Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTR9WUC)

DOT Name E3 ubiquitin-protein ligase TTC3 (TTC3)
Synonyms EC 2.3.2.27; Protein DCRR1; RING finger protein 105; RING-type E3 ubiquitin transferase TTC3; TPR repeat protein D; Tetratricopeptide repeat protein 3; TPR repeat protein 3
Gene Name TTC3
Related Disease
Familial Alzheimer disease ( )
Myocardial infarction ( )
Type-1 diabetes ( )
UniProt ID
TTC3_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
2.3.2.27
Pfam ID
PF19179 ; PF13639
Sequence
MDNFAEGDFTVADYALLEDCPHVDDCVFAAEFMSNDYVRVTQLYCDGVGVQYKDYIQSER
NLEFDICSIWCSKPISVLQDYCDAIKINIFWPLLFQHQNSSVISRLHPCVDANNSRASEI
NLKKLQHLELMEDIVDLAKKVANDSFLIGGLLRIGCKIENKILAMEEALNWIKYAGDVTI
LTKLGSIDNCWPMLSIFFTEYKYHITKIVMEDCNLLEELKTQSCMDCIEEGELMKMKGNE
EFSKERFDIAIIYYTRAIEYRPENYLLYGNRALCFLRTGQFRNALGDGKRATILKNTWPK
GHYRYCDALSMLGEYDWALQANIKAQKLCKNDPEGIKDLIQQHVKLQKQIEDLQGRTANK
DPIKAFYENRAYTPRSLSAPIFTTSLNFVEKERDFRKINHEMANGGNQNLKVADEALKVD
DCDCHPEFSPPSSQPPKHKGKQKSRNNESEKFSSSSPLTLPADLKNILEKQFSKSSRAAH
QDFANIMKMLRSLIQDGYMALLEQRCRSAAQAFTELLNGLDPQKIKQLNLAMINYVLVVY
GLAISLLGIGQPEELSEAENQFKRIIEHYPSEGLDCLAYCGIGKVYLKKNRFLEALNHFE
KARTLIYRLPGVLTWPTSNVIIEESQPQKIKMLLEKFVEECKFPPVPDAICCYQKCHGYS
KIQIYITDPDFKGFIRISCCQYCKIEFHMNCWKKLKTTTFNDKIDKDFLQGICLTPDCEG
VISKIIIFSSGGEVKCEFEHKVIKEKVPPRPILKQKCSSLEKLRLKEDKKLKRKIQKKEA
KKLAQERMEEDLRESNPPKNEEQKETVDNVQRCQFLDDRILQCIKQYADKIKSGIQNTAM
LLKELLSWKVLSTEDYTTCFSSRNFLNEAVDYVIRHLIQENNRVKTRIFLHVLSELKEVE
PKLAAWIQKLNSFGLDATGTFFSRYGASLKLLDFSIMTFLWNEKYGHKLDSIEGKQLDYF
SEPASLKEARCLIWLLEEHRDKFPALHSALDEFFDIMDSRCTVLRKQDSGEAPFSSTKVK
NKSKKKKPKDSKPMLVGSGTTSVTSNNEIITSSEDHSNRNSDSAGPFAVPDHLRQDVEEF
EALYDQHSNEYVVRNKKLWDMNPKQKCSTLYDYFSQFLEEHGPLDMSNKMFSAEYEFFPE
ETRQILEKAGGLKPFLLGCPRFVVIDNCIALKKVASRLKKKRKKKNIKTKVEEISKAGEY
VRVKLQLNPAAREFKPDVKSKPVSDSSSAPAFENVKPKPVSANSPKPACEDVKAKPVSDN
SSRQVSEDGQPKGVSSNSPKPGSEDANYKRVSCNSPKPVLEDVKPTYWAQSHLVTGYCTY
LPFQRFDITQTPPAYINVLPGLPQYTSIYTPLASLSPEYQLPRSVPVVPSFVANDRADKN
AAAYFEGHHLNAENVAGHQIASETQILEGSLGISVKSHCSTGDAHTVLSESNRNDEHCGN
SNNKCEVIPESTSAVTNIPHVQMVAIQVSWNIIHQEVNTEPYNPFEERQGEISRIEKEHQ
VLQDQLQEVYENYEQIKLKGLEETRDLEEKLKRHLEENKISKTELDWFLQDLEREIKKWQ
QEKKEIQERLKSLKKKIKKVSNASEMYTQKNDGKEKEHELHLDQSLEISNTLTNEKMKIE
EYIKKGKEDYEESHQRAVAAEVSVLENWKESEVYKLQIMESQAEAFLKKLGLISRDPAAY
PDMESDIRSWELFLSNVTKEIEKAKSQFEEQIKAIKNGSRLSELSKVQISELSFPACNTV
HPELLPESSGDDGQGLVTSASDVTGNHAALHRDPSVFSAGDSPGEAPSALLPGPPPGQPE
ATQLTGPKRAGQAALSERSPVADRKQPVPPGRAARSSQSPKKPFNSIIEHLSVVFPCYNS
TELAGFIKKVRSKNKNSLSGLSIDEIVQRVTEHILDEQKKKKPNPGKDKRTYEPSSATPV
TRSSQGSPSVVVAPSPKTKGQKAEDVPVRIALGASSCEICHEVFKSKNVRVLKCGHKYHK
GCFKQWLKGQSACPACQGRDLLTEESPSGRGWPSQNQELPSCSSR
Function
E3 ubiquitin-protein ligase which catalyzes the formation of 'Lys-48'-polyubiquitin chains. Mediates the ubiquitination and subsequent degradation of phosphorylated Akt (AKT1, AKT2 and AKT3) in the nucleus. Acts as a terminal regulator of Akt signaling after activation; its phosphorylation by Akt, which is a prerequisite for ubiquitin ligase activity, suggests the existence of a regulation mechanism required to control Akt levels after activation. Positively regulates TGFB1-induced epithelial-mesenchymal transition and myofibroblast differentiation by mediating the ubiquitination and subsequent degradation of SMURF2. Regulates neuronal differentiation by regulating actin remodeling and Golgi organization via a signaling cascade involving RHOA, CIT and ROCK. Inhibits cell proliferation.
Tissue Specificity Found in all tissues examined.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Familial Alzheimer disease DISE75U4 Strong Biomarker [1]
Myocardial infarction DIS655KI Strong Biomarker [2]
Type-1 diabetes DIS7HLUB Limited Genetic Variation [3]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
