Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase Praja-1 (PJA1)
• Synonyms: Praja1; EC 2.3.2.27; RING finger protein 70; RING-type E3 ubiquitin transferase Praja-1
• Gene Name: PJA1
• Related Disease:
  X-linked intellectual disability
  Congenital diaphragmatic hernia
  Glioblastoma multiforme
  Craniofrontonasal syndrome
  Enterovirus infection
  Hepatitis B virus infection
  Herpes simplex infection
  Intellectual disability
• UniProt ID: PJA1_HUMAN
• PDB ID: 2L0B
• EC Number: 2.3.2.27
• Pfam ID: PF13639
• Sequence:
  MGQESSKPVWPNPTGGYQSNTGRRYGRRHAYVSFRPPTSQRERIASQRKTNSEVPMHRSA
  PSQTTKRSRSPFSTTRRSWDDSESSGTNLNIDNEDYSRYPPREYRASGSRRGMAYGHIDS
  YGADDSEEEGAGPVERPPVRGKTGKFKDDKLYDPEKGARSLAGPPPHFSSFSRDVREERD
  KLDPVPAARCSASRADFLPQSSVASQSSSEGKLATKGDSSERERREQNLPARPSRAPVSI
  CGGGENTSKSAEEPVVRPKIRNLASPNCVKPKIFFDTDDDDDMPHSTSRWRDTANDNEGH
  SDGLARRGRGESSSGYPEPKYPEDKREARSDQVKPEKVPRRRRTMADPDFWTHSDDYYKY
  CDEDSDSDKEWIAALRRKYRSREQTLSSSGESWETLPGKEEREPPQAKVSASTGTSPGPG
  ASASAGAGAGASAGSNGSNYLEEVREPSLQEEQASLEEGEIPWLQYHENDSSSEGDNDSG
  HELMQPGVFMLDGNNNLEDDSSVSEDLEVDWSLFDGFADGLGVAEAISYVDPQFLTYMAL
  EERLAQAMETALAHLESLAVDVEVANPPASKESIDALPEILVTEDHGAVGQEMCCPICCS
  EYVKGEVATELPCHHYFHKPCVSIWLQKSGTCPVCRCMFPPPL
• Function: Has E2-dependent E3 ubiquitin-protein ligase activity. Ubiquitinates MAGED1 antigen leading to its subsequent degradation by proteasome. May be involved in protein sorting.
• Tissue Specificity: Expressed in various regions of the brain including the cerebellum, cerebral cortex, medulla, occipital pole, frontal lobe, temporal lobe and putamen. Highest levels in the cerebral cortex.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked intellectual disability	DISYJBY3	Definitive	Biomarker	[1]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Craniofrontonasal syndrome	DISSO9WK	Limited	Biomarker	[4]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[5]
Hepatitis B virus infection	DISLQ2XY	Limited	Biomarker	[5]
Herpes simplex infection	DISL1SAV	Limited	Biomarker	[5]
Intellectual disability	DISMBNXP	Limited	Biomarker	[4]

12 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 E3 ubiquitin-protein ligase Praja-1 (PJA1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[13]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[17]

3 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 Praja-1 (PJA1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of E3 ubiquitin-protein ligase Praja-1 (PJA1).	[18]

References

• [1] PJA1, encoding a RING-H2 finger ubiquitin ligase, is a novel human X chromosome gene abundantly expressed in brain.Genomics. 2002 Jun;79(6):869-74. doi: 10.1006/geno.2002.6770.
• [2] Xq12q13.1 microduplication encompassing the EFNB1 gene in a boy with congenital diaphragmatic hernia.Eur J Med Genet. 2011 Sep-Oct;54(5):e525-7. doi: 10.1016/j.ejmg.2011.06.011. Epub 2011 Jul 14.
• [3] CIC protein instability contributes to tumorigenesis in glioblastoma.Nat Commun. 2019 Feb 8;10(1):661. doi: 10.1038/s41467-018-08087-9.
• [4] Identification of genes expressed in the amygdala during the formation of fear memory.Learn Mem. 2001 Jul-Aug;8(4):209-19. doi: 10.1101/lm.39401.
• [5] PJA1 Coordinates with the SMC5/6 Complex To Restrict DNA Viruses and Episomal Genes in an Interferon-Independent Manner.J Virol. 2018 Oct 29;92(22):e00825-18. doi: 10.1128/JVI.00825-18. Print 2018 Nov 15.
• [6] 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.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [13] 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.
• [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] 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.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] 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.