Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT34Z10B)

• DOT Name: Periaxin (PRX)
• Gene Name: PRX
• Related Disease:
  Charcot-Marie-Tooth disease type 4
  Neuralgia
  Advanced cancer
  Alzheimer disease
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 2B2
  Charcot-Marie-Tooth disease type 4F
  Colitis
  Demyelinating polyneuropathy
  Familial adenomatous polyposis
  Inflammatory bowel disease
  Non-alcoholic steatohepatitis
  Peripheral neuropathy
  Pulmonary fibrosis
  Uveal Melanoma
  Castration-resistant prostate carcinoma
  Charcot-Marie-Tooth disease type 3
  Neural tube defect
  Otitis media
  Gastric cancer
  Stomach cancer
• UniProt ID: PRAX_HUMAN
• PDB ID: 4CMZ
• Sequence:
  MEARSRSAEELRRAELVEIIVETEAQTGVSGINVAGGGKEGIFVRELREDSPAARSLSLQ
  EGDQLLSARVFFENFKYEDALRLLQCAEPYKVSFCLKRTVPTGDLALRPGTVSGYEIKGP
  RAKVAKLNIQSLSPVKKKKMVPGALGVPADLAPVDVEFSFPKFSRLRRGLKAEAVKGPVP
  AAPARRRLQLPRLRVREVAEEAQAARLAAAAPPPRKAKVEAEVAAGARFTAPQVELVGPR
  LPGAEVGVPQVSAPKAAPSAEAAGGFALHLPTLGLGAPAPPAVEAPAVGIQVPQVELPAL
  PSLPTLPTLPCLETREGAVSVVVPTLDVAAPTVGVDLALPGAEVEARGEAPEVALKMPRL
  SFPRFGARAKEVAEAKVAKVSPEARVKGPRLRMPTFGLSLLEPRPAAPEVVESKLKLPTI
  KMPSLGIGVSGPEVKVPKGPEVKLPKAPEVKLPKVPEAALPEVRLPEVELPKVSEMKLPK
  VPEMAVPEVRLPEVELPKVSEMKLPKVPEMAVPEVRLPEVQLLKVSEMKLPKVPEMAVPE
  VRLPEVQLPKVSEMKLPEVSEVAVPEVRLPEVQLPKVPEMKVPEMKLPKVPEMKLPEMKL
  PEVQLPKVPEMAVPDVHLPEVQLPKVPEMKLPEMKLPEVKLPKVPEMAVPDVHLPEVQLP
  KVPEMKLPKMPEMAVPEVRLPEVQLPKVSEMKLPKVPEMAVPDVHLPEVQLPKVCEMKVP
  DMKLPEIKLPKVPEMAVPDVHLPEVQLPKVSEIRLPEMQVPKVPDVHLPKAPEVKLPRAP
  EVQLKATKAEQAEGMEFGFKMPKMTMPKLGRAESPSRGKPGEAGAEVSGKLVTLPCLQPE
  VDGEAHVGVPSLTLPSVELDLPGALGLQGQVPAAKMGKGERVEGPEVAAGVREVGFRVPS
  VEIVTPQLPAVEIEEGRLEMIETKVKPSSKFSLPKFGLSGPKVAKAEAEGAGRATKLKVS
  KFAISLPKARVGAEAEAKGAGEAGLLPALDLSIPQLSLDAHLPSGKVEVAGADLKFKGPR
  FALPKFGVRGRDTEAAELVPGVAELEGKGWGWDGRVKMPKLKMPSFGLARGKEAEVQGDR
  ASPGEKAESTAVQLKIPEVELVTLGAQEEGRAEGAVAVSGMQLSGLKVSTAGQVVTEGHD
  AGLRMPPLGISLPQVELTGFGEAGTPGQQAQSTVPSAEGTAGYRVQVPQVTLSLPGAQVA
  GGELLVGEGVFKMPTVTVPQLELDVGLSREAQAGEAATGEGGLRLKLPTLGARARVGGEG
  AEEQPPGAERTFCLSLPDVELSPSGGNHAEYQVAEGEGEAGHKLKVRLPRFGLVRAKEGA
  EEGEKAKSPKLRLPRVGFSQSEMVTGEGSPSPEEEEEEEEEGSGEGASGRRGRVRVRLPR
  VGLAAPSKASRGQEGDAAPKSPVREKSPKFRFPRVSLSPKARSGSGDQEEGGLRVRLPSV
  GFSETGAPGPARMEGAQAAAV
• Function: Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells. Required for the maintenance of the peripheral myelin sheath that is essential for normal transmission of nerve impulses and normal perception of sensory stimuli. Required for normal transport of MBP mRNA from the perinuclear to the paranodal regions. Required for normal remyelination after nerve injury. Required for normal elongation of Schwann cells and normal length of the internodes between the nodes of Ranvier. The demyelinated nodes of Ranvier permit saltatory transmission of nerve impulses; shorter internodes cause slower transmission of nerve impulses. Required for the formation of appositions between the abaxonal surface of the myelin sheath and the Schwann cell plasma membrane; the Schwann cell cytoplasm is restricted to regions between these appositions. Required for the formation of Cajal bands and of Schmidt-Lanterman incisures that correspond to short, cytoplasm-filled regions on myelinated nerves. Recruits DRP2 to the Schwann cell plasma membrane. Required for normal protein composition of the eye lens fiber cell plasma membrane and normal eye lens fiber cell morphology.
• Tissue Specificity: Detected in spinal cord . Isoform 1 and isoform 2 are found in sciatic nerve and Schwann cells .

