Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9F6LPN)

• DOT Name: Peroxisome assembly protein 12 (PEX12)
• Synonyms: Peroxin-12; Peroxisome assembly factor 3; PAF-3
• Gene Name: PEX12
• Related Disease:
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 3A (Zellweger)
  Peroxisome biogenesis disorder type 3B
  Peroxisomal disorder
  Zellweger spectrum disorders
  Peroxisome biogenesis disorder 1B
• UniProt ID: PEX12_HUMAN
• Pfam ID: PF04757
• Sequence:
  MAEHGAHFTAASVADDQPSIFEVVAQDSLMTAVRPALQHVVKVLAESNPTHYGFLWRWFD
  EIFTLLDLLLQQHYLSRTSASFSENFYGLKRIVMGDTHKSQRLASAGLPKQQLWKSIMFL
  VLLPYLKVKLEKLVSSLREEDEYSIHPPSSRWKRFYRAFLAAYPFVNMAWEGWFLVQQLR
  YILGKAQHHSPLLRLAGVQLGRLTVQDIQALEHKPAKASMMQQPARSVSEKINSALKKAV
  GGVALSLSTGLSVGVFFLQFLDWWYSSENQETIKSLTALPTPPPPVHLDYNSDSPLLPKM
  KTVCPLCRKTRVNDTVLATSGYVFCYRCVFHYVRSHQACPITGYPTEVQHLIKLYSPEN
• Function: 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. PEX12 also regulates PEX5 recycling by activating the E3 ubiquitin-protein ligase activity of PEX10. When PEX5 recycling is compromised, PEX12 stimulates PEX10-mediated polyubiquitination of PEX5, leading to its subsequent degradation.
• 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

6 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 3A (Zellweger)	DISL6B7K	Definitive	Autosomal recessive	[1]
Peroxisome biogenesis disorder type 3B	DIS8FORA	Definitive	Autosomal recessive	[2]
Peroxisomal disorder	DISV185U	Strong	Genetic Variation	[3]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[4]
Peroxisome biogenesis disorder 1B	DISCYF3O	Disputed	Genetic Variation	[3]

5 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 assembly protein 12 (PEX12).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisome assembly protein 12 (PEX12).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peroxisome assembly protein 12 (PEX12).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Peroxisome assembly protein 12 (PEX12).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Peroxisome assembly protein 12 (PEX12).	[9]

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] Identification of the molecular defect in patients with peroxisomal mosaicism using a novel method involving culturing of cells at 40 degrees C: implications for other inborn errors of metabolism.Hum Mutat. 2004 Aug;24(2):130-9. doi: 10.1002/humu.20062.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] 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.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.