Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNBVM2U)

• DOT Name: Proteasome subunit alpha type-1 (PSMA1)
• Synonyms: 30 kDa prosomal protein; PROS-30; Macropain subunit C2; Multicatalytic endopeptidase complex subunit C2; Proteasome component C2; Proteasome nu chain
• Gene Name: PSMA1
• Related Disease:
  Prostate carcinoma
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Gastric cancer
  Head and neck carcinoma
  Hepatitis B virus infection
  Neoplasm
  Prostate cancer
  Stomach cancer
  Vulvar squamous intraepithelial lesion
  Advanced cancer
  Head and neck cancer
  Human papillomavirus infection
  Nervous system disease
• UniProt ID: PSA1_HUMAN
• PDB ID: 4R3O ; 4R67 ; 5A0Q ; 5GJQ ; 5GJR ; 5L4G ; 5LE5 ; 5LEX ; 5LEY ; 5LEZ ; 5LF0 ; 5LF1 ; 5LF3 ; 5LF4 ; 5LF6 ; 5LF7 ; 5LN3 ; 5M32 ; 5T0C ; 5T0G ; 5T0H ; 5T0I ; 5T0J ; 5VFO ; 5VFP ; 5VFQ ; 5VFR ; 5VFS ; 5VFT ; 5VFU ; 6AVO ; 6E5B ; 6KWY ; 6MSB ; 6MSD ; 6MSE ; 6MSG ; 6MSH ; 6MSJ ; 6MSK ; 6R70 ; 6REY ; 6RGQ ; 6WJD ; 6WJN ; 6XMJ ; 7AWE ; 7B12 ; 7LXV ; 7NAN ; 7NAO ; 7NAP ; 7NAQ ; 7NHT ; 7PG9 ; 7QXN ; 7QXP ; 7QXU ; 7QXW ; 7QXX ; 7QY7 ; 7QYA ; 7QYB ; 7V5G ; 7V5M ; 7W37 ; 7W38 ; 7W39 ; 7W3A ; 7W3B ; 7W3C ; 7W3F ; 7W3G ; 7W3H ; 7W3I ; 7W3J ; 7W3K ; 7W3M ; 8CVR ; 8CVS ; 8CVT ; 8CXB
• Pfam ID: PF00227 ; PF10584
• Sequence:
  MFRNQYDNDVTVWSPQGRIHQIEYAMEAVKQGSATVGLKSKTHAVLVALKRAQSELAAHQ
  KKILHVDNHIGISIAGLTADARLLCNFMRQECLDSRFVFDRPLPVSRLVSLIGSKTQIPT
  QRYGRRPYGVGLLIAGYDDMGPHIFQTCPSANYFDCRAMSIGARSQSARTYLERHMSEFM
  ECNLNELVKHGLRALRETLPAEQDLTTKNVSIGIVGKDLEFTIYDDDDVSPFLEGLEERP
  QRKAQPAQPADEPAEKADEPMEH
• Function: Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).
• KEGG Pathway:
  Proteasome (hsa03050)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)
  ER-Phagosome pathway (R-HSA-1236974)
  Cross-presentation of soluble exogenous antigens (endosomes) (R-HSA-1236978)
  Autodegradation of Cdh1 by Cdh1 (R-HSA-174084)
  SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113)
  APC/C (R-HSA-174154)
  APC/C (R-HSA-174178)
  Cdc20 (R-HSA-174184)
  Vpu mediated degradation of CD4 (R-HSA-180534)
  Vif-mediated degradation of APOBEC3G (R-HSA-180585)
  SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Downstream TCR signaling (R-HSA-202424)
  Regulation of activated PAK-2p34 by proteasome mediated degradation (R-HSA-211733)
  Separation of Sister Chromatids (R-HSA-2467813)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425)
  Regulation of ornithine decarboxylase (ODC) (R-HSA-350562)
  ABC-family proteins mediated transport (R-HSA-382556)
  AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  Degradation of AXIN (R-HSA-4641257)
  Degradation of DVL (R-HSA-4641258)
  Hedgehog ligand biogenesis (R-HSA-5358346)
  Hh mutants are degraded by ERAD (R-HSA-5362768)
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)
  Degradation of GLI2 by the proteasome (R-HSA-5610783)
  GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785)
  Hedgehog 'on' state (R-HSA-5632684)
  Regulation of RAS by GAPs (R-HSA-5658442)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  UCH proteinases (R-HSA-5689603)
  Ub-specific processing proteases (R-HSA-5689880)
  Assembly of the pre-replicative complex (R-HSA-68867)
  Orc1 removal from chromatin (R-HSA-68949)
  CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017)
  G2/M Checkpoints (R-HSA-69481)
  Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-HSA-69601)
  Ubiquitin-dependent degradation of Cyclin D (R-HSA-75815)
  The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276)
  FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  Regulation of RUNX3 expression and activity (R-HSA-8941858)
  Regulation of PTEN stability and activity (R-HSA-8948751)
  Neddylation (R-HSA-8951664)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Interleukin-1 signaling (R-HSA-9020702)
  Negative regulation of NOTCH4 signaling (R-HSA-9604323)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  GSK3B and BTRC (R-HSA-9762114)
  Somitogenesis (R-HSA-9824272)
  Antigen processing (R-HSA-983168)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[2]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Head and neck carcinoma	DISOU1DS	Strong	Altered Expression	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Vulvar squamous intraepithelial lesion	DISULIZR	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Head and neck cancer	DISBPSQZ	Limited	Altered Expression	[4]
Human papillomavirus infection	DISX61LX	Limited	Genetic Variation	[2]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Proteasome subunit alpha type-1 (PSMA1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Proteasome subunit alpha type-1 (PSMA1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Proteasome subunit alpha type-1 (PSMA1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Proteasome subunit alpha type-1 (PSMA1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Proteasome subunit alpha type-1 (PSMA1).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Proteasome subunit alpha type-1 (PSMA1).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Proteasome subunit alpha type-1 (PSMA1).	[16]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Proteasome subunit alpha type-1 (PSMA1).	[17]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 increases the expression of Proteasome subunit alpha type-1 (PSMA1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Proteasome subunit alpha type-1 (PSMA1).	[20]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Proteasome subunit alpha type-1 (PSMA1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Proteasome subunit alpha type-1 (PSMA1).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Proteasome subunit alpha type-1 (PSMA1).	[23]
D-glucose	DMMG2TO	Investigative	D-glucose decreases the expression of Proteasome subunit alpha type-1 (PSMA1).	[24]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of Proteasome subunit alpha type-1 (PSMA1).	[25]

