Epoxomicin

- Overview
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    Background
    
    Epoxomicin was originally isolated from the culture medium of an Actinomycetes strain based on its in vivo antitumor activity against murine B16 melanoma. Epoxomicin is a naturally occurring selective proteasome inhibitor with anti-inflammatory activity. [1] Epoxomicin primarily inhibits the activity of CTRL (chymotrypsin-like proteasome).
    The novel α-epoxy ketone moiety of Epoxomicin forms covalent bonds with residues in particular catalytic subunits of the enzyme, disabling activity. The trypsin-like and peptidyl-glutamyl peptide hydrolyzing behaviors of the proteasome were both inhibited by Epoxomicin as well (at 100 and 1,000-fold slower rates, respectively). The ubiquitin-proteasome pathway heavily regulates bone formation, and Epoxomicin was shown to increase both bone volume and bone formation rates in rodents.
    Another study demonstrates that exposure to Epoxomicin and other proteasome inhibitors leads to dopaminergic cell death, producing a model of Parkinson's disease in vivo. Epoxomicin is an inhibitor of 20S Proteasome. [2]
    
    1. Meng, L; Mohan, R; Kwok, BH; Elofsson, M; Sin, N; Crews, CM (1999). "Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity". PNAS 96 (18): 10403–10408.2. Epoxomicin, Santa Cruz Biotechnology.
- Properties
  - Alternative Name
    
    Epoxomicin, BU4061T, BU-4061T; (2S,3S)-2-[[(2S,3S)-2-[acetyl(methyl)amino]-3-methylpentanoyl]amino]-N-[(2S,3R)-3-hydroxy-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxobutan-2-yl]-3-methylpentanamide
    
