Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK4LMG7)

• DOT Name: Peroxisomal targeting signal 1 receptor (PEX5)
• Synonyms: PTS1 receptor; PTS1R; PTS1-BP; Peroxin-5; Peroxisomal C-terminal targeting signal import receptor; Peroxisome receptor 1
• Gene Name: PEX5
• Related Disease:
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 1A (Zellweger)
  Peroxisome biogenesis disorder 2B
  Asthma
  Colon carcinoma
  Epilepsy
  Glaucoma/ocular hypertension
  Hepatocellular carcinoma
  Microcephaly
  Mulibrey nanism
  Peripheral neuropathy
  Peroxisome biogenesis disorder 2A (Zellweger)
  Peroxisome biogenesis disorder type 3B
  Rhizomelic chondrodysplasia punctata
  Rhizomelic chondrodysplasia punctata type 1
  Rhizomelic chondrodysplasia punctata type 5
  Zellweger spectrum disorders
  OPTN-related open angle glaucoma
• UniProt ID: PEX5_HUMAN
• PDB ID: 1FCH; 2C0L; 2C0M; 2J9Q; 2W84; 3R9A; 4BXU; 4KXK; 4KYO; 7Z0K
• Pfam ID: PF13432 ; PF13181
• Sequence:
  MAMRELVEAECGGANPLMKLAGHFTQDKALRQEGLRPGPWPPGAPASEAASKPLGVASED
  ELVAEFLQDQNAPLVSRAPQTFKMDDLLAEMQQIEQSNFRQAPQRAPGVADLALSENWAQ
  EFLAAGDAVDVTQDYNETDWSQEFISEVTDPLSVSPARWAEEYLEQSEEKLWLGEPEGTA
  TDRWYDEYHPEEDLQHTASDFVAKVDDPKLANSEFLKFVRQIGEGQVSLESGAGSGRAQA
  EQWAAEFIQQQGTSDAWVDQFTRPVNTSALDMEFERAKSAIESDVDFWDKLQAELEEMAK
  RDAEAHPWLSDYDDLTSATYDKGYQFEEENPLRDHPQPFEEGLRRLQEGDLPNAVLLFEA
  AVQQDPKHMEAWQYLGTTQAENEQELLAISALRRCLELKPDNQTALMALAVSFTNESLQR
  QACETLRDWLRYTPAYAHLVTPAEEGAGGAGLGPSKRILGSLLSDSLFLEVKELFLAAVR
  LDPTSIDPDVQCGLGVLFNLSGEYDKAVDCFTAALSVRPNDYLLWNKLGATLANGNQSEE
  AVAAYRRALELQPGYIRSRYNLGISCINLGAHREAVEHFLEALNMQRKSRGPRGEGGAMS
  ENIWSTLRLALSMLGQSDAYGAADARDLSTLLTMFGLPQ
• Function: Receptor that mediates peroxisomal import of proteins containing a C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type). Binds to cargo proteins containing a PTS1 peroxisomal targeting signal in the cytosol, and translocates them into the peroxisome matrix by passing through the PEX13-PEX14 docking complex along with cargo proteins. PEX5 receptor is then retrotranslocated into the cytosol, leading to release of bound cargo in the peroxisome matrix, and reset for a subsequent peroxisome import cycle ; [Isoform 1]: In addition to promoting peroxisomal translocation of proteins containing a PTS1 peroxisomal targeting signal, mediates peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal via its interaction with PEX7. Interaction with PEX7 only takes place when PEX7 is associated with cargo proteins containing a PTS2 peroxisomal targeting signal. PEX7 along with PTS2-containing cargo proteins are then translocated through the PEX13-PEX14 docking complex together with PEX5 ; [Isoform 2]: Does not mediate translocation of peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal.
• Tissue Specificity: Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Pexophagy (R-HSA-9664873)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)

Molecular Interaction Atlas (MIA) of This DOT

18 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 1A (Zellweger)	DISDO833	Definitive	Autosomal recessive	[2]
Peroxisome biogenesis disorder 2B	DISQ29H1	Definitive	Autosomal recessive	[3]
Asthma	DISW9QNS	Strong	CausalMutation	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	CausalMutation	[3]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Microcephaly	DIS2GRD8	Strong	CausalMutation	[3]
Mulibrey nanism	DIS138YX	Strong	Biomarker	[7]
Peripheral neuropathy	DIS7KN5G	Strong	CausalMutation	[3]
Peroxisome biogenesis disorder 2A (Zellweger)	DISV9IUH	Strong	Autosomal recessive	[8]
Peroxisome biogenesis disorder type 3B	DIS8FORA	Strong	Biomarker	[2]
Rhizomelic chondrodysplasia punctata	DISF3YE7	Strong	Genetic Variation	[9]
Rhizomelic chondrodysplasia punctata type 1	DISG7Y7E	Strong	Genetic Variation	[3]
Rhizomelic chondrodysplasia punctata type 5	DISKG6SP	Strong	Autosomal recessive	[3]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[10]
OPTN-related open angle glaucoma	DISDR98A	Limited	Genetic Variation	[5]

5 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 Peroxisomal targeting signal 1 receptor (PEX5).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Peroxisomal targeting signal 1 receptor (PEX5).	[12]
Liothyronine	DM6IR3P	Approved	Liothyronine increases the expression of Peroxisomal targeting signal 1 receptor (PEX5).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Peroxisomal targeting signal 1 receptor (PEX5).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Peroxisomal targeting signal 1 receptor (PEX5).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Peroxisomal targeting signal 1 receptor (PEX5).	[13]

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] Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nat Genet. 1995 Feb;9(2):115-25. doi: 10.1038/ng0295-115.
• [3] A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform. Hum Mol Genet. 2015 Oct 15;24(20):5845-54. doi: 10.1093/hmg/ddv305. Epub 2015 Jul 28.
• [4] Impairment of peroxisomal biogenesis in human colon carcinoma.Carcinogenesis. 1999 Jun;20(6):985-9. doi: 10.1093/carcin/20.6.985.
• [5] Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure.Hum Mol Genet. 2007 Mar 15;16(6):609-17. doi: 10.1093/hmg/ddm001. Epub 2007 Feb 22.
• [6] Protein-mimicking nanoparticles for the reproduction of transient protein-receptor interactions.Colloids Surf B Biointerfaces. 2017 Dec 1;160:682-687. doi: 10.1016/j.colsurfb.2017.10.023. Epub 2017 Oct 7.
• [7] TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import.J Cell Biol. 2017 Sep 4;216(9):2843-2858. doi: 10.1083/jcb.201611170. Epub 2017 Jul 19.
• [8] Mitochondrial alterations caused by defective peroxisomal biogenesis in a mouse model for Zellweger syndrome (PEX5 knockout mouse). Am J Pathol. 2001 Oct;159(4):1477-94. doi: 10.1016/S0002-9440(10)62534-5.
• [9] Growth charts for individuals with rhizomelic chondrodysplasia punctata.Am J Med Genet A. 2017 Jan;173(1):108-113. doi: 10.1002/ajmg.a.37961. Epub 2016 Sep 12.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] 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.
• [14] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [15] 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.
• [16] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.