Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFGGM9R)

• DOT Name: Peroxidasin homolog (PXDN)
• Synonyms: EC 1.11.2.-; Melanoma-associated antigen MG50; Peroxidasin 1; hsPxd01; Vascular peroxidase 1; p53-responsive gene 2 protein
• Gene Name: PXDN
• Related Disease:
  Anterior segment dysgenesis 7
  Microphthalmia
  Abdominal aortic aneurysm
  Acute myelogenous leukaemia
  Advanced cancer
  Autism
  Cardiovascular disease
  Chronic kidney disease
  Congenital glaucoma
  Epithelial ovarian cancer
  Juvenile open angle glaucoma
  Lung carcinoma
  Myocardial infarction
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Vasculitis
  Chronic obstructive pulmonary disease
  High blood pressure
  Melanoma
  Neoplasm
  Renal fibrosis
  Type-1/2 diabetes
• UniProt ID: PXDN_HUMAN
• EC Number: 1.11.2.-
• Pfam ID: PF03098 ; PF07679 ; PF00560 ; PF13855 ; PF00093
• Sequence:
  MAKRSRGPGRRCLLALVLFCAWGTLAVVAQKPGAGCPSRCLCFRTTVRCMHLLLEAVPAV
  APQTSILDLRFNRIREIQPGAFRRLRNLNTLLLNNNQIKRIPSGAFEDLENLKYLYLYKN
  EIQSIDRQAFKGLASLEQLYLHFNQIETLDPDSFQHLPKLERLFLHNNRITHLVPGTFNH
  LESMKRLRLDSNTLHCDCEILWLADLLKTYAESGNAQAAAICEYPRRIQGRSVATITPEE
  LNCERPRITSEPQDADVTSGNTVYFTCRAEGNPKPEIIWLRNNNELSMKTDSRLNLLDDG
  TLMIQNTQETDQGIYQCMAKNVAGEVKTQEVTLRYFGSPARPTFVIQPQNTEVLVGESVT
  LECSATGHPPPRISWTRGDRTPLPVDPRVNITPSGGLYIQNVVQGDSGEYACSATNNIDS
  VHATAFIIVQALPQFTVTPQDRVVIEGQTVDFQCEAKGNPPPVIAWTKGGSQLSVDRRHL
  VLSSGTLRISGVALHDQGQYECQAVNIIGSQKVVAHLTVQPRVTPVFASIPSDTTVEVGA
  NVQLPCSSQGEPEPAITWNKDGVQVTESGKFHISPEGFLTINDVGPADAGRYECVARNTI
  GSASVSMVLSVNVPDVSRNGDPFVATSIVEAIATVDRAINSTRTHLFDSRPRSPNDLLAL
  FRYPRDPYTVEQARAGEIFERTLQLIQEHVQHGLMVDLNGTSYHYNDLVSPQYLNLIANL
  SGCTAHRRVNNCSDMCFHQKYRTHDGTCNNLQHPMWGASLTAFERLLKSVYENGFNTPRG
  INPHRLYNGHALPMPRLVSTTLIGTETVTPDEQFTHMLMQWGQFLDHDLDSTVVALSQAR
  FSDGQHCSNVCSNDPPCFSVMIPPNDSRARSGARCMFFVRSSPVCGSGMTSLLMNSVYPR
  EQINQLTSYIDASNVYGSTEHEARSIRDLASHRGLLRQGIVQRSGKPLLPFATGPPTECM
  RDENESPIPCFLAGDHRANEQLGLTSMHTLWFREHNRIATELLKLNPHWDGDTIYYETRK
  IVGAEIQHITYQHWLPKILGEVGMRTLGEYHGYDPGINAGIFNAFATAAFRFGHTLVNPL
  LYRLDENFQPIAQDHLPLHKAFFSPFRIVNEGGIDPLLRGLFGVAGKMRVPSQLLNTELT
  ERLFSMAHTVALDLAAINIQRGRDHGIPPYHDYRVYCNLSAAHTFEDLKNEIKNPEIREK
  LKRLYGSTLNIDLFPALVVEDLVPGSRLGPTLMCLLSTQFKRLRDGDRLWYENPGVFSPA
  QLTQIKQTSLARILCDNADNITRVQSDVFRVAEFPHGYGSCDEIPRVDLRVWQDCCEDCR
  TRGQFNAFSYHFRGRRSLEFSYQEDKPTKKTRPRKIPSVGRQGEHLSNSTSAFSTRSDAS
  GTNDFREFVLEMQKTITDLRTQIKKLESRLSTTECVDAGGESHANNTKWKKDACTICECK
  DGQVTCFVEACPPATCAVPVNIPGACCPVCLQKRAEEKP
• Function: Catalyzes the two-electron oxidation of bromide by hydrogen peroxide and generates hypobromite as a reactive intermediate which mediates the formation of sulfilimine cross-links between methionine and hydroxylysine residues within an uncross-linked collagen IV/COL4A1 NC1 hexamer. In turns, directly contributes to the collagen IV network-dependent fibronectin/FN and laminin assembly, which is required for full extracellular matrix (ECM)-mediated signaling. Thus, sulfilimine cross-links are essential for growth factor-induced cell proliferation and survival in endothelial cells, an event essential to basement membrane integrity. In addition, through the bromide oxidation, may promote tubulogenesis and induce angiogenesis through ERK1/2, Akt, and FAK pathways. Moreover brominates alpha2 collagen IV chain/COL4A2 at 'Tyr-1485' and leads to bromine enrichment of the basement membranes. In vitro, can also catalyze the two-electron oxidation of thiocyanate and iodide and these two substrates could effectively compete with bromide and thus inhibit the formation of sulfilimine bonds. Binds laminins. May play a role in the organization of eyeball structure and lens development during eye development.
