The ubiquitin-proteasome pathway and proteasome inhibitors

The ubiquitin-proteasome pathway has emerged as a central player in the reg ulation of several diverse cellular processes. Here. we describe the import ant components of this complex biochemical machinery as well as several imp ortant cellular substrates targeted by this pathway and examples of human d iseases resulting from defects in various components of the ubiquitin-prote asome pathway. In addition, this review covers the chemistry of synthetic a nd natural proteasome inhibitors, emphasizing their mode of actions toward the 20S proteasome. Given the importance of proteasome-mediated protein deg radation in various intracellular processes, inhibitors of this pathway wil l continue to serve as both molecular probes of major cellular networks as well as potential therapeutic agents for various human diseases. (C) 2001 J ohn Wiley & Sons. Inc.