Proteasome Inhibitors

Proteasomes are large (2.4 Mega Dalton) multi-subunit protein complexes functioning as the "garbage can" of the cell at the last step of the Ubiquitin Proteasome protein quality control pathway. The 26S proteasome is a highly conserved protein degradation machine that consists of the 20S proteasome core unit and 19S regulatory particles at either end of the core. The primary function of the core 20S particle is to degrade improperly folded or damaged proteins by proteolysis using energy from ATP hydrolysis. Structurally, the proteasome is a cylindrical unit containing a "core" of four stacked rings forming a central pore (20S). Each ring is made up of seven individual protein subunits. The inner two rings are made of seven β subunits that contain three to seven protease active sites. Three distinct catalytic activities have been identified in the purified 20S complex: chymotrypsin-like, trypsin-like and peptidyl glutamyl-peptide hydrolyzing. These sites are located on the interior surface of the rings, which means that a target protein has to be partially/completely unfolded to enter the central pore before it is degraded. Each of the outer two rings contains seven α subunits whose function is to maintain a "gate" through which proteins enter the barrel. These α-subunits are controlled by binding to "cap" structures or regulatory particles (19S) that recognize poly-ubiquitin tags attached to protein substrates and initiate the degradation process by removing the ubiquitin tags from the substrate and unfolding the structure so that it can be threaded through the narrow central pore (pore entrance 13 angstrom wide and center around 53 angstrom wide). The 19S regulatory cap consists of 19 proteins divisible into two subassemblies, a 9-subunit base that binds directly to the α-ring of the 20S core particle, and a 10-subunit lid. Six of the nine base proteins are ATPase subunits belonging to the AAA (ATPases Associated with diverse cellular Activities) family. Binding of the C-terminal ends of the ATPases of the 19S base with the 20S pockets stimulates opening of the gate that blocks the entry of substrates into the degradation chamber in the 20S just like a key turns a lock to open a door.

Proteasome inhibitors are small molecules or drugs that block the function of the proteasome and thus stop protein degradation. Several groups of proteasome inhibitors typically classified according to the mechanism of action have been developed and are being widely used as research tools to investigate the role of the ubiquitin-proteasome pathway in various cellular processes including but not limited to antigen presentation, drug metabolism, aging, oxidative stress etc. Developing an understanding of cellular responses in normal (proteasome-active) and pathophysiological conditions (proteasome function inhibited leading to accumulation of protein load) can be instrumental in finding cures for a large number of human diseases. In fact Bortezomib (PS-341) and Carfilzomib which are proteasome inhibitors are now approved by the FDA for treatment of multiple myeloma. BioVision offers a large number of proteasome inhibitors in their product portfolio including Epoxomicin, Lactacystin, MG-132 and PS-341.


Proteasome Inhibitors Products

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