Proteasome & Ubiquitination Inhibitors
Proteasomes are large multi-subunit complexes, localized in the nucleus and cytosol that selectively degrade intracellular proteins. A protein marked for degradation is covalently attached to multiple molecules of ubiquitin (Ubq). Four or more Ubq are required to set a protein for degradation by the proteasome. Ubq is a highly conserved 76-amino acid (8.6 kDa) protein, which escorts proteins for rapid hydrolysis to the multi-component enzymatic complex, the 26S proteasome. The proteolytic core of this complex, the 20S proteasome, contains multiple peptidase activities and functions as the catalytic machine. This core is composed of 28 subunits arranged in four heptameric, tightly stacked, rings (α7, β7, β7, α7) to form a cylindrical structure. The α-subunits make up the two outer and the β-subunits the two inner rings of the stack. The entrance of substrate proteins to the active site of the complex is guarded by the a-subunits that allow access only to unfolded and extended polypeptides. The proteolytic activity is confined to the β-subunits. The 19S complex "caps" at each end of the 20S proteasome help in unfolding protein substrates. The 19S cap contains subunits with ATPase activity, subunits that recognize and bind polyubiquitin chains and putative unfoldases that unfold protein chains and translocate them into the 20S proteasome. In the Ubq-proteosome degradation pathway, Ubq is first covalently ligated to target proteins by a multi-enzymatic system consisting of Ubq-activating (E1), Ubq-conjugating (E2), and the Ubq-ligating (E3) enzymes. The E1 activates a Ubq monomer at its C-terminal cysteine residue to a highenergy thioester bond which is then transferred to a reactive cysteine residue of the E2 enzyme. The final transfer of Ubq to the η-amino group of a reactive lysine residue of substrate proteins is brought about by the E3 enzyme. Ubiquitinated protein is then escorted to the 26S proteasome where it undergoes final degradation and the ubiquitin is released and recycled. The ubiquitin-proteasome system plays a major role in the degradation of many proteins involved in cell cycle, proliferation, and apoptosis. Proteasomes also breakdown abnormal proteins that result from oxidative stress and mutations that might otherwise disrupt normal cellular homeostasis. This pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases, and in the pathology of muscle wasting. It is also involved in the destruction of proteins that participate in cell cycle progression, transcription control, signal transduction, and metabolic regulation.
Several distinct groups of compounds, designed to act as selective proteasome inhibitors, have helped immensely in understanding the biological role and importance of the ubiquitin-proteasome pathway. These compounds are designed to block proteasome function in cancer cells without significantly affecting biological processes in the normal cell.
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