Proteases

Proteases are the major degradation pathways for misfolded proteins and other proteins that are proteolyzed during protein synthesis. It is present in all eukaryotic cells, archaea and some bacteria and is a protease with multiple catalytic activities composed of multiple catalytic and regulatory proteins. It has three to four different peptidase activities, including the hydrolytic activity of tryptase, chymotrypsin and peptidylglutamyl-polypeptide. According to the difference in sedimentation coefficient, it can be divided into two types of proteases. The relative molecular mass of the 26S proteasome is about 2000 kDa, which depends on ATP. The relative molecular mass of the 20S proteasome is about 750 kDa, which is independent of ATP. Most proteins require ubiquitination before being degraded by the proteasome. The 26s proteasome is a 2-MDa multi-subunit protease that degrades most cytoplasm, endoplasmic reticulum and nuclear proteins. Understanding the most clear target protein degradation mechanism is related to the degradation of ubiquitin, an 8-kDa protein. The 26s proteasome is composed of a 20s core protein and a 19s regulatory complex. The 19s chaperone protein unfolds the ubiquitin-labeled protein substrate and feeds it into a 20s column core with three pairs of proteolytic active sites in the core. The three pairs of loci are named for their similarity to the cleavage specificity of chymotrypsin, trypsin and caspase, respectively. Studies of budding yeast mutants have fundamentally suggested the different roles of these three pairs of sites, and chymotrypsin-like active sites are the most important for normal growth. Proteasome inhibitors have been used in the treatment of diseases such as cancer, and are also widely used in laboratory research. MG-341 is an FDA-approved treatment for multiple myeloma and mantle cell lymphoma. It can also be used in laboratory studies to inhibit the activity of the proteasome. Several other protease inhibitors have also been developed as drugs or are in clinical trials and testing, including disulfiram, epigallocatechin-3-gallate, Salinosporamide A, carfilzomib, ONX0912, CEP-18770, and MLN9708. MG132, also known as benzyloxycarbonyl-L-leucine-L-leucine-L-leucinal, Z-LLL-CHO, is a peptide aldehyde that inhibits the activity of different types of proteases, including serine proteases and calpains. a chemical substance. MG132 and other peptide aldehydes can effectively inhibit the protease activity of multiple proteolytic enzymes of the proteasome and inhibit the activity of calpain.