Clasto-Lactacystin β-lactone (Synonyms: β-Clastolactacystin; Omuralide)

Lactacystin is a microbial metabolite isolated from Streptomyces that is now widely used as a selective inhibitor of the 20S proteasome.[1],[2],[3] Clasto-lactacystin β-lactone was later identified as the active metabolite of lactacystin, resulting from the elimination of cysteine and the formation of a reactive β-lactone. Both lactacystin and its β-lactone metabolite induce differentiation and inhibit cell cycle progression in several tumor cell lines.[4] Clasto-lactacystin β-lactone irreversibly alkylates subunit X of the 20S proteasome.[3] It is at least 10 times more active than the parent compound; this increased activity may be a function of increased cell permeability. Inhibition of proteasome peptidase activity results in the accumulation of a variety of ubiquitinated proteins which would normally undergo rapid degradation. Thus, the effects of clasto-lactacystin β-lactone are pleiotropic and depend substantially on the expression pattern of signaling proteins within the treated cell.

Reference:
1. Omura, S., Fujimoto, T.T., Otoguro, K., et al. Lactacystin, a novel microbial metabolite, induces neuritogenesis of neuroblastoma cells. Journal of Antibiotics 44, 113-116 (1991).
2. Corey, E.J., and Reichard, G.A. Total synthesis of lactacystin. Journal of the American Chemical Society 114, 10677-10678 (1992).
3. Fenteany, G., and Schreiber, S.L. Lactacystin, proteasome function, and cell fate. The Journal of Biological Chemisty 273(15), 8545-8548 (1998).
4. Fenteany, G., Standaert, R.F., Reichard, G.A., et al. A β-lactone related to lactacystin induces neurite outgrowth in a neuroblastoma cell line and inhibits cell cycle progression in an osteosarcoma cell line. Proceedings of the National Academy of Sciences of the United States of America 91, 3358-3362 (1994).