A concise, total synthesis of the proteasome inhibitors TMC-95A/B has been accomplished. The synthesis features the use of an L-serine-derived E-selective modified Julia olefination reaction to ultimately control the stereochemical outcome of the highly oxidized tryptophan fragment. Additionally, the limited use of protecting groups at a late stage of the total synthesis allowed for its complet...

The structures of tyropeptins A and B, new proteasome inhibitors produced by