[The] Proteasome: A New Target for Novel Drug Therapies
[The] Proteasome: A New Target for Novel Drug Therapies
The proteasome is an enzyme present in all cells, from yeast to human, and has a central role in the proteolytic degradation of the vast majority of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in controlling inflammatory processes, cell cycle regulation, and gene expression. As such, agents that inhibit the proteasome have been shown to be active in numerous animal models of inflammation and cancer. Two proteasome inhibitors are under clinical evaluation. PS-519 is being studied for the treatment of reperfusion injury that occurs following cerebral ischemia and myocardial infarction. The other, PS-341, has recently entered multiple phase 2 clinical trials for the treatment of multiple myeloma, chronic lymphocytic leukemia, and a variety of solid tumors. The proteasome may have an important role in the evolution of HIV-related disorders including AIDS and inflammatory disorders. Therapeutic strategies using proteasome inhibitors for the treatment of these conditions have now entered preclinical development.
The multicatalytic proteasome is the ubiquitous proteinase found in cells throughout the plant and animal kingdoms that is responsible for the degradation of intracellular proteins. Thousands of copies are found in all cells, in both the cytoplasm and the nucleus, and constitute up to 3% of all cellular protein content. Proteasomes serve multiple intracellular functions, including the degradation of damaged proteins and the modulation of many regulatory proteins that affect inflammatory processes, viral shedding, the cell cycle, growth, and differentiation, to name but a few.
The proteasome structure consists of a cylindrical central core, 20S particle, which is composed of 4 stacked rings of 7 proteins in each ring. The outer 2 rings are identical to each other and are called the alpha-rings; the inner beta-rings also are identical to each other and contain the catalytic proteinase functions on their inner, central channel-facing surfaces. The 20S core is bound symmetrically to 2 copies of a regulatory, 19S, particle. The role of the regulatory complex is to allow for recognition of substrates destined for degradation as well as adenosinetriphosphatases required to hydrolyze adenosine triphosphate that is necessary for the unwinding of proteins before degradation. Unwound proteins are fed down the central channel in the 20S core and undergo progressive degradation by the threonine residues in the beta-rings that function as the catalytic nucleophiles. There are up to 3 catalytic residues in the beta-rings that account for the cleavage preferences: chymotryptic, tryptic, and peptidylglutamyl. The 20S core and the 2 19S regulatory unit copies are referred to collectively as the 26S proteasome.
The ubiquitination of cellular proteins is a highly regulated and multifaceted process termed the ubiquitin-proteasome pathway. This pathway helps define the turnover rates for cellular proteins. Proteins targeted for degradation are attached to a single ubiquitin molecule that binds to other ubiquitin molecules to form a "tail" of the protein Figure 1. This tail needs to be a certain size (at least 7 copies long) to be recognized by the 19S regulatory unit. As such, only proteins with such polyubiquitin tags are degraded by the proteasome. Smaller proteins (up to 5-7 amino acids) can be degraded by the 20S core without this ubiquitin tag.
(Enlarge Image)
Figure 1. The ubiquitin-proteasome pathway. This pathway helps define the turnover rates for multiple (>85%) intracellular proteins. Proteins targeted for degradation are attached initially to a single ubiquitin molecule that subsequently binds to other ubiquitin molecules to form a "tail" off the protein. Only proteins with such polyubiquitin tags are degraded by the proteasome into small peptides with cleaved ubiquitin reavailable for further proteolysis.
Proteasomes degrade damaged cellular proteins and various short-lived regulatory proteins that govern a wide array of cellular functions. The expression of cell cycle stimulatory and inhibitory proteins has a major role in the development and progression of cancer. Proteasome inhibitors can stabilize many cell cycle inhibitory proteins and cause cell cycle arrest and apoptosis, thus limiting tumor development. The fact that tumor cells seem to be more sensitive to the proapoptotic effects of proteasome inhibitors than normal cells provides a therapeutic window that can be used for anticancer drug development. Other substrates degraded by the proteasome lead to activation of associated proteins that are involved in the inflammatory process in multiple disease states. Inhibition of these "activated" proteins (eg, transcription factors such as nuclear factor-kappa B [NF-kappa B]) can successfully attenuate the inflammatory cascade, leading to physiologic improvements in numerous animal models.
