Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPZ38BT)

• DOT Name: T-complex protein 1 subunit epsilon (CCT5)
• Synonyms: TCP-1-epsilon; CCT-epsilon
• Gene Name: CCT5
• Related Disease:
  Adult glioblastoma
  Glioblastoma multiforme
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  HIV infectious disease
  Lung adenocarcinoma
  Neoplasm
  Non-small-cell lung cancer
  Paraplegia
  Peripheral sensory neuropathies
  Hereditary sensory and autonomic neuropathy with spastic paraplegia
  Colorectal carcinoma
• UniProt ID: TCPE_HUMAN
• PDB ID: 5UYX ; 5UYZ ; 6NR8 ; 6NR9 ; 6NRA ; 6NRB ; 6NRC ; 6NRD ; 6QB8 ; 7LUM ; 7LUP ; 7NVL ; 7NVM ; 7NVN ; 7NVO ; 7TRG ; 7TTN ; 7TTT ; 7TUB ; 7WU7 ; 7WZ3 ; 7X0A ; 7X0S ; 7X0V ; 7X3J ; 7X3U ; 7X6Q ; 7X7Y ; 8AJM ; 8AJO ; 8SFE ; 8SFF ; 8SG8 ; 8SG9 ; 8SGC ; 8SGL ; 8SGQ ; 8SH9 ; 8SHA ; 8SHD ; 8SHE ; 8SHF ; 8SHG ; 8SHL ; 8SHN ; 8SHO ; 8SHP ; 8SHQ ; 8SHT
• Pfam ID: PF00118
• Sequence:
  MASMGTLAFDEYGRPFLIIKDQDRKSRLMGLEALKSHIMAAKAVANTMRTSLGPNGLDKM
  MVDKDGDVTVTNDGATILSMMDVDHQIAKLMVELSKSQDDEIGDGTTGVVVLAGALLEEA
  EQLLDRGIHPIRIADGYEQAARVAIEHLDKISDSVLVDIKDTEPLIQTAKTTLGSKVVNS
  CHRQMAEIAVNAVLTVADMERRDVDFELIKVEGKVGGRLEDTKLIKGVIVDKDFSHPQMP
  KKVEDAKIAILTCPFEPPKPKTKHKLDVTSVEDYKALQKYEKEKFEEMIQQIKETGANLA
  ICQWGFDDEANHLLLQNNLPAVRWVGGPEIELIAIATGGRIVPRFSELTAEKLGFAGLVQ
  EISFGTTKDKMLVIEQCKNSRAVTIFIRGGNKMIIEEAKRSLHDALCVIRNLIRDNRVVY
  GGGAAEISCALAVSQEADKCPTLEQYAMRAFADALEVIPMALSENSGMNPIQTMTEVRAR
  QVKEMNPALGIDCLHKGTNDMKQQHVIETLIGKKQQISLATQMVRMILKIDDIRKPGESE
  E
• Function: Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis. The TRiC complex mediates the folding of WRAP53/TCAB1, thereby regulating telomere maintenance. As part of the TRiC complex may play a role in the assembly of BBSome, a complex involved in ciliogenesis regulating transports vesicles to the cilia. The TRiC complex plays a role in the folding of actin and tubulin (Probable).
• Reactome Pathway:
  Formation of tubulin folding intermediates by CCT/TriC (R-HSA-389960)
  Folding of actin by CCT/TriC (R-HSA-390450)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)
  BBSome-mediated cargo-targeting to cilium (R-HSA-5620922)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  Prefoldin mediated transfer of substrate to CCT/TriC (R-HSA-389957)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
HIV infectious disease	DISO97HC	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Paraplegia	DISSKWBI	Strong	Genetic Variation	[6]
Peripheral sensory neuropathies	DISYWI6M	Strong	Genetic Variation	[7]
Hereditary sensory and autonomic neuropathy with spastic paraplegia	DISEL12B	Supportive	Autosomal recessive	[6]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of T-complex protein 1 subunit epsilon (CCT5).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of T-complex protein 1 subunit epsilon (CCT5).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of T-complex protein 1 subunit epsilon (CCT5).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of T-complex protein 1 subunit epsilon (CCT5).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of T-complex protein 1 subunit epsilon (CCT5).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of T-complex protein 1 subunit epsilon (CCT5).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of T-complex protein 1 subunit epsilon (CCT5).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of T-complex protein 1 subunit epsilon (CCT5).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of T-complex protein 1 subunit epsilon (CCT5).	[16]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of T-complex protein 1 subunit epsilon (CCT5).	[17]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of T-complex protein 1 subunit epsilon (CCT5).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of T-complex protein 1 subunit epsilon (CCT5).	[22]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of T-complex protein 1 subunit epsilon (CCT5).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of T-complex protein 1 subunit epsilon (CCT5).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of T-complex protein 1 subunit epsilon (CCT5).	[21]

References

• [1] Extracellular Vesicles from Neurosurgical Aspirates Identifies Chaperonin Containing TCP1 Subunit 6A as a Potential Glioblastoma Biomarker with Prognostic Significance.Proteomics. 2019 Jan;19(1-2):e1800157. doi: 10.1002/pmic.201800157.
• [2] Prediction of metastatic relapse in node-positive breast cancer: establishment of a clinicogenomic model after FEC100 adjuvant regimen.Breast Cancer Res Treat. 2008 Jun;109(3):491-501. doi: 10.1007/s10549-007-9673-x. Epub 2007 Jul 21.
• [3] 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.
• [4] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [5] Chaperonin containing TCP1 subunit 5 is a tumor associated antigen of non-small cell lung cancer.Oncotarget. 2017 Jul 18;8(38):64170-64179. doi: 10.18632/oncotarget.19369. eCollection 2017 Sep 8.
• [6] Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia. J Med Genet. 2006 May;43(5):441-3. doi: 10.1136/jmg.2005.039230. Epub 2006 Jan 6.
• [7] Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms.Acta Neuropathol. 2013 Sep;126(3):307-28. doi: 10.1007/s00401-013-1115-8. Epub 2013 Jul 30.
• [8] Discovery and scoring of protein interaction subnetworks discriminative of late stage human colon cancer.Mol Cell Proteomics. 2009 Apr;8(4):827-45. doi: 10.1074/mcp.M800428-MCP200. Epub 2008 Dec 19.
• [9] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] 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.
• [17] 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.
• [18] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [19] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [20] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [21] 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.
• [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.