Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQJF0V7)

• DOT Name: Peroxisomal ATPase PEX1 (PEX1)
• Synonyms: EC 3.6.4.-; Peroxin-1; Peroxisome biogenesis disorder protein 1; Peroxisome biogenesis factor 1
• Gene Name: PEX1
• Related Disease:
  Peroxisome biogenesis disorder
  Peroxisome biogenesis disorder 1A (Zellweger)
  Amelogenesis imperfecta
  Cholestasis
  Intellectual disability
  Nervous system disease
  Obesity
  Obsolete Heimler syndrome 1
  Periventricular leukomalacia
  Peroxisome biogenesis disorder 1B
  Respiratory papillomatosis
  Retinitis pigmentosa
  Sensorineural hearing loss disorder
  Adrenoleukodystrophy
  Age-related macular degeneration
  Hereditary macular dystrophy
  Peroxisomal disorder
  Zellweger spectrum disorders
  Retinopathy
• UniProt ID: PEX1_HUMAN
• EC Number: 3.6.4.-
• Pfam ID: PF00004 ; PF17862 ; PF09262 ; PF09263
• Sequence:
  MWGSDRLAGAGGGGAAVTVAFTNARDCFLHLPRRLVAQLHLLQNQAIEVVWSHQPAFLSW
  VEGRHFSDQGENVAEINRQVGQKLGLSNGGQVFLKPCSHVVSCQQVEVEPLSADDWEILE
  LHAVSLEQHLLDQIRIVFPKAIFPVWVDQQTYIFIQIVALIPAASYGRLETDTKLLIQPK
  TRRAKENTFSKADAEYKKLHSYGRDQKGMMKELQTKQLQSNTVGITESNENESEIPVDSS
  SVASLWTMIGSIFSFQSEKKQETSWGLTEINAFKNMQSKVVPLDNIFRVCKSQPPSIYNA
  SATSVFHKHCAIHVFPWDQEYFDVEPSFTVTYGKLVKLLSPKQQQSKTKQNVLSPEKEKQ
  MSEPLDQKKIRSDHNEEDEKACVLQVVWNGLEELNNAIKYTKNVEVLHLGKVWIPDDLRK
  RLNIEMHAVVRITPVEVTPKIPRSLKLQPRENLPKDISEEDIKTVFYSWLQQSTTTMLPL
  VISEEEFIKLETKDGLKEFSLSIVHSWEKEKDKNIFLLSPNLLQKTTIQVLLDPMVKEEN
  SEEIDFILPFLKLSSLGGVNSLGVSSLEHITHSLLGRPLSRQLMSLVAGLRNGALLLTGG
  KGSGKSTLAKAICKEAFDKLDAHVERVDCKALRGKRLENIQKTLEVAFSEAVWMQPSVVL
  LDDLDLIAGLPAVPEHEHSPDAVQSQRLAHALNDMIKEFISMGSLVALIATSQSQQSLHP
  LLVSAQGVHIFQCVQHIQPPNQEQRCEILCNVIKNKLDCDINKFTDLDLQHVAKETGGFV
  ARDFTVLVDRAIHSRLSRQSISTREKLVLTTLDFQKALRGFLPASLRSVNLHKPRDLGWD
  KIGGLHEVRQILMDTIQLPAKYPELFANLPIRQRTGILLYGPPGTGKTLLAGVIARESRM
  NFISVKGPELLSKYIGASEQAVRDIFIRAQAAKPCILFFDEFESIAPRRGHDNTGVTDRV
  VNQLLTQLDGVEGLQGVYVLAATSRPDLIDPALLRPGRLDKCVYCPPPDQVSRLEILNVL
  SDSLPLADDVDLQHVASVTDSFTGADLKALLYNAQLEALHGMLLSSGLQDGSSSSDSDLS
  LSSMVFLNHSSGSDDSAGDGECGLDQSLVSLEMSEILPDESKFNMYRLYFGSSYESELGN
  GTSSDLSSQCLSAPSSMTQDLPGVPGKDQLFSQPPVLRTASQEGCQELTQEQRDQLRADI
  SIIKGRYRSQSGEDESMNQPGPIKTRLAISQSHLMTALGHTRPSISEDDWKNFAELYESF
  QNPKRRKNQSGTMFRPGQKVTLA
• 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.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway: Peroxisomal protein import (R-HSA-9033241)