1 Drug(s) Affected the Biochemical Pathways of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the metabolism of Proteasome subunit alpha type-1 (PSMA1).	[13]

References

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• [2] HPV test by Hybrid Capture II for the diagnosis of HR-HPV persistent infection.Med Mal Infect. 2017 Nov;47(7):484-489. doi: 10.1016/j.medmal.2017.05.013. Epub 2017 Sep 22.
• [3] Association between human papillomavirus DNA load and development of cervical intraepithelial neoplasia and cervical cancer.Int J Gynecol Cancer. 2008 Jul-Aug;18(4):755-60. doi: 10.1111/j.1525-1438.2007.01092.x. Epub 2007 Nov 16.
• [4] The transcription levels and prognostic values of seven proteasome alpha subunits in human cancers.Oncotarget. 2017 Jan 17;8(3):4501-4519. doi: 10.18632/oncotarget.13885.
• [5] Clinical evaluation of the digene hybrid capture II test and the COBAS AMPLICOR monitor test for determination of hepatitis B virus DNA levels.J Clin Microbiol. 2004 Aug;42(8):3513-7. doi: 10.1128/JCM.42.8.3513-3517.2004.
• [6] The use of molecular volumetric parameters for the evaluation of Lu-177 PSMA I&T therapy response and survival.Ann Nucl Med. 2019 Sep;33(9):681-688. doi: 10.1007/s12149-019-01376-3. Epub 2019 Jun 13.
• [7] HPV oligonucleotide microarray-based detection of HPV genotypes in cervical neoplastic lesions.Gynecol Oncol. 2003 May;89(2):210-7. doi: 10.1016/s0090-8258(02)00069-0.
• [8] Prognostic value of 68Ga PSMA I&T PET/CT SUV parameters on survival outcome in advanced prostat cancer.Ann Nucl Med. 2018 Oct;32(8):542-552. doi: 10.1007/s12149-018-1277-5. Epub 2018 Jul 13.
• [9] Quantitative proteomic analysis of age-related subventricular zone proteins associated with neurodegenerative disease.Sci Rep. 2016 Nov 18;6:37443. doi: 10.1038/srep37443.
• [10] 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.
• [11] 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.
• [12] Synergistic effects of retinoic acid and tamoxifen on human breast cancer cells: proteomic characterization. Exp Cell Res. 2007 Jan 15;313(2):357-68. doi: 10.1016/j.yexcr.2006.10.016. Epub 2006 Oct 25.
• [13] Changes in composition and activities of 26S proteasomes under the action of doxorubicin--apoptosis inductor of erythroleukemic K562 cells. Cell Biol Int. 2007 Apr;31(4):338-48. doi: 10.1016/j.cellbi.2007.01.018. Epub 2007 Jan 21.
• [14] 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.
• [15] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [16] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [17] 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.
• [18] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [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] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [21] Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity. J Biol Chem. 2020 Jan 31;295(5):1271-1287. doi: 10.1074/jbc.RA119.011174. Epub 2019 Dec 5.
• [22] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [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] Proteomic analysis of proteins associated with cellular senescence by calorie restriction in mesenchymal stem cells. In Vitro Cell Dev Biol Anim. 2012 Mar;48(3):186-95.
• [25] Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). Toxicol Lett. 2012 Jul 7;212(1):18-28. doi: 10.1016/j.toxlet.2012.04.013. Epub 2012 May 1.