• Tissue Specificity: Expressed at higher levels in heart, lung, ovary, spleen, intestine and placenta, and at lower levels in liver, colon, pancreas, kidney, thymus, skeletal muscle and prostate. Expressed in tumors such as melanoma, breast cancer, ovarian cancer and glioblastoma. A shorter form probably lacking the signal sequence is found in testis and in EB1 cells undergoing p53/TP53-dependent apoptosis.
• Reactome Pathway: Crosslinking of collagen fibrils (R-HSA-2243919)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anterior segment dysgenesis 7	DISP6CEE	Definitive	Autosomal recessive	[1]
Microphthalmia	DISGEBES	Definitive	Genetic Variation	[2]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Autism	DISV4V1Z	Strong	Biomarker	[6]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[7]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[8]
Congenital glaucoma	DISHN3GO	Strong	Genetic Variation	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Juvenile open angle glaucoma	DISZ43T5	Strong	Genetic Variation	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Myocardial infarction	DIS655KI	Strong	Biomarker	[11]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[12]
Vasculitis	DISQRKDX	Strong	Biomarker	[13]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[14]
High blood pressure	DISY2OHH	moderate	Biomarker	[14]
Melanoma	DIS1RRCY	Limited	Biomarker	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[16]
Renal fibrosis	DISMHI3I	Limited	Biomarker	[11]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[17]

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 Peroxidasin homolog (PXDN).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Peroxidasin homolog (PXDN).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Peroxidasin homolog (PXDN).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Peroxidasin homolog (PXDN).	[20]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Peroxidasin homolog (PXDN).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peroxidasin homolog (PXDN).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Peroxidasin homolog (PXDN).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Peroxidasin homolog (PXDN).	[24]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Peroxidasin homolog (PXDN).	[25]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Peroxidasin homolog (PXDN).	[26]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Peroxidasin homolog (PXDN).	[27]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Peroxidasin homolog (PXDN).	[28]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of Peroxidasin homolog (PXDN).	[29]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Peroxidasin homolog (PXDN).	[28]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Peroxidasin homolog (PXDN).	[30]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peroxidasin homolog (PXDN).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Peroxidasin homolog (PXDN).	[33]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Peroxidasin homolog (PXDN).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Peroxidasin homolog (PXDN).	[35]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Peroxidasin homolog (PXDN).	[36]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Peroxidasin homolog (PXDN).	[37]

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] Biallelic Deletion of Pxdn in Mice Leads to Anophthalmia and Severe Eye Malformation.Int J Mol Sci. 2019 Dec 5;20(24):6144. doi: 10.3390/ijms20246144.
