Lactacystin, a proteasome inhibitor: Discovery and its application in cellbiology

Lactacystin was isolated from the culture broth of Streptomyces lactacystin aeus as an inducer of neurite outgrowth in Neuro 2a cells (a mouse neurobla stoma cell line). The structure of lactacystin, elucidated by spectroscopic analyses including NMR and X-ray crystallography, possesses a non-peptide skeleton consisting of two alpha-amino acids, N-acetylcysteine and a novel pyroglutamic acid derivative. Extensive studies on its mode of action revea led that lactacystin inhibits proteasome, a high molecular weight, multicat alytic protease complex responsible for most non-lysosomal intracellular pr otein degradation, by binding covalently to the active site N-terminal thre onine residue in certain beta-subunits of proteasome. Lactacystin and its c ell-permeable beta-lactone form, later designated omuralide by Prof. E. J. Corey, which are structurally different from the synthetic peptide aldehyde s, are much more specific proteasome inhibitors. The demonstration of this lactacystin action gave decisive understanding of proteasome as a novel thr eonine protease. Since then, specific inhibitors have allowed researchers t o simplify studies of proteasome functions, leading to many unexpected find ings about the importance of the ubiquitin-proteasome pathway in various ce llular processes, such as cell cycle, apoptosis, antigen presentation and t he degradation of regulatory or membrane proteins. In this review, potentia l biomedical applications are also described.