Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPT0PKZ)

• DOT Name: Ornithine decarboxylase antizyme 1 (OAZ1)
• Synonyms: AZ1; ODC-Az
• Gene Name: OAZ1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Oral cancer
  Pancreatic tumour
  Systemic lupus erythematosus
  Neuroblastoma
  Prostate cancer
  Prostate carcinoma
  Pulmonary emphysema
  leukaemia
  Leukemia
  Rheumatoid arthritis
• UniProt ID: OAZ1_HUMAN
• PDB ID: 4ZGY; 4ZGZ; 5BWA
• Pfam ID: PF02100
• Sequence:
  MVKSSLQRILNSHCFAREKEGDKPSATIHASRTMPLLSLHSRGGSSSESSRVSLHCCSNP
  GPGPRWCSDAPHPPLKIPGGRGNSQRDHNLSANLFYSDDRLNVTEELTSNDKTRILNVQS
  RLTDAKRINWRTVLSGGSLYIEIPGGALPEGSKDSFAVLLEFAEEQLRADHVFICFHKNR
  EDRAALLRTFSFLGFEIVRPGHPLVPKRPDACFMAYTFERESSGEEEE
• Function: Ornithine decarboxylase (ODC) antizyme protein that negatively regulates ODC activity and intracellular polyamine biosynthesis and uptake in response to increased intracellular polyamine levels. Binds to ODC monomers, inhibiting the assembly of the functional ODC homodimer, and targets the monomers for ubiquitin-independent proteolytic destruction by the 26S proteasome. Triggers ODC degradation by inducing the exposure of a cryptic proteasome-interacting surface of ODC. Stabilizes AZIN2 by interfering with its ubiquitination. Also inhibits cellular uptake of polyamines by inactivating the polyamine uptake transporter. SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1. Involved in the translocation of AZIN2 from ER-Golgi intermediate compartment (ERGIC) to the cytosol.
• Reactome Pathway: Regulation of ornithine decarboxylase (ODC) (R-HSA-350562)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[4]
Oral cancer	DISLD42D	Strong	Biomarker	[5]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[6]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[7]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[8]
Prostate cancer	DISF190Y	moderate	Altered Expression	[9]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[9]
Pulmonary emphysema	DIS5M7HZ	moderate	Altered Expression	[10]
leukaemia	DISS7D1V	Limited	Altered Expression	[11]
Leukemia	DISNAKFL	Limited	Altered Expression	[11]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[12]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Ornithine decarboxylase antizyme 1 (OAZ1) affects the response to substance of Doxorubicin.	[25]
Vinblastine	DM5TVS3	Approved	Ornithine decarboxylase antizyme 1 (OAZ1) affects the response to substance of Vinblastine.	[25]

11 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 Ornithine decarboxylase antizyme 1 (OAZ1).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ornithine decarboxylase antizyme 1 (OAZ1).	[14]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Ornithine decarboxylase antizyme 1 (OAZ1).	[15]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ornithine decarboxylase antizyme 1 (OAZ1).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Ornithine decarboxylase antizyme 1 (OAZ1).	[17]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Ornithine decarboxylase antizyme 1 (OAZ1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ornithine decarboxylase antizyme 1 (OAZ1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Ornithine decarboxylase antizyme 1 (OAZ1).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Ornithine decarboxylase antizyme 1 (OAZ1).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Ornithine decarboxylase antizyme 1 (OAZ1).	[23]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone affects the splicing of Ornithine decarboxylase antizyme 1 (OAZ1).	[24]

1 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 Ornithine decarboxylase antizyme 1 (OAZ1).	[19]

References

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• [3] Effect of Oaz1 overexpression on goose ovarian granulosa cells.Amino Acids. 2017 Jun;49(6):1123-1132. doi: 10.1007/s00726-017-2411-8. Epub 2017 Mar 21.
• [4] Targeting HDAC/OAZ1 axis with a novel inhibitor effectively reverses cisplatin resistance in non-small cell lung cancer.Cell Death Dis. 2019 May 24;10(6):400. doi: 10.1038/s41419-019-1597-y.
• [5] Effects of ornithine decarboxylase antizyme 1 on the proliferation and differentiation of human oral cancer cells.Int J Mol Med. 2014 Dec;34(6):1606-12. doi: 10.3892/ijmm.2014.1961. Epub 2014 Oct 10.
• [6] Antizyme is necessary for conversion of pancreatic tumor cells into glucagon-producing differentiated cells.Endocr Relat Cancer. 2009 Jun;16(2):649-59. doi: 10.1677/ERC-09-0004. Epub 2009 Apr 6.
• [7] Restored immunosuppressive effect of mesenchymal stem cells on B cells after olfactory 1/early B cell factor-associated zinc-finger protein down-regulation in patients with systemic lupus erythematosus.Arthritis Rheumatol. 2014 Dec;66(12):3413-23. doi: 10.1002/art.38879.
• [8] The polyamine metabolism genes ornithine decarboxylase and antizyme 2 predict aggressive behavior in neuroblastomas with and without MYCN amplification.Int J Cancer. 2010 May 1;126(9):2012-24. doi: 10.1002/ijc.25074.
• [9] Inducible expression of antizyme 1 in prostate cancer cell lines after lentivirus mediated gene transfer.Amino Acids. 2012 Feb;42(2-3):559-64. doi: 10.1007/s00726-011-1033-9. Epub 2011 Jul 29.
• [10] Lung fibroblasts from patients with emphysema show markers of senescence in vitro.Respir Res. 2006 Feb 21;7(1):32. doi: 10.1186/1465-9921-7-32.
• [11] Assay of OAZ1 mRNA levels in chronic myeloid leukemia combined with application of leukemia PCR array identified relevant gene changes affected by antizyme.Acta Haematol. 2014;131(3):141-7. doi: 10.1159/000353406. Epub 2013 Oct 26.
• [12] Olf1/EBF associated zinc finger protein interfered with antinuclear antibody production in patients with systemic lupus erythematosus.Arthritis Res Ther. 2010;12(2):R59. doi: 10.1186/ar2972. Epub 2010 Apr 1.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] 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.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] 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.
• [17] 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.
• [18] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [19] 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.
• [20] 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.
• [21] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [24] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [25] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.