• [3] VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal-regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms.J Am Heart Assoc. 2018 Sep 4;7(17):e010069. doi: 10.1161/JAHA.118.010069.
• [4] Discovery of epigenetically silenced genes in acute myeloid leukemias.Leukemia. 2007 May;21(5):1026-34. doi: 10.1038/sj.leu.2404611. Epub 2007 Mar 1.
• [5] High expression of PXDN is associated with poor prognosis and promotes proliferation, invasion as well as migration in ovarian cancer.Ann Diagn Pathol. 2018 Jun;34:161-165. doi: 10.1016/j.anndiagpath.2018.03.002. Epub 2018 Mar 14.
• [6] Germline mosaic transmission of a novel duplication of PXDN and MYT1L to two male half-siblings with autism.Psychiatr Genet. 2012 Jun;22(3):137-40. doi: 10.1097/YPG.0b013e32834dc3f5.
• [7] Coordination between NADPH oxidase and vascular peroxidase 1 promotes dysfunctions of endothelial progenitor cells in hypoxia-induced pulmonary hypertensive rats.Eur J Pharmacol. 2019 Aug 15;857:172459. doi: 10.1016/j.ejphar.2019.172459. Epub 2019 Jun 16.
• [8] Peroxidasin and eosinophil peroxidase, but not myeloperoxidase, contribute to renal fibrosis in the murine unilateral ureteral obstruction model.Am J Physiol Renal Physiol. 2019 Feb 1;316(2):F360-F371. doi: 10.1152/ajprenal.00291.2018. Epub 2018 Dec 19.
• [9] Identification of Novel Variants in LTBP2 and PXDN Using Whole-Exome Sequencing in Developmental and Congenital Glaucoma.PLoS One. 2016 Jul 13;11(7):e0159259. doi: 10.1371/journal.pone.0159259. eCollection 2016.
• [10] A novel melanoma gene (MG50) encoding the interleukin 1 receptor antagonist and six epitopes recognized by human cytolytic T lymphocytes.Cancer Res. 2000 Nov 15;60(22):6448-56.
• [11] Vascular peroxidase 1 is a novel regulator of cardiac fibrosis after myocardial infarction.Redox Biol. 2019 Apr;22:101151. doi: 10.1016/j.redox.2019.101151. Epub 2019 Feb 27.
• [12] Proteomics-Metabolomics Combined Approach Identifies Peroxidasin as a Protector against Metabolic and Oxidative Stress in Prostate Cancer.Int J Mol Sci. 2019 Jun 21;20(12):3046. doi: 10.3390/ijms20123046.
• [13] Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes.J Am Soc Nephrol. 2018 Nov;29(11):2619-2625. doi: 10.1681/ASN.2018050519. Epub 2018 Oct 2.
• [14] Mechanisms of oxidative stress effects of the NADPH oxidase-ROS-NF-B transduction pathway and VPO1 on patients with chronic obstructive pulmonary disease combined with pulmonary hypertension.Eur Rev Med Pharmacol Sci. 2017 Aug;21(15):3459-3464.
• [15] Identifying and targeting determinants of melanoma cellular invasion.Oncotarget. 2016 Jul 5;7(27):41186-41202. doi: 10.18632/oncotarget.9227.
• [16] Perspective on allogeneic melanoma lysates in active specific immunotherapy.Semin Oncol. 1998 Dec;25(6):623-35.
• [17] Role of vascular peroxidase 1 in senescence of endothelial cells in diabetes rats.Int J Cardiol. 2015 Oct 15;197:182-91. doi: 10.1016/j.ijcard.2015.06.098. Epub 2015 Jun 27.
• [18] 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.
• [19] 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.
• [20] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [21] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [22] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [23] Influence of Iron on Cytotoxicity and Gene Expression Profiles Induced by Arsenic in HepG2 Cells. Int J Environ Res Public Health. 2019 Nov 14;16(22):4484. doi: 10.3390/ijerph16224484.
• [24] 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.
• [25] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [26] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [27] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [28] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [29] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [30] 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.
• [31] 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.
• [32] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [33] 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.
• [34] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [35] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [37] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.