Proteasomes are a subcellular organelle found throughout the cytosol, nucleus, endoplasmic reticulum (ER), and lysosomes of eukaryotic cells.⁽¹⁾ They are cylindrical in shape and are comprised of several different proteolytic (protein digesting) enzymes. The functions of proteasomes include:

Digestion of unassembled proteins.
Digestion of damaged or misfolded proteins.
The generation of peptides that are recognized by the immune system.
Regulation of the cellular lifespan (half-life)of regulatory proteins such as those that control the cell cycle.⁽²⁾

Over 80% of a cell's proteins are processed by proteasomes.⁽³⁾

Proteasomes act on proteins that have been specifically tagged for degradation by attachment to another protein called ubiquitin. Degradation signals are generally hidden in a properly folded protein, but become accessible when the protein is misfolded or denatured. When these signals are exposed, enzymes add another small protein (ubiquitin; shown as a yellow sphere below) to the target. The ubiquitinated protein is then recognized by a receptor protein on the proteasome and the target protein is taken into the proteasome and digested. The fragmented protein is then released from the proteasome as shown below.⁽²⁾

Proteasomes control the half-life of many short-lived regulatory proteins, such as those involved in the cell cycle. Therefore, proteasome malfunction can lead to abnormal regulation of the cell cycle and uncontrolled cell proliferation. The cell cycle is controlled by both positive and negative signals. An alteration in the proteins involved in these controls can tip the balance and may play a major role in the development and progression of cancer. In a normal cell, proteasomes break down proteins that inhibit the cell cycle, such as cyclin-dependent kinase inhibitors (CKI). ⁽¹⁾

Inhibition of proteasome function causes cell cycle arrest and cell death. Tumor cells are more susceptible to these effects than normal cells, in part because they divide more rapidly and in part because many of their normal regulatory pathways are disrupted. The mechanism for the differential response of normal and cancer cells to proteasome inhibition is not fully understood. Overall, cancer cells are more susceptible to proteasome inhibitors and, as a result, these inhibitors may be an effective treatment for certain cancers.⁽¹⁾

The first proteasome inhibitor to enter clinical trials as a cancer treatment was PS-341 (now: MLN-341). The drug is produced by Millenium Pharmaceuticals. The drug specifically interacts with a key threonine (an amino acid) within the digestive site (catalytic site) of the proteasome. Although this interaction blocks only 1 of the 3 catalytic activities of the proteasome, the resulting inhibition seems to be sufficient to prevent the degradation of ubiquitinated proteins.⁽⁴⁾ On May 13, 2003 PS-341, now known as bortezomib or Velcade™ became the first proteasome inhibitor to be approved for use in the US. It is now used to treat several blood cell cancers.⁽⁵⁾

A second proteasome inhibitor was isolated from a marine bacteria. The agent is called salinosporin or salinosporamide and it is currently being studied. ⁽⁶⁾

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Borezomib (VELCADE®)

A Closer Look at Proteosome Structure and Function

The proteasome has a structure that is related to its function. Each proteasome consists of a cylindrical central 20S core composed of four stacked rings containing seven proteins each. The outer two rings are identical and composed of 'alpha' subunits, and the middle two are identical and contain 'beta' subunits. The beta subunits exhibit active protein digesting activity. The digestion occurs on the sides of the enzymes facing the inner chamber.

The core of the proteasome is bound on each end to a (19S) regulatory protein. The 19S cap proteins are responsible for the recognition of proteins to be degraded. In a process that requires energy (ATP), tagged proteins are unfolded and fed into the inner chamber. The proteins are then digested into peptides 6 to 9 amino acids in length and released. The peptides can then be recycled. Together the 19S caps and the 20S core make up the human proteasome.

Proteasomes and the immune system.
Some digested protein fragments enter the endoplasmic reticulum (ER) where they are joined to proteins that function in generating immune responses. The complex of the peptides and the immune system protein (MHC protein) is then transported to the surface of the cell. This complex can act as a flag for cells of the immune system and lead to an immune response. An example of this would be the processing of proteins produced by viruses within an infected cell.

Proteasome Inhibitors

A Closer Look at Proteosome Structure and Function