Preliminary comments on proteasome inhibition and cardiovascular disease

Abstract

Proteasomes are large protein complexes inside all eukaryotic cells and some bacteria. The proteasome functions to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that carry out such reactions are called proteases. Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into amino acids and used in synthesizing new proteins. Proteins are tagged for degradation by a small protein called ubiquitin. Enzymes called ubiquitin ligases catalyze the tagging reaction. Once a protein is tagged with a single ubiquitin molecule, the tagging is a signal to other ligases to attach additional ubiquitin molecules. The result is a polyubiquitin chain that is bound by the proteasome, allowing it to degrade the tagged protein. The proteasome is built as a large barrel-like complex containing a “core” of four stacked rings around a central pore. Each ring is composed of seven individual proteins. The inner two rings are made of seven β subunits that contain the six protease active sites. These sites are located on the interior surface of the rings, so that the target protein must enter the central pore before it is degraded. The outer two rings each contain seven α subunits whose function is to maintain a “gate” through which proteins enter the barrel. Binding to “cap” structures controls these α subunits or regulatory particles that recognize polyubiquitin tags attached to protein substrates and initiate the degradation process. The overall system of ubiquitination and proteasomal degradation is known as the ubiquitin–proteasome system. The proteasomal degradation pathway is essential for many cellular processes, including the cell cycle, the regulation of gene expression, and responses to oxidative stress. The importance of proteolytic degradation inside cells and the role of ubiquitin in proteolytic pathways was a Nobel Prize-winning event in 2004. Proteasome inhibitors can block the proteasome pathway. Disulfiram, an anti-alcohol drug inhibiting alcohol dehydrogenase and epigallocatechin-3 gallate, an agent in “green tea,” which therefore must be good for you, have been identified as possible proteasome inhibitors. However, bortezomib is the first drug developed for this purpose; the compound has been used therapeutically since 2003 [1]. The boron atom in bortezomib binds the catalytic site of the 26S proteasome with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitinylated proteins and also cleanses the cell of abnormal or misfolded proteins. Clinical and preclinical data support a role for proteasomes in maintaining the immortal phenotype of myeloma cells, and cell-culture and xenograft data support a similar function in solid tumors. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways. Bortezomib has become a backbone in the treatment of refractory multiple myeloma. However, perhaps bortezomib might have a place in the treatment of other B-cell-related diseases. Long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, Neubert et al. [2] showed that the sensitivity of myeloma J Mol Med (2009) 87:749–751 DOI 10.1007/s00109-009-0492-x