Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ6RPX5)

• DOT Name: Proteasome subunit alpha type-6 (PSMA6)
• Synonyms: 27 kDa prosomal protein; PROS-27; p27K; Macropain iota chain; Multicatalytic endopeptidase complex iota chain; Proteasome iota chain
• Gene Name: PSMA6
• Related Disease:
  Advanced cancer
  Autoimmune disease
  Bone osteosarcoma
  Burkitt lymphoma
  Cardiovascular disease
  Coronary atherosclerosis
  Diabetic kidney disease
  Graves disease
  Hepatocellular carcinoma
  HIV infectious disease
  Juvenile idiopathic arthritis
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Myocardial infarction
  Nephropathy
  Osteosarcoma
  Plasma cell myeloma
  Severe combined immunodeficiency
  Type-1/2 diabetes
  Stroke
  Neoplasm
  Chronic renal failure
  End-stage renal disease
  Non-insulin dependent diabetes
  Type-1 diabetes
• UniProt ID: PSA6_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 ; 6MSG ; 6MSH ; 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:
  MSRGSSAGFDRHITIFSPEGRLYQVEYAFKAINQGGLTSVAVRGKDCAVIVTQKKVPDKL
  LDSSTVTHLFKITENIGCVMTGMTADSRSQVQRARYEAANWKYKYGYEIPVDMLCKRIAD
  ISQVYTQNAEMRPLGCCMILIGIDEEQGPQVYKCDPAGYYCGFKATAAGVKQTESTSFLE
  KKVKKKFDWTFEQTVETAITCLSTVLSIDFKPSEIEVGVVTVENPKFRILTEAEIDAHLV
  ALAERD
• 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

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[3]
Burkitt lymphoma	DIS9D5XU	Strong	Genetic Variation	[4]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[5]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[6]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[7]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
HIV infectious disease	DISO97HC	Strong	Biomarker	[10]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Genetic Variation	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[12]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[6]
Nephropathy	DISXWP4P	Strong	Biomarker	[7]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[13]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Altered Expression	[14]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[5]
Stroke	DISX6UHX	moderate	Genetic Variation	[15]
Neoplasm	DISZKGEW	Disputed	Biomarker	[16]
Chronic renal failure	DISGG7K6	Limited	Genetic Variation	[6]
End-stage renal disease	DISXA7GG	Limited	Genetic Variation	[6]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[17]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[18]

10 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-6 (PSMA6).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Proteasome subunit alpha type-6 (PSMA6).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Proteasome subunit alpha type-6 (PSMA6).	[22]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Proteasome subunit alpha type-6 (PSMA6).	[23]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Proteasome subunit alpha type-6 (PSMA6).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Proteasome subunit alpha type-6 (PSMA6).	[25]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Proteasome subunit alpha type-6 (PSMA6).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Proteasome subunit alpha type-6 (PSMA6).	[28]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Proteasome subunit alpha type-6 (PSMA6).	[29]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Proteasome subunit alpha type-6 (PSMA6).	[30]

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-6 (PSMA6).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Proteasome subunit alpha type-6 (PSMA6).	[26]

