Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ891OS)

• DOT Name: E3 ubiquitin-protein ligase PDZRN3 (PDZRN3)
• Synonyms: EC 2.3.2.27; Ligand of Numb protein X 3; PDZ domain-containing RING finger protein 3; RING-type E3 ubiquitin transferase PDZRN3; Semaphorin cytoplasmic domain-associated protein 3; Protein SEMACAP3
• Gene Name: PDZRN3
• Related Disease:
  Chronic renal failure
  Neoplasm
  Acute myelogenous leukaemia
  Epithelial ovarian cancer
  Ovarian cancer
• UniProt ID: PZRN3_HUMAN
• PDB ID: 1UHP; 1WH1
• EC Number: 2.3.2.27
• Pfam ID: PF00595 ; PF13923
• Sequence:
  MGFELDRFDGDVDPDLKCALCHKVLEDPLTTPCGHVFCAGCVLPWVVQEGSCPARCRGRL
  SAKELNHVLPLKRLILKLDIKCAYATRGCGRVVKLQQLPEHLERCDFAPARCRHAGCGQV
  LLRRDVEAHMRDACDARPVGRCQEGCGLPLTHGEQRAGGHCCARALRAHNGALQARLGAL
  HKALKKEALRAGKREKSLVAQLAAAQLELQMTALRYQKKFTEYSARLDSLSRCVAAPPGG
  KGEETKSLTLVLHRDSGSLGFNIIGGRPSVDNHDGSSSEGIFVSKIVDSGPAAKEGGLQI
  HDRIIEVNGRDLSRATHDQAVEAFKTAKEPIVVQVLRRTPRTKMFTPPSESQLVDTGTQT
  DITFEHIMALTKMSSPSPPVLDPYLLPEEHPSAHEYYDPNDYIGDIHQEMDREELELEEV
  DLYRMNSQDKLGLTVCYRTDDEDDIGIYISEIDPNSIAAKDGRIREGDRIIQINGIEVQN
  REEAVALLTSEENKNFSLLIARPELQLDEGWMDDDRNDFLDDLHMDMLEEQHHQAMQFTA
  SVLQQKKHDEDGGTTDTATILSNQHEKDSGVGRTDESTRNDESSEQENNGDDATASSNPL
  AGQRKLTCSQDTLGSGDLPFSNESFISADCTDADYLGIPVDECERFRELLELKCQVKSAT
  PYGLYYPSGPLDAGKSDPESVDKELELLNEELRSIELECLSIVRAHKMQQLKEQYRESWM
  LHNSGFRNYNTSIDVRRHELSDITELPEKSDKDSSSAYNTGESCRSTPLTLEISPDNSLR
  RAAEGISCPSSEGAVGTTEAYGPASKNLLSITEDPEVGTPTYSPSLKELDPNQPLESKER
  RASDGSRSPTPSQKLGSAYLPSYHHSPYKHAHIPAHAQHYQSYMQLIQQKSAVEYAQSQM
  SLVSMCKDLSSPTPSEPRMEWKVKIRSDGTRYITKRPVRDRLLRERALKIREERSGMTTD
  DDAVSEMKMGRYWSKEERKQHLVKAKEQRRRREFMMQSRLDCLKEQQAADDRKEMNILEL
  SHKKMMKKRNKKIFDNWMTIQELLTHGTKSPDGTRVYNSFLSVTTV
• Function: E3 ubiquitin-protein ligase. Plays an important role in regulating the surface level of MUSK on myotubes. Mediates the ubiquitination of MUSK, promoting its endocytosis and lysosomal degradation. Might contribute to terminal myogenic differentiation.
• Tissue Specificity: Widely expressed, including in the heart, skeletal muscle and liver and, at lower levels, in the brain, colon, small intestine, placenta and lung. Down-regulated in ovarian serous papillary tumors.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[3]
Epithelial ovarian cancer	DIS56MH2	moderate	Altered Expression	[4]
Ovarian cancer	DISZJHAP	moderate	Altered Expression	[4]

10 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 E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[10]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase PDZRN3 (PDZRN3).	[15]

References

• [1] Genome-wide association scan for survival on dialysis in African-Americans with type 2 diabetes.Am J Nephrol. 2011;33(6):502-9. doi: 10.1159/000327985. Epub 2011 May 5.
• [2] Molecular analysis of germline t(3;6) and t(3;12) associated with conventional renal cell carcinomas indicates their rate-limiting role and supports the three-hit model of carcinogenesis.Cancer Genet Cytogenet. 2010 Aug;201(1):15-23. doi: 10.1016/j.cancergencyto.2010.04.018.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] Gene expression fingerprint of uterine serous papillary carcinoma: identification of novel molecular markers for uterine serous cancer diagnosis and therapy.Br J Cancer. 2005 Apr 25;92(8):1561-73. doi: 10.1038/sj.bjc.6602480.
• [5] 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.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] 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.
• [8] 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.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.