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The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are the two major degradation systems for both native and misfolded proteins in eukaryotic cells. They do not act independently from each other. Defective autophagy results in the accumulation of ubiquitinated proteins, impacting the flux of the UPS, while dysfunction of the UPS can promote a compensatory induction of autophagy. Through protein degradation and the maintenance of protein homeostasis, the UPS regulates many normal cellular processes including signal transduction, cell cycle control, transcription and apoptosis (see Figure). The regulated proteolysis of bulk and misfolded proteins is strictly controlled by the 26S proteasome complex.
Figure: The Ubiquitin-Proteasome System Inhibition and affected Cellular Processes
The 26S proteasome complex recognizes polyubiquitinated proteins, which were marked for elimination by the E1, E2 and E3 ubiquitinating enzymes (see Figure). Upon recognition, unfolding and transfer of the de-ubiquitinated target protein by the 19S regulatory cap into the interior of the cylindrical 20S proteasome core particle, protein degradation is facilitated by catalytic β-subunits having nucleophilic N-terminal threonine (Thr1) residues. Although eukaryotic 20S proteasomes harbor seven different β-subunits in their two-fold symmetrical α7β7β7α7 stacked complexes, only three β-subunits per β-ring [subunits β1 (caspase-like), β2 (trypsin-like) and β5 (chymotrypsin-like)] are proteolytically active. These three β-subunits are major targets for small molecule proteasome inhibitors. Proteasome inhibition has implications in a number of human diseases such as cancer (e.g. multiple myeloma (MM)), inflammation and ischemic stroke and is an important therapeutic target.
Several components of the UPS have been validated as potential anticancer targets, including 20S proteasomes, 19S proteasome-associated deubiquitinases (DUBs) and ubiquitin ligases (E3s). One of the strategies to improve the current status of cancer treatment is to repurpose old drugs with UPS-inhibitory properties as new anticancer agents.
Inhibits the chymotrypsin-like β5 subunit of the constitutive 20S proteasome (IC50=5.2nM) and the β5i subunit [LMP7] of the 20S immunoproteasome (IC50=14nM).
Inhibits all the three catalytic activities of the constitutive 20S proteasome: chymotrypsin-like β5 subunit (IC50=3.4nM), trypsin-like β2 subunit (IC50=3.5μM) and the caspase-like β1 subunit (IC50=0.03μM).
Inhibits all the three catalytic activities of the constitutive 20S proteasome: chymotrypsin-like β5 subunit (IC50=3.4nM), trypsin-like β2 subunit (IC50=3.5μM) and the caspase-like β1 subunit (IC50=0.03μM).
Inhibits the β5i subunit [LMP7] of the 20S immunoproteasome (IC50=73nM) with minimal cross-reactivity to the chymotrypsin-like β5 subunit of the constitutive 20S proteasome (IC50=1.04μM).
Inhibits the chymotrypsin-like β5 subunit of the constitutive 20S proteasome (IC50=36nM) and the β5i subunit [LMP7] of the 20S immunoproteasome (IC50=82nM).
Inhibits the chymotrypsin-like β5-subunit of the constitutive 20S proteasome (IC50=27nM), with minimal trypsin-like (β2) and caspase-like (β1) activity (IC50= >100μM, for both).
Inhibits all the three catalytic activities of the constitutive 20S proteasome: chymotrypsin-like (IC50=3.5nm); trypsin-like (IC50=28nm); caspase-like (IC50=430nm).
Inhibits all the three catalytic activities of the constitutive 20S proteasome: chymotrypsin-like (IC50=50-100nm); trypsin-like (IC50=1nm); caspase-like (IC50=3μm).
RBR E3 ligase inhibitor. Effects by inactivating the E2-conjugating enzymes Ubc13 and UbcH7 and the E3 ligase LUBAC, preventing the formation of Lys63-linked and linear polyubiquitin chains.
The two proteasome kits are designed to test for specific activity of 20S immunoproteasome or 20S constitutive proteasome, and include purified proteasomes, AMC-conjugated substrates, specific inhibitors and necessary buffers and solutions. Fluorescence detection can be performed at Excitation/Emission (nm): 345/445, allowing for a real-time readout of specific activity.
All highly active and pure proteasomes offered by AdipoGen Life Sciences are able to proteolytically degrade substrates in an ATP-independent manner.
Exploits the intracellular ubiquitin-proteasome system to selectively degrade target proteins. D-Biotin p-nitrophenyl ester is commonly used as a biotin-tagged photoaffinity probe and an alkyl chain-based PROTAC linker that can be used in the synthesis of PROTACs.
TRIM21 (tripartite motif-containing protein 21) is a cytosolic Fc receptor induced by interferon (IFN). TRIM21 functions as a E3 ligase. During infection, antibodies are delivered efficiently to the cytosol when bound to intracellular pathogens such as viruses and bacteria. The antibody-pathogen complex in the cytosol upon engagement of the protein TRIM21 is ubiquitinylated and degraded by the proteasome machinery.