EPOXOMICIN

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′-epoxyketonederived from leucine or a γ,δ-dehydroleucine. It is a natural product isolated fromActinomycessp., 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.

20S proteasome

+4°C

[1] L MENG. Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity.[J]. Proceedings of the National Academy of Sciences of the United States of America, 1999, 96 18: 10403-10408. DOI:10.1073/pnas.96.18.10403
[2] M HANADA. Epoxomicin, a new antitumor agent of microbial origin.[J]. Journal of Antibiotics, 1992, 45 11: 1746-1752. DOI:10.7164/antibiotics.45.1746
[3] KEVIN ST. P. MCNAUGHT PHD. Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease[J]. Annals of Neurology, 2004, 56 1: 149-162. DOI:10.1002/ana.20186
[4] HIDEAKI MATSUI. Proteasome inhibition in medaka brain induces the features of Parkinson’s disease[J]. Journal of Neurochemistry, 2010, 115 1: 178-187. DOI:10.1111/j.1471-4159.2010.06918.x
[5] M J METCALFE  M E F P  Q Huang. Coordination between proteasome impairment and caspase activation leading to TAU pathology: neuroprotection by cAMP[J]. Cell Death & Disease, 2012, 3 6: e326-e326. DOI:10.1038/cddis.2012.70
[6] JEFFREY H. KORDOWER PHD. Failure of proteasome inhibitor administration to provide a model of Parkinson’s disease in rats and monkeys[J]. Annals of Neurology, 2006, 60 2: 264-268. DOI:10.1002/ana.20935
[7] WENJIE XIE. Proteasome inhibition modeling nigral neuron degeneration in Parkinson’s disease[J]. Journal of Neurochemistry, 2010, 115 1: 188-199. DOI:10.1111/j.1471-4159.2010.06914.x