Molecular Interaction Atlas (MIA) of This DOT

19 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	[1]
Amelogenesis imperfecta	DISGYR9E	Strong	Biomarker	[2]
Cholestasis	DISDJJWE	Strong	Genetic Variation	[3]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[4]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Obsolete Heimler syndrome 1	DISH9OB4	Strong	Autosomal recessive	[6]
Periventricular leukomalacia	DIS152XL	Strong	Genetic Variation	[7]
Peroxisome biogenesis disorder 1B	DISCYF3O	Strong	Autosomal recessive	[8]
Respiratory papillomatosis	DISXL96I	Strong	Altered Expression	[9]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[2]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[2]
Adrenoleukodystrophy	DISTUD1F	moderate	Biomarker	[10]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[11]
Hereditary macular dystrophy	DISEYSYY	moderate	Genetic Variation	[11]
Peroxisomal disorder	DISV185U	moderate	Biomarker	[12]
Zellweger spectrum disorders	DISW52CE	Supportive	Autosomal recessive	[13]
Retinopathy	DISB4B0F	Limited	Genetic Variation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Peroxisomal ATPase PEX1 (PEX1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peroxisomal ATPase PEX1 (PEX1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Peroxisomal ATPase PEX1 (PEX1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peroxisomal ATPase PEX1 (PEX1).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Peroxisomal ATPase PEX1 (PEX1).	[19]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Peroxisomal ATPase PEX1 (PEX1).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Peroxisomal ATPase PEX1 (PEX1).	[20]
Lithium	DMZ3OU6	Phase 2	Lithium increases the expression of Peroxisomal ATPase PEX1 (PEX1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Peroxisomal ATPase PEX1 (PEX1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Peroxisomal ATPase PEX1 (PEX1).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Peroxisomal ATPase PEX1 (PEX1).	[22]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Peroxisomal ATPase PEX1 (PEX1).	[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] Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene.Eur J Med Genet. 2016 Oct;59(10):507-11. doi: 10.1016/j.ejmg.2016.09.004. Epub 2016 Sep 12.
• [3] The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder.Mol Genet Metab. 2014 Apr;111(4):522-532. doi: 10.1016/j.ymgme.2014.01.008. Epub 2014 Jan 23.
• [4] 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.
• [5] Exome sequencing reveals novel genetic loci influencing obesity-related traits in Hispanic children.Obesity (Silver Spring). 2017 Jul;25(7):1270-1276. doi: 10.1002/oby.21869. Epub 2017 May 16.
• [6] Mild form of Zellweger Spectrum Disorders (ZSD) due to variants in PEX1: Detailed clinical investigation in a 9-years-old female. Mol Genet Metab Rep. 2020 Jun 20;24:100615. doi: 10.1016/j.ymgmr.2020.100615. eCollection 2020 Sep.
• [7] Zellweger syndrome - a lethal peroxisome biogenesis disorder.J Pediatr Endocrinol Metab. 2013;26(3-4):377-9. doi: 10.1515/jpem-2012-0320.
• [8] PEX1 mutations in the Zellweger spectrum of the peroxisome biogenesis disorders. Hum Mutat. 2005 Sep;26(3):167-75. doi: 10.1002/humu.20211.
• [9] 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.
• [10] Genetic and clinical aspects of Zellweger spectrum patients with PEX1 mutations.J Med Genet. 2005 Sep;42(9):e58. doi: 10.1136/jmg.2005.033324.
• [11] Ophthalmic manifestations of Heimler syndrome due to PEX6 mutations.Ophthalmic Genet. 2018 Jun;39(3):384-390. doi: 10.1080/13816810.2018.1432063.
• [12] Human PEX1 cloned by functional complementation on a CHO cell mutant is responsible for peroxisome-deficient Zellweger syndrome of complementation group I.Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4350-5. doi: 10.1073/pnas.95.8.4350.
• [13] 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.
• [14] A longitudinal study of retinopathy in the PEX1-Gly844Asp mouse model for mild Zellweger Spectrum Disorder.Exp Eye Res. 2019 Sep;186:107713. doi: 10.1016/j.exer.2019.107713. Epub 2019 Jun 27.
• [15] 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.
• [16] 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.
• [17] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [20] 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.
• [21] Effect of mood stabilizers on gene expression in lymphoblastoid cells. J Neural Transm (Vienna). 2010 Feb;117(2):155-64.
• [22] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [24] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.