Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT38E6Y1)

• DOT Name: Proteasome subunit alpha type-5 (PSMA5)
• Synonyms: Macropain zeta chain; Multicatalytic endopeptidase complex zeta chain; Proteasome zeta chain
• Gene Name: PSMA5
• Related Disease:
  Narcolepsy
  Alpha thalassemia
  Astrocytoma
  Beta thalassemia
  Carcinoma
  Fatty liver disease
  Hematologic disease
  Hemoglobin H disease
  HIV infectious disease
  Metastatic malignant neoplasm
  Neoplasm
  Osteoporosis
  Prostate cancer
  Prostate carcinoma
  Systemic lupus erythematosus
  Kidney cancer
  Renal carcinoma
• UniProt ID: PSA5_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:
  MFLTRSEYDRGVNTFSPEGRLFQVEYAIEAIKLGSTAIGIQTSEGVCLAVEKRITSPLME
  PSSIEKIVEIDAHIGCAMSGLIADAKTLIDKARVETQNHWFTYNETMTVESVTQAVSNLA
  LQFGEEDADPGAMSRPFGVALLFGGVDEKGPQLFHMDPSGTFVQCDARAIGSASEGAQSS
  LQEVYHKSMTLKEAIKSSLIILKQVMEEKLNATNIELATVQPGQNFHMFTKEELEEVIKD
  I
• 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).
• Tissue Specificity: Expressed in fetal brain (at protein level).
• 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)
  Neutrophil degranulation (R-HSA-6798695)
  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

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[2]
Astrocytoma	DISL3V18	Strong	Biomarker	[3]
Beta thalassemia	DIS5RCQK	Strong	Genetic Variation	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[6]
Hematologic disease	DIS9XD9A	Strong	Genetic Variation	[7]
Hemoglobin H disease	DISHFWO5	Strong	Genetic Variation	[8]
HIV infectious disease	DISO97HC	Strong	Biomarker	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Osteoporosis	DISF2JE0	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[13]
Kidney cancer	DISBIPKM	Limited	Altered Expression	[14]
Renal carcinoma	DISER9XT	Limited	Altered Expression	[14]

4 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-5 (PSMA5).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Proteasome subunit alpha type-5 (PSMA5).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Proteasome subunit alpha type-5 (PSMA5).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Proteasome subunit alpha type-5 (PSMA5).	[28]

15 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-5 (PSMA5).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Proteasome subunit alpha type-5 (PSMA5).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Proteasome subunit alpha type-5 (PSMA5).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Proteasome subunit alpha type-5 (PSMA5).	[20]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Proteasome subunit alpha type-5 (PSMA5).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Proteasome subunit alpha type-5 (PSMA5).	[22]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Proteasome subunit alpha type-5 (PSMA5).	[23]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Proteasome subunit alpha type-5 (PSMA5).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Proteasome subunit alpha type-5 (PSMA5).	[25]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Proteasome subunit alpha type-5 (PSMA5).	[26]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Proteasome subunit alpha type-5 (PSMA5).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Proteasome subunit alpha type-5 (PSMA5).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Proteasome subunit alpha type-5 (PSMA5).	[31]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Proteasome subunit alpha type-5 (PSMA5).	[32]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of Proteasome subunit alpha type-5 (PSMA5).	[33]

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-5 (PSMA5).	[17]

References

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• [18] 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.
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