Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM7VBRC)

• DOT Name: Peroxisomal targeting signal 2 receptor (PEX7)
• Synonyms: PTS2 receptor; Peroxin-7
• Gene Name: PEX7
• Related Disease:
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 9B
  Rhizomelic chondrodysplasia punctata type 1
  Autism spectrum disorder
  Chondrodysplasia punctata
  Huntington disease
  Intellectual disability
  Peroxisome biogenesis disorder 1B
  Pervasive developmental disorder
  Zellweger spectrum disorders
  Adult Refsum disease
• UniProt ID: PEX7_HUMAN
• Pfam ID: PF00400
• Sequence:
  MSAVCGGAARMLRTPGRHGYAAEFSPYLPGRLACATAQHYGIAGCGTLLILDPDEAGLRL
  FRSFDWNDGLFDVTWSENNEHVLITCSGDGSLQLWDTAKAAGPLQVYKEHAQEVYSVDWS
  QTRGEQLVVSGSWDQTVKLWDPTVGKSLCTFRGHESIIYSTIWSPHIPGCFASASGDQTL
  RIWDVKAAGVRIVIPAHQAEILSCDWCKYNENLLVTGAVDCSLRGWDLRNVRQPVFELLG
  HTYAIRRVKFSPFHASVLASCSYDFTVRFWNFSKPDSLLETVEHHTEFTCGLDFSLQSPT
  QVADCSWDETIKIYDPACLTIPA
• Function: Receptor required for the peroxisomal import of proteins containing a C-terminal PTS2-type peroxisomal targeting signal. Specifically binds to cargo proteins containing a PTS2 peroxisomal targeting signal in the cytosol. Cargo protein-binding triggers interaction with PEX5 and formation of a ternary complex composed of PEX5 and PEX7 along with PTS2-containing cargo proteins, which is tranlocated into peroxisomes by passing through the PEX13-PEX14 docking complex.
• Tissue Specificity: Ubiquitous . Highest expression in pancreas, skeletal muscle and heart .
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway: Peroxisomal protein import (R-HSA-9033241)

Molecular Interaction Atlas (MIA) of This DOT

11 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 9B	DIST2B72	Definitive	Autosomal recessive	[2]
Rhizomelic chondrodysplasia punctata type 1	DISG7Y7E	Definitive	Autosomal recessive	[1]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[3]
Chondrodysplasia punctata	DISERVGO	Strong	Biomarker	[4]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[5]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Peroxisome biogenesis disorder 1B	DISCYF3O	Strong	Genetic Variation	[7]
Pervasive developmental disorder	DIS51975	Strong	Genetic Variation	[6]
Zellweger spectrum disorders	DISW52CE	Strong	Biomarker	[7]
Adult Refsum disease	DISU2BLL	Supportive	Autosomal recessive	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Peroxisomal targeting signal 2 receptor (PEX7).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peroxisomal targeting signal 2 receptor (PEX7).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Peroxisomal targeting signal 2 receptor (PEX7).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisomal targeting signal 2 receptor (PEX7).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Peroxisomal targeting signal 2 receptor (PEX7).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Peroxisomal targeting signal 2 receptor (PEX7).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Peroxisomal targeting signal 2 receptor (PEX7).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Peroxisomal targeting signal 2 receptor (PEX7).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Peroxisomal targeting signal 2 receptor (PEX7).	[16]

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] Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum Mutat. 2002 Oct;20(4):284-97. doi: 10.1002/humu.10124.
• [3] Using whole-exome sequencing to identify inherited causes of autism.Neuron. 2013 Jan 23;77(2):259-73. doi: 10.1016/j.neuron.2012.11.002.
• [4] A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton.Mol Genet Metab. 2010 Apr;99(4):408-16. doi: 10.1016/j.ymgme.2009.12.005. Epub 2009 Dec 11.
• [5] ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease.J Mol Med (Berl). 2008 Apr;86(4):485-90. doi: 10.1007/s00109-007-0299-6. Epub 2008 Mar 8.
• [6] Association between peroxisomal biogenesis factor 7 and autism spectrum disorders in a Korean population.J Child Neurol. 2012 Oct;27(10):1270-5. doi: 10.1177/0883073811435507. Epub 2012 Feb 28.
• [7] Genotype-phenotype correlations in disorders of peroxisome biogenesis.Mol Genet Metab. 1999 Oct;68(2):316-27. doi: 10.1006/mgme.1999.2926.
• [8] Adult Refsum Disease. 2006 Mar 20 [updated 2021 Sep 30]. 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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [15] 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.
• [16] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.