A2606-1mg | Epoxomicin [134381-21-8] Clinisciences

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]

References:
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.

1. Ly Thi Huong Luu Le, Seoyoung Park, et al. "N-recognins UBR1 and UBR2 as central ER stress sensors in mammals." Molecules and Cells. January 2024.
2. Xufeng Chen, Qiao Lu, et al. "A membrane-associated MHC-I inhibitory axis for cancer immune evasion." Cell. 2023 Aug 31;186(18):3903-3920.e21. PMID: 37557169
3. Yang, Liuqing. "SER14-RPN6 Phosphorylation Mediates the Activation of 26S Proteasomes by Cyclic AMP and Protects Against Cardiac Proteotoxic Stress in Mice." University of South Dakota ProQuest Dissertation & Theses, 2023. 30634748.
4. 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
5. Zhijun Liu, Himani Nailwal, et al. "A class of viral inducer of degradation of the necroptosis adaptor RIPK3 regulates virus-induced inflammation." Immunity. 2021 Feb 9;54(2):247-258.e7. PMID: 33444549
6. 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
7. 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
8. 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
9. Azimi M, Brown NL. "Jagged1 protein processing in the developing mammalian lens." Biol Open. 2019 Mar 26;8(3). pii: bio041095. PMID: 30890522
10. Felix Lambrecht. "Computational methods for the structure determination of highly dynamic molecular machines by cryo-EM." Georg-August-Universität Göttingen. 2019.
11. 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
12. 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
13. 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
14. 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
15. Selvarangan Ponnazhagan, Vinayak Khattar, et al. "Structural determinants and genetic modifications enhance BMP2 stability and extracellular secretion." bioRxiv. 2018 July 20.
16. 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.
17. 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
18. 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
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. 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
26. Marina Torres Figueiredo. "MAPT as pathogenic risk factor for Parkinson's Disease." repositorio-aberto.up.pt.2017.
27. 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
28. Welk V, Coux O, et al. "Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes." J Biol Chem. 2016 Apr 18. PMID: 27129254
29. 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
30. Downey, Sondra L, et al. "Use of Proteasome Inhibitors." Current Protocols in Immunology (2015): 9-10.
31. 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
32. 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
33. 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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Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	554.7
Cas No.	134381-21-8
Formula	C₂₈H₅₀N₄O₇
Synonyms	Epoxomicin, BU4061T, BU-4061T
Solubility	≥27.73 mg/mL in DMSO; insoluble in H2O; ≥77.4 mg/mL in EtOH
Chemical Name	(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
SDF	Download SDF
Canonical SMILES	CCC(C)C(C(=O)NC(C(C)O)C(=O)NC(CC(C)C)C(=O)C1(CO1)C)NC(=O)C(C(C)CC)N(C)C(=O)C
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Cell experiment:[1]
Cell lines	HEK293T cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	Incubated at 0.2 μM or 2 μM epoxomicin for 1 hour
Applications	Peptides were degraded by proteasome from cytosolic, mitochondrial, and nuclear proteins. Epoxomicin is a proteasome inhibitor. It decreased the levels of the majority of intracellular peptides, companying with inhibition of the proteasome beta-2 and beta-5 subunits in HEK293T cells.
Animal experiment:[2]
Animal models	C57BL6
Dosage form	Epoxomicin (0.58 mg/kg) solubilized in 10% DMSO/PBS were injected i.p. daily for 6 days
Applications	Epoxomicin reduced inflammation in response to picrylchloride. Epoxomicin potently inhibited the irritant-associated inflammatory response by 95% when ear edema measurements were made 24 h postchallenge.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: 1. Fricker LD1, Gelman JS, Castro LM et al. Peptidomic analysis of HEK293T cells: effect of the proteasome inhibitor epoxomicin on intracellular peptides. J Proteome Res. 2012 Mar 2; 11 (3): 1981-90. 2. Meng L1, Mohan R, Kwok BH et al. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci U S A. 1999 Aug 31; 96 (18): 10403-8.