21 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 E3 ubiquitin-protein ligase TTC3 (TTC3). [4]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [5]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [6]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [7]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [8]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [9]
Cisplatin DMRHGI9 Approved Cisplatin affects the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [10]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide increases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [11]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [12]
Decitabine DMQL8XJ Approved Decitabine affects the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [10]
Marinol DM70IK5 Approved Marinol increases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [13]
Selenium DM25CGV Approved Selenium decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [14]
Phenobarbital DMXZOCG Approved Phenobarbital affects the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [15]
Testosterone enanthate DMB6871 Approved Testosterone enanthate affects the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [16]
Tamibarotene DM3G74J Phase 3 Tamibarotene decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [6]
Tocopherol DMBIJZ6 Phase 2 Tocopherol decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [14]
Geldanamycin DMS7TC5 Discontinued in Phase 2 Geldanamycin increases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [18]
Torcetrapib DMDHYM7 Discontinued in Phase 2 Torcetrapib increases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [19]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [20]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [21]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of E3 ubiquitin-protein ligase TTC3 (TTC3). [22]
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⏷ Show the Full List of 21 Drug(s)
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 affects the methylation of E3 ubiquitin-protein ligase TTC3 (TTC3). [17]
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References

1 Overexpressed TTC3 Protein Tends to be Cleaved into Fragments and Form Aggregates in the Nucleus.Neuromolecular Med. 2019 Mar;21(1):85-96. doi: 10.1007/s12017-018-8509-7. Epub 2018 Sep 10.
2 Circular RNA Ttc3 regulates cardiac function after myocardial infarction by sponging miR-15b.J Mol Cell Cardiol. 2019 May;130:10-22. doi: 10.1016/j.yjmcc.2019.03.007. Epub 2019 Mar 12.
3 Fine mapping of a region on chromosome 21q21.11-q22.3 showing linkage to type 1 diabetes.J Med Genet. 2005 Jan;42(1):17-25. doi: 10.1136/jmg.2004.022004.
4 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
5 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
6 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
7 Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
8 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.
9 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
10 Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
11 Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
12 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
13 Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
14 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.
15 Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
16 Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
17 Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
18 Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
19 Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
20 Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
21 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
22 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.