State of the art: Targeting the ubiquitin-proteasome system for drug discovery

Abstract

The ubiquitin-proteasome proteolytic pathway plays a major role in selective protein degradation and regulates various cellular events including cell cycle, signal transduction, stress response, antigen presentation, and protein quality control. Ubiquitin, a highly conserved small protein in eukaryotes, attaches to a target protein prior to degradation. The polyubiquitin chain tagged to the target protein is recognized by the 26 S proteasome, a high-molecular-mass protease subunit complex, and the protein portion is degraded by the proteolytic active sites in a cavity of the 26 S proteasome. The potential of specific proteasome inhibitors, which act as anti-cancer agents, is now under intensive investigation. In addition, various inhibitors of a ubiquitin-activating enzyme, ubiquitin ligases, and deubiquitinating enzymes have been isolated from natural resources. Recently, we found that girolline, an antitumor compound, inhibits the recruitment of polyubiquitinated proteins to the proteasome. In this review, we summarize the structures and biological activities of natural products that inhibit various factors involved in the ubiquitin-proteasome proteolytic pathway.