biogenesis factor 3 (PEX3).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Peroxisomal biogenesis factor 3 (PEX3).	[18]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[19]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[20]
Chenodiol	DMQ8JIK	Approved	Chenodiol decreases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Peroxisomal biogenesis factor 3 (PEX3).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Peroxisomal biogenesis factor 3 (PEX3).	[24]

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] Novel PEX3 Gene Mutations Resulting in a Moderate Zellweger Spectrum Disorder. JIMD Rep. 2017;34:71-75. doi: 10.1007/8904_2016_10. Epub 2016 Aug 25.
• [4] Demonstration of antibodies against human papillomavirus type-11 E6 and L2 proteins in patients with recurrent respiratory papillomatosis.Auris Nasus Larynx. 1997 Apr;24(2):185-91. doi: 10.1016/s0385-8146(96)00000-4.
• [5] Evolutionary divergent PEX3 is essential for glycosome biogenesis and survival of trypanosomatid parasites.Biochim Biophys Acta Mol Cell Res. 2019 Dec;1866(12):118520. doi: 10.1016/j.bbamcr.2019.07.015. Epub 2019 Jul 29.
• [6] Zellweger syndrome with unusual findings: non-immune hydrops fetalis, dermal erythropoiesis and hypoplastic toe nails.J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S345-8. doi: 10.1007/s10545-009-9010-0. Epub 2009 Dec 23.
• [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] Biochemical and genetic characterization of an unusual mild PEX3-related Zellweger spectrum disorder.Mol Genet Metab. 2017 Aug;121(4):325-328. doi: 10.1016/j.ymgme.2017.06.004. Epub 2017 Jun 17.
• [9] WIPI1, BAG1, and PEX3 Autophagy-Related Genes Are Relevant Melanoma Markers.Oxid Med Cell Longev. 2018 Dec 2;2018:1471682. doi: 10.1155/2018/1471682. eCollection 2018.
• [10] 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.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [17] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] 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.
• [20] 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.
• [21] Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes. Life Sci. 2016 Jul 1;156:47-56.
• [22] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [23] 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.
• [24] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.