Epoxomicin (134381-21-8) is a potent, selective and cell permeable irreversible inhibitor of the 20S proteasome.1 It does not inhibit non-proteasomal proteases such as papain, chymotrypsin, trypsin, calpain and cathepsin B at concentrations up to 50 μM.1 Epoxomicin was isolated from Actinomycete strain Q996-17 and displayed in vivo antitumor activity against B16 melanoma cells.2 Epoxomicin caused a progressive model of Parkinson’s disease in various systems.3,4,5 This model has been disputed.6,7
Epoxomicin has been used:
- as an ubiquitin–proteosome system (UPS) inhibitor in pheochromocytoma PC12 cells
- as a proteasome inhibitor in mammary epithelial MCF-10A cells
- as a proteasome inhibitor in chymotryptic assay in cardiomyocytes
In studies of proteasome biology.
ChEBI: A tripeptide consisting of an Ile-Ile-Thr-NH2 sequence N-substituted on the threonamide amidic nitrogen with a (2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl group and with acetyl and meth
l groups on the nitrogen of the isoleucine residue distal to the threonamide; a naturally occurring selective proteasome inhibitor with anti-inflammatory activity.
Epoxomicin is a linear peptide consisting of a threonine or serine residue with α′, β′-epoxyketone?derived from leucine or a γ,δ-dehydroleucine. It is a natural product isolated from?Actinomyces?sp., and is a cell-permeable, potent, selective and irreversible proteasome inhibitor.
Epoxomicin binds covalently to the catalytic subunits of proteasome. It forms an adduct with target proteins. It inhibits chymotrypsin-like activity of the proteasome. Epoxomicin also inhibits the nuclear factor κ light chain enhancer of activated B cells (NF-κB) mediated proinflammatory signalling pathway. It is also a potent antitumor and anti-inflammatory agent.
1) Meng et al. (1999), Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo anti-inflammatory activity; Proc. Natl. Acad. Sci. USA, 96 10403
2) Hanada et al. (1992), Epoxomicin, a new antitumor agent of microbial origin; J. Antibiot. (Tokyo), 45 1746
3) McNaught et al. (2004), Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease; Ann. Neurol., 56 149
4) Matsui et al. (2010), Proteasome inhibition in medaka brain induces the features of Parkinson’s disease; J. Neurochem., 115 178
5) Metcalfe et al. (2012), Coordination between proteasome impairment and caspase activation leading to TAU pathology:neuroprotection by cAMP; Cell Death Diff., 3 e326
6) Kordower et al. (2006), Failure of proteasome inhibitor administration to provide a model of Parkinson’s disease in rats and monkeys; Ann. Neurol., 60 264
7) Bove et al. (2006), Proteasome inhibition and Parkinson’s disease modeling; Ann. Neurol., 60 260