The proteasome is an enzyme present in all cells, from yeast to human, and has a central role in the proteolytic degradation of the vast majority of intracellular proteins. Among the key proteins modulated by the proteasome are those involved in controlling inflammatory processes, cell cycle regulation, and gene expression. As such, agents that inhibit the proteasome have been shown to be active in numerous animal models of inflammation and cancer. Two proteasome inhibitors are under clinical evaluation. PS-519 is being studied for the treatment of reperfusion injury that occurs following cerebral ischemia and myocardial infarction. The other, PS-341, has recently entered multiple phase 2 clinical trials for the treatment of multiple myeloma, chronic lymphocytic leukemia, and a variety of solid tumors. The proteasome may have an important role in the evolution of HIV-related disorders including AIDS and inflammatory disorders. Therapeutic strategies using proteasome inhibitors for the treatment of these conditions have now entered preclinical development.
The multicatalytic proteasome is the ubiquitous proteinase found in cells throughout the plant and animal kingdoms that is responsible for the degradation of intracellular proteins. Thousands of copies are found in all cells, in both the cytoplasm and the nucleus, and constitute up to 3% of all cellular protein content. Proteasomes serve multiple intracellular functions, including the degradation of damaged proteins and the modulation of many regulatory proteins that affect inflammatory processes, viral shedding, the cell cycle, growth, and differentiation, to name but a few.
The proteasome structure consists of a cylindrical central core, 20S particle, which is composed of 4 stacked rings of 7 proteins in each ring. The outer 2 rings are identical to each other and are called the alpha-rings; the inner beta-rings also are identical to each other and contain the catalytic proteinase functions on their inner, central channel-facing surfaces. The 20S core is bound symmetrically to 2 copies of a regulatory, 19S, particle. The role of the regulatory complex is to allow for recognition of substrates destined for degradation as well as adenosinetriphosphatases required to hydrolyze adenosine triphosphate that is necessary for the unwinding of proteins before degradation. Unwound proteins are fed down the central channel in the 20S core and undergo progressive degradation by the threonine residues in the beta-rings that function as the catalytic nucleophiles. There are up to 3 catalytic residues in the beta-rings that account for the cleavage preferences: chymotryptic, tryptic, and peptidylglutamyl. The 20S core and the 2 19S regulatory unit copies are referred to collectively as the 26S proteasome.
The ubiquitination of cellular proteins is a highly regulated and multifaceted process termed the ubiquitin-proteasome pathway. This pathway helps define the turnover rates for cellular proteins. Proteins targeted for degradation are attached to a single ubiquitin molecule that binds to other ubiquitin molecules to form a "tail" of the protein Figure 1. This tail needs to be a certain size (at least 7 copies long) to be recognized by the 19S regulatory unit. As such, only proteins with such polyubiquitin tags are degraded by the proteasome. Smaller proteins (up to 5-7 amino acids) can be degraded by the 20S core without this ubiquitin tag.
(Enlarge Image)
Figure 1. The ubiquitin-proteasome pathway. This pathway helps define the turnover rates for multiple (>85%) intracellular proteins. Proteins targeted for degradation are attached initially to a single ubiquitin molecule that subsequently binds to other ubiquitin molecules to form a "tail" off the protein. Only proteins with such polyubiquitin tags are degraded by the proteasome into small peptides with cleaved ubiquitin reavailable for further proteolysis.
Proteasomes degrade damaged cellular proteins and various short-lived regulatory proteins that govern a wide array of cellular functions. The expression of cell cycle stimulatory and inhibitory proteins has a major role in the development and progression of cancer. Proteasome inhibitors can stabilize many cell cycle inhibitory proteins and cause cell cycle arrest and apoptosis, thus limiting tumor development. The fact that tumor cells seem to be more sensitive to the proapoptotic effects of proteasome inhibitors than normal cells provides a therapeutic window that can be used for anticancer drug development. Other substrates degraded by the proteasome lead to activation of associated proteins that are involved in the inflammatory process in multiple disease states. Inhibition of these "activated" proteins (eg, transcription factors such as nuclear factor-kappa B [NF-kappa B]) can successfully attenuate the inflammatory cascade, leading to physiologic improvements in numerous animal models.
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