References

• [1] Identification of proteasomal catalytic subunit PSMA6 as a therapeutic target for lung cancer.Cancer Sci. 2017 Apr;108(4):732-743. doi: 10.1111/cas.13185. Epub 2017 Apr 25.
• [2] Identification of a novel candidate locus for juvenile idiopathic arthritis at 14q13.2 in the Latvian population by association analysis with microsatellite markers.DNA Cell Biol. 2010 Sep;29(9):543-51. doi: 10.1089/dna.2009.0970.
• [3] A p27Kip1 mutant that does not inhibit CDK activity promotes centrosome amplification and micronucleation.Oncogene. 2012 Aug 30;31(35):3989-98. doi: 10.1038/onc.2011.550. Epub 2011 Dec 12.
• [4] Detection of genomic aberrations in molecularly defined Burkitt's lymphoma by array-based, high resolution, single nucleotide polymorphism analysis.Haematologica. 2010 Dec;95(12):2047-55. doi: 10.3324/haematol.2010.026831. Epub 2010 Sep 7.
• [5] 1,4-Dihydropyridine derivatives without Ca2+-antagonist activity up-regulate Psma6 mRNA expression in kidneys of intact and diabetic rats.Cell Biochem Funct. 2016 Jan;34(1):3-6. doi: 10.1002/cbf.3160. Epub 2015 Dec 4.
• [6] Association between functional variant of inflammatory system gene (PSMA6) and end-stage kidney disease.Int Urol Nephrol. 2016 Dec;48(12):2083-2087. doi: 10.1007/s11255-016-1420-y. Epub 2016 Sep 26.
• [7] Proteasome subunit- type-6 protein is post-transcriptionally repressed by the microRNA-4490 in diabetic nephropathy.Biosci Rep. 2018 Oct 31;38(5):BSR20180815. doi: 10.1042/BSR20180815. Print 2018 Oct 31.
• [8] Microsatellite genotyping of chromosome 14q13.2-14q13 in the vicinity of proteasomal gene PSMA6 and association with Graves' disease in the Latvian population.Immunogenetics. 2004 Jul;56(4):238-43. doi: 10.1007/s00251-004-0687-9. Epub 2004 Jun 17.
• [9] Significance and expression of atypical protein kinase C-iota in human hepatocellular carcinoma.J Surg Res. 2009 Jun 1;154(1):143-9. doi: 10.1016/j.jss.2008.05.036. Epub 2008 Jun 30.
• [10] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [11] Juvenile idiopathic arthritis subtype- and sex-specific associations with genetic variants in the PSMA6/PSMC6/PSMA3 gene cluster.Pediatr Neonatol. 2014 Oct;55(5):393-403. doi: 10.1016/j.pedneo.2014.01.007. Epub 2014 May 27.
• [12] Genome-wide CRISPR screen reveals PSMA6 to be an essential gene in pancreatic cancer cells.BMC Cancer. 2019 Mar 21;19(1):253. doi: 10.1186/s12885-019-5455-1.
• [13] The G-Allele of the PSMA6-8C>G polymorphism is associated with poor outcome in multiple myeloma independently of circulating proteasome serum levels.Eur J Haematol. 2010 Aug;85(2):108-13. doi: 10.1111/j.1600-0609.2010.01455.x. Epub 2010 Apr 8.
• [14] Identification of Proteins Differentially Expressed by Adipose-derived Mesenchymal Stem Cells Isolated from Immunodeficient Mice.Int J Mol Sci. 2019 May 30;20(11):2672. doi: 10.3390/ijms20112672.
• [15] Inflammatory system gene polymorphism and the risk of stroke: a case-control study in an Indian population.Brain Res Bull. 2008 Jan 31;75(1):158-65. doi: 10.1016/j.brainresbull.2007.08.007. Epub 2007 Sep 24.
• [16] Protein kinase C iota: human oncogene, prognostic marker and therapeutic target.Pharmacol Res. 2007 Jun;55(6):487-97. doi: 10.1016/j.phrs.2007.04.015. Epub 2007 May 5.
• [17] Validation of the association between PSMA6 -8 C/G polymorphism and type 2 diabetes mellitus in Chinese Dongxiang and Han populations.Diabetes Res Clin Pract. 2012 Nov;98(2):295-301. doi: 10.1016/j.diabres.2012.09.021. Epub 2012 Sep 29.
• [18] Genetic variations in the PSMA3, PSMA6 and PSMC6 genes are associated with type 1 diabetes in Latvians and with expression level of number of UPS-related and T1DM-susceptible genes in HapMap individuals.Mol Genet Genomics. 2016 Apr;291(2):891-903. doi: 10.1007/s00438-015-1153-0. Epub 2015 Dec 12.
• [19] 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.
• [20] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Benzo[a]pyrene treatment leads to changes in nuclear protein expression and alternative splicing. Mutat Res. 2010 Apr 1;686(1-2):47-56. doi: 10.1016/j.mrfmmm.2010.01.015. Epub 2010 Jan 25.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [30] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.