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Charcot-Marie-Tooth disease type 4	DISM8IZN	Definitive	Autosomal recessive	[1]
Neuralgia	DISWO58J	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Charcot marie tooth disease	DIS3BT2L	Strong	Biomarker	[5]
Charcot-Marie-Tooth disease type 2B2	DISNPA2O	Strong	Genetic Variation	[6]
Charcot-Marie-Tooth disease type 4F	DISUOVV5	Strong	Autosomal recessive	[7]
Colitis	DISAF7DD	Strong	Altered Expression	[8]
Demyelinating polyneuropathy	DIS7IO4W	Strong	Biomarker	[9]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[10]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[11]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[11]
Peripheral neuropathy	DIS7KN5G	Strong	Biomarker	[12]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[13]
Uveal Melanoma	DISA7ZGL	Strong	Biomarker	[14]
Castration-resistant prostate carcinoma	DISVGAE6	moderate	Altered Expression	[15]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Moderate	Autosomal recessive	[7]
Neural tube defect	DIS5J95E	Disputed	Genetic Variation	[16]
Otitis media	DISGZDUO	Disputed	Genetic Variation	[17]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[18]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Periaxin (PRX).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Periaxin (PRX).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Periaxin (PRX).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Periaxin (PRX).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Periaxin (PRX).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Periaxin (PRX).	[23]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Periaxin (PRX).	[24]
Selenium	DM25CGV	Approved	Selenium increases the expression of Periaxin (PRX).	[25]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Periaxin (PRX).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Periaxin (PRX).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Periaxin (PRX).	[29]

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] Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron. 2000 May;26(2):523-31. doi: 10.1016/s0896-6273(00)81184-8.
• [3] ER stress-mediated autophagic cell death induction through methylated -cyclodextrins-threaded acid-labile polyrotaxanes.J Control Release. 2018 Apr 10;275:20-31. doi: 10.1016/j.jconrel.2018.02.010. Epub 2018 Feb 8.
• [4] Novel prodrug PRX-P4-003, selectively activated by gut enzymes, may reduce the risk of iatrogenic addiction and abuse.Drug Alcohol Depend. 2018 May 1;186:159-166. doi: 10.1016/j.drugalcdep.2017.12.042. Epub 2018 Mar 2.
• [5] Linkage analysis and whole exome sequencing reveals AHNAK2 as a novel genetic cause for autosomal recessive CMT in a Malaysian family. Neurogenetics. 2019 Aug;20(3):117-127. doi: 10.1007/s10048-019-00576-3. Epub 2019 Apr 22.
• [6] A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.Am J Hum Genet. 2001 Jan;68(1):269-74. doi: 10.1086/316934. Epub 2000 Dec 7.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] A plant cell-expressed recombinant anti-TNF fusion protein is biologically active in the gut and alleviates immune-mediated hepatitis and colitis.Immunobiology. 2017 Mar;222(3):544-551. doi: 10.1016/j.imbio.2016.11.001. Epub 2016 Nov 4.
• [9] Direct Binding of the Flexible C-Terminal Segment of Periaxin to 4 Integrin Suggests a Molecular Basis for CMT4F.Front Mol Neurosci. 2019 Apr 9;12:84. doi: 10.3389/fnmol.2019.00084. eCollection 2019.
• [10] Interaction of tankyrase and peroxiredoxin II is indispensable for the survival of colorectal cancer cells.Nat Commun. 2017 Jun 28;8(1):40. doi: 10.1038/s41467-017-00054-0.
• [11] An oral administration of a recombinant anti-TNF fusion protein is biologically active in the gut promoting regulatory T cells: Results of a phase I clinical trial using a novel oral anti-TNF alpha-based therapy.J Immunol Methods. 2017 Jul;446:21-29. doi: 10.1016/j.jim.2017.03.023. Epub 2017 Apr 7.
• [12] Involvement of Charcot-Marie-Tooth disease gene mitofusin 2 expression in paclitaxel-induced mechanical allodynia in rats.Neurosci Lett. 2017 Jul 13;653:337-340. doi: 10.1016/j.neulet.2017.05.069. Epub 2017 Jun 3.
• [13] Expression of Peroxiredoxins and Pulmonary Surfactant Protein A Induced by Silica in Rat Lung Tissue.Biomed Environ Sci. 2016 Aug;29(8):584-588. doi: 10.3967/bes2016.077.
• [14] Expression of the serotonin receptor 2B in uveal melanoma and effects of an antagonist on cell lines.Clin Exp Metastasis. 2018 Mar;35(3):123-134. doi: 10.1007/s10585-018-9894-x. Epub 2018 Apr 25.
• [15] Peroxiredoxin 2 in the nucleus and cytoplasm distinctly regulates androgen receptor activity in prostate cancer cells.Free Radic Biol Med. 2011 Jul 1;51(1):78-87. doi: 10.1016/j.freeradbiomed.2011.04.001. Epub 2011 Apr 14.
• [16] A regulating element essential for PDGFRA transcription is recognized by neural tube defect-associated PRX homeobox transcription factors.Biochim Biophys Acta. 2002 Dec 12;1588(3):254-60. doi: 10.1016/s0925-4439(02)00175-8.
• [17] Genome-wide association analysis reveals variants on chromosome 19 that contribute to childhood risk of chronic otitis media with effusion.Sci Rep. 2016 Sep 16;6:33240. doi: 10.1038/srep33240.
• [18] Peroxiredoxin V Inhibits Emodin-induced Gastric Cancer Cell Apoptosis via the ROS/Bcl2 Pathway.In Vivo. 2019 Jul-Aug;33(4):1183-1192. doi: 10.21873/invivo.11589.
• [19] 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.
• [20] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [23] 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.
• [24] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [25] 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.
• [26] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [29] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.