    CAS Number
    
    134381-21-8
    
    Molecular Formula
    
    C28H50N4O7
    
    Molecular Weight
    
    554.7
    
    Appearance
    
    A solid
    
    Purity
    
    98.54%
    
    Solubility
    
    ≥27.73 mg/mL in DMSO; insoluble in H2O; ≥77.4 mg/mL in EtOH
    
    Storage
    
    Store at -20°C
    
    * For Research Use Only
- Reference
  - 1. He Jiang, Charlotte Hooper, et al. "Functional analysis of a gene-edited mouse model to gain insights into the disease mechanisms of a titin missense variant." Basic Res Cardiol. 2021 Feb 26;116(1):14. PMID:33637999
    2. Dunlop RA, Carney JM. "Mechanisms of L-Serine-Mediated Neuroprotection Include Selective Activation of Lysosomal Cathepsins B and L." Neurotox Res. 2020;10.1007/s12640-020-00168-2. PMID:32242285
    3. Wang LJ, Chiou JT, et al. "SIRT3, PP2A and TTP protein stability in the presence of TNF-α on vincristine-induced apoptosis of leukaemia cells." J Cell Mol Med. 2020;24(4):2552–2565. PMID:31930676
    4. Akpinar HA, Kahraman H, et al. "Ochratoxin A Sequentially Activates Autophagy and the Ubiquitin-Proteasome System." Toxins (Basel). 2019 Oct 24;11(11). pii: E615. PMID:31653047
    5. Azimi M, Brown NL. "Jagged1 protein processing in the developing mammalian lens." Biol Open. 2019 Mar 26;8(3). pii: bio041095. PMID:30890522
    6. Felix Lambrecht. "Computational methods for the structure determination of highly dynamic molecular machines by cryo-EM." Georg-August-Universität Göttingen. 2019.
    7. Zhu Y, Li M, et al. "Ilexgenin A inhibits mitochondrial fission and promote Drp1 degradation by Nrf2-induced PSMB5 in endothelial cells." Drug Dev Res. 2019 Feb 14. PMID:30762899
    8. Yousefelahiyeh M, Xu J, et al. "DCAF7/WDR68 is required for normal levels of DYRK1A and DYRK1B." PLoS One. 2018 Nov 9;13(11):e0207779. PMID:30496304
    9. Xiang Y, Wang M, et al. "Mechanisms controlling the multistage post-translational processing of endogenous Nrf1α/TCF11 proteins to yield distinct isoforms within the coupled positive and negative feedback circuits." Toxicol Appl Pharmacol. 2018 Dec 1;360:212-235. PMID:30287392
    10. Lu Q, Grotzke JE, Cresswell P. "A novel probe to assess cytosolic entry of exogenous proteins." Nat Commun. 2018 Aug 6;9(1):3104. PMID:30082832
    11. Selvarangan Ponnazhagan, Vinayak Khattar, et al. "Structural determinants and genetic modifications enhance BMP2 stability and extracellular secretion." bioRxiv. 2018 July 20.
    12. Yuancai Xiang, et al."Molecular mechanisms controlling the multistage post-translational processing of endogenous Nrf1/TCF11 proteins to yield distinct proteoforms within the coupled positive and negative feedback circuits."bioRxiv.2018. April 12.
    13. Mañas A, Chen W, et al. "BaxΔ2 sensitizes colorectal cancer cells to proteasome inhibitor-induced cell death." Biochem Biophys Res Commun.2018 Jan 29;496(1):18-24. PMID:29291406
    14. Angelina C, Tan ISY, et al. "KIF1Bβ increases ROS to mediate apoptosis and reinforces its protein expression through O (2)(-) in a positive feedback mechanism in neuroblastoma." Sci Rep. 2017 Dec 4;7(1):16867. PMID:29203804
    15. Susman MW, Karuna EP, et al. "Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates." Elife. 2017 Sep 8;6. pii: e26509. PMID:28885975
    16. Worden EJ, Dong KC, Martin A. "An AAA Motor-Driven Mechanical Switch in Rpn11 Controls Deubiquitination at the 26S Proteasome." Mol Cell. 2017 Aug 16. pii:S1097-2765(17)30547-6. PMID:28844860
    17. Charpak-Amikam Y, Kubsch T, et al. "Human cytomegalovirus escapes immune recognition by NK cells through the downregulation of B7-H6 by the viral genes US18 and US20." Sci Rep. 2017 Aug 17;7(1):8661. PMID:28819195
    18. Tsai YC, Kotiya A, et al. "Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication." Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):E5158-E5166. PMID:28584101
    19. Haselbach D, Schrader J, et al."Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs." Nat Commun. 2017 May 25;8:15578. PMID:28541292
    20. Sabouny R, Fraunberger E, et al. "The Keap1-Nrf2 stress response pathway promotes mitochondrial hyperfusion through degradation of the mitochondrial fission protein Drp1." Antioxid Redox Signal. 2017 May 11. PMID:28494652
    21. Fuchs ACD, Alva V, et al. "The Architecture of the Anbu Complex Reflects an Evolutionary Intermediate at the Origin of the Proteasome System." Structure. 2017 Jun 6;25(6):834-845.e5. PMID:28479063
    22. Marina Torres Figueiredo. "MAPT as pathogenic risk factor for Parkinson's Disease." repositorio-aberto.up.pt.2017.
    23. Schrader J, Henneberg F, et al. "The inhibition mechanism of human 20S proteasomes enables next-generation inhibitor design." Science. 2016 Aug 5;353(6299):594-8. PMID:27493187
    24. Welk V, Coux O, et al. "Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes." J Biol Chem. 2016 Apr 18. PMID:27129254
    25. Tang, Pei-Ciao, and Glen M. Watson. "Proteomic identification of hair cell repair proteins in the model sea anemone Nematostella vectensis." Hearing research (2015). PMID:26183436
    26. Downey, Sondra L, et al. "Use of Proteasome Inhibitors." Current Protocols in Immunology (2015): 9-10.
    27. Khattar, Vinayak, et al. "Cks1 proteasomal degradation is induced by inhibiting Hsp90-mediated chaperoning in cancer cells." Cancer chemotherapy and pharmacology (2014): 1-10. PMID:25544127
    28. Khattar, Vinayak, et al. "Cks1 proteasomal turnover is a predominant mode of regulation in breast cancer cells: Role of key tyrosines and lysines." International journal of oncology 46.1 (2015): 395-406. PMID:25353373
    29. Villamor JG, Kaschani F, et al. "Profiling protein kinases and other ATP binding proteins in Arabidopsis using Acyl-ATP probes." Mol Cell Proteomics. 2013 Sep;12(9):2481-96. PMID:23722185

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Epoxomicin

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