Abstract
The ubiquitin-proteasome proteolytic pathway plays a major role in selective protein degradation and regulates various cellular events including cell cycle progression, transcription, DNA repair, signal transduction, and immune response. Ubiquitin, a highly conserved small protein in eukaryotes, attaches to a target protein prior to degradation. The polyubiquitin chain tagged to the target protein is recognized by the 26S proteasome, a high-molecular-mass protease subunit complex, and the protein portion is degraded by the 26S proteasome. The potential of specific proteasome inhibitors, which act as anti-cancer agents, is now under intensive investigation, and bortezomib (PS-341), a proteasome inhibitor, has been recently approved by FDA for multiple myeloma treatment. Since ubiquitination of proteins requires the sequential action of three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), and polyubiquitination is a prerequisite for proteasome-mediated protein degradation, inhibitors of E1, E2, and E3 are reasonably thought to be drug candidates for treatment of diseases related to ubiquitination. Recently, various compounds inhibiting the ubiquitin-proteasome pathway have been isolated from natural resources. We also succeeded in isolating inhibitors against the proteasome and E1 enzyme from marine natural resources. In this review, we summarize the structures and biological activities of natural products that inhibit the ubiquitinproteasome proteolytic pathway.
Keywords: Natural product, ubiquitin-proteasome proteolytic pathway, ubiquitin, ubiquitination, ubiquitin-activating enzyme, ubiquitin-conjugating enzyme, ubiquitin-protein ligase, proteasome
Current Medicinal Chemistry
Title: Natural Products Inhibiting the Ubiquitin-Proteasome Proteolytic Pathway, A Target for Drug Development
Volume: 13 Issue: 7
Author(s): Sachiko Tsukamoto and Hideyoshi Yokosawa
Affiliation:
Keywords: Natural product, ubiquitin-proteasome proteolytic pathway, ubiquitin, ubiquitination, ubiquitin-activating enzyme, ubiquitin-conjugating enzyme, ubiquitin-protein ligase, proteasome
Abstract: The ubiquitin-proteasome proteolytic pathway plays a major role in selective protein degradation and regulates various cellular events including cell cycle progression, transcription, DNA repair, signal transduction, and immune response. Ubiquitin, a highly conserved small protein in eukaryotes, attaches to a target protein prior to degradation. The polyubiquitin chain tagged to the target protein is recognized by the 26S proteasome, a high-molecular-mass protease subunit complex, and the protein portion is degraded by the 26S proteasome. The potential of specific proteasome inhibitors, which act as anti-cancer agents, is now under intensive investigation, and bortezomib (PS-341), a proteasome inhibitor, has been recently approved by FDA for multiple myeloma treatment. Since ubiquitination of proteins requires the sequential action of three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), and polyubiquitination is a prerequisite for proteasome-mediated protein degradation, inhibitors of E1, E2, and E3 are reasonably thought to be drug candidates for treatment of diseases related to ubiquitination. Recently, various compounds inhibiting the ubiquitin-proteasome pathway have been isolated from natural resources. We also succeeded in isolating inhibitors against the proteasome and E1 enzyme from marine natural resources. In this review, we summarize the structures and biological activities of natural products that inhibit the ubiquitinproteasome proteolytic pathway.
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Cite this article as:
Tsukamoto Sachiko and Yokosawa Hideyoshi, Natural Products Inhibiting the Ubiquitin-Proteasome Proteolytic Pathway, A Target for Drug Development, Current Medicinal Chemistry 2006; 13 (7) . https://dx.doi.org/10.2174/092986706776055571
DOI https://dx.doi.org/10.2174/092986706776055571 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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