The ubiquitin-proteasome pathway and proteasome inhibitors

Abstract

The ubiquitin-proteasome pathway has emerged as a central player in the regulation of several diverse cellular processes. Here, we describe the important components of this complex biochemical machinery as well as several important cellular substrates targeted by this pathway and examples of human diseases resulting from defects in various components of the ubiquitin-proteasome pathway. In addition, this review covers the chemistry of synthetic and natural proteasome inhibitors, emphasizing their mode of actions toward the 20S proteasome. Given the importance of proteasome-mediated protein degradation in various intracellular processes, inhibitors of this pathway will continue to serve as both molecular probes of major cellular networks as well as potential therapeutic agents for various human diseases.

Figure 1

The proposed mechanism for the proteolysis catalyzed by the 20S proteasome.

Figure 2

Proteasome inhibitor family of synthetic peptide aldehydes.

Figure 3

The proposed mechanism for the inhibition of the 20S proteasome by the peptide aldehyde.

Figure 4

A family of reversible synthetic proteasome inhibitors.

Figure 5

(a) A family of irreversible synthetic proteasome inhibitors. (b) The proposedmechanism for the inhibition of the 20S proteasome by NLVS.

Figure 6

A synthetic peptide boronic acid inhibitor (PS-341) and its proposed inhibition mechanism.

Figure 7

Natural product Lactacystin, its active component, clasto-lactacystin β-lactone, and its proposed inhibition mechanism.

Figure 8

A family of natural product peptide α′,β′-epoxyketone-based proteasome inhibitors.

Figure 9

The proposed morpholino adduct formation mechanism by epoxomicin.

Figure 10

Natural product proteasome inhibitors with unusual scaffolds.

Figure 11

Subunit-specific proteasome inhibitors.