Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFAK5EF)

• DOT Name: Peroxisomal ATPase PEX6 (PEX6)
• Synonyms: EC 3.6.4.-; Peroxin-6; Peroxisomal biogenesis factor 6; Peroxisomal-type ATPase 1; Peroxisome assembly factor 2; PAF-2
• Gene Name: PEX6
• Related Disease:
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 1B
  Peroxisome biogenesis disorder 4A (Zellweger)
  Peroxisome biogenesis disorder 4B
  Prostate cancer
  Prostate carcinoma
  Esophageal squamous cell carcinoma
  Intellectual disability
  Nervous system disease
  Peroxisomal disorder
  Usher syndrome
  Adrenoleukodystrophy
  Autosomal recessive cerebellar ataxia-blindness-deafness syndrome
  Zellweger spectrum disorders
  Dental enamel hypoplasia
  Isolated congenital microcephaly
• UniProt ID: PEX6_HUMAN
• EC Number: 3.6.4.-
• Pfam ID: PF00004
• Sequence:
  MALAVLRVLEPFPTETPPLAVLLPPGGPWPAAELGLVLALRPAGESPAGPALLVAALEGP
  DAGTEEQGPGPPQLLVSRALLRLLALGSGAWVRARAVRRPPALGWALLGTSLGPGLGPRV
  GPLLVRRGETLPVPGPRVLETRPALQGLLGPGTRLAVTELRGRARLCPESGDSSRPPPPP
  VVSSFAVSGTVRRLQGVLGGTGDSLGVSRSCLRGLGLFQGEWVWVAQARESSNTSQPHLA
  RVQVLEPRWDLSDRLGPGSGPLGEPLADGLALVPATLAFNLGCDPLEMGELRIQRYLEGS
  IAPEDKGSCSLLPGPPFARELHIEIVSSPHYSTNGNYDGVLYRHFQIPRVVQEGDVLCVP
  TIGQVEILEGSPEKLPRWREMFFKVKKTVGEAPDGPASAYLADTTHTSLYMVGSTLSPVP
  WLPSEESTLWSSLSPPGLEALVSELCAVLKPRLQPGGALLTGTSSVLLRGPPGCGKTTVV
  AAACSHLGLHLLKVPCSSLCAESSGAVETKLQAIFSRARRCRPAVLLLTAVDLLGRDRDG
  LGEDARVMAVLRHLLLNEDPLNSCPPLMVVATTSRAQDLPADVQTAFPHELEVPALSEGQ
  RLSILRALTAHLPLGQEVNLAQLARRCAGFVVGDLYALLTHSSRAACTRIKNSGLAGGLT
  EEDEGELCAAGFPLLAEDFGQALEQLQTAHSQAVGAPKIPSVSWHDVGGLQEVKKEILET
  IQLPLEHPELLSLGLRRSGLLLHGPPGTGKTLLAKAVATECSLTFLSVKGPELINMYVGQ
  SEENVREVFARARAAAPCIIFFDELDSLAPSRGRSGDSGGVMDRVVSQLLAELDGLHSTQ
  DVFVIGATNRPDLLDPALLRPGRFDKLVFVGANEDRASQLRVLSAITRKFKLEPSVSLVN
  VLDCCPPQLTGADLYSLCSDAMTAALKRRVHDLEEGLEPGSSALMLTMEDLLQAAARLQP
  SVSEQELLRYKRIQRKFAAC
• Function: Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling. Specifically recognizes PEX5 monoubiquitinated at 'Cys-11', and pulls it out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel. Extraction by the PEX1-PEX6 AAA ATPase complex is accompanied by unfolding of the TPR repeats and release of bound cargo from PEX5.
• Tissue Specificity: Expressed in the retina, at higher levels in the photoreceptor layer at the joint between the outer and inner segments.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway: Peroxisomal protein import (R-HSA-9033241)

Molecular Interaction Atlas (MIA) of This DOT

16 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 1B	DISCYF3O	Definitive	Genetic Variation	[2]
Peroxisome biogenesis disorder 4A (Zellweger)	DISHZ2TM	Definitive	Autosomal recessive	[1]
Peroxisome biogenesis disorder 4B	DIS1YKZQ	Definitive	Autosomal recessive	[3]
Prostate cancer	DISF190Y	Definitive	Genetic Variation	[4]
Prostate carcinoma	DISMJPLE	Definitive	Genetic Variation	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[5]
Intellectual disability	DISMBNXP	Strong	Biomarker	[6]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[2]
Peroxisomal disorder	DISV185U	Strong	Biomarker	[7]
Usher syndrome	DIS9YIS7	Strong	Biomarker	[8]
Adrenoleukodystrophy	DISTUD1F	moderate	Genetic Variation	[9]
Autosomal recessive cerebellar ataxia-blindness-deafness syndrome	DISRO2JZ	Supportive	Autosomal recessive	[10]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[11]
Dental enamel hypoplasia	DISN6ZMR	Limited	Biomarker	[12]
Isolated congenital microcephaly	DISUXHZ6	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Peroxisomal ATPase PEX6 (PEX6).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peroxisomal ATPase PEX6 (PEX6).	[14]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Peroxisomal ATPase PEX6 (PEX6).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Peroxisomal ATPase PEX6 (PEX6).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Peroxisomal ATPase PEX6 (PEX6).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Peroxisomal ATPase PEX6 (PEX6).	[17]

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] Disruption of a PEX1-PEX6 interaction is the most common cause of the neurologic disorders Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8630-5. doi: 10.1073/pnas.95.15.8630.
• [3] Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6. Am J Hum Genet. 2015 Oct 1;97(4):535-45. doi: 10.1016/j.ajhg.2015.08.011. Epub 2015 Sep 17.
• [4] Strong cis-acting expression quantitative trait loci for the genes encoding SNHG5 and PEX6.Medicine (Baltimore). 2016 Dec;95(52):e5793. doi: 10.1097/MD.0000000000005793.
• [5] miRNA-Related Polymorphisms in miR-423 (rs6505162) and PEX6 (rs1129186) and Risk of Esophageal Squamous Cell Carcinoma in an Iranian Cohort.Genet Test Mol Biomarkers. 2017 Jun;21(6):382-390. doi: 10.1089/gtmb.2016.0346. Epub 2017 Apr 21.
• [6] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [7] Peroxisome assembly factor-2, a putative ATPase cloned by functional complementation on a peroxisome-deficient mammalian cell mutant.Nat Genet. 1995 Dec;11(4):395-401. doi: 10.1038/ng1295-395.
• [8] A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents.Am J Hum Genet. 2002 Apr;70(4):1062-8. doi: 10.1086/339766. Epub 2002 Feb 28.
• [9] Late-onset Zellweger spectrum disorder caused by PEX6 mutations mimicking X-linked adrenoleukodystrophy.Pediatr Neurol. 2014 Aug;51(2):262-5. doi: 10.1016/j.pediatrneurol.2014.03.020. Epub 2014 Mar 28.
• [10] Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2). Eur J Hum Genet. 2016 Aug;24(8):1154-9. doi: 10.1038/ejhg.2015.259. Epub 2015 Dec 16.
• [11] 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.
• [12] PEX6 is Expressed in Photoreceptor Cilia and Mutated in Deafblindness with Enamel Dysplasia and Microcephaly.Hum Mutat. 2016 Feb;37(2):170-4. doi: 10.1002/humu.22934. Epub 2015 Dec 14.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [17] Exposure to environmental bisphenol A inhibits HTR-8/SVneo cell migration and invasion. J Biomed Res. 2020 Jun 30;34(5):369-378. doi: 10.7555/JBR.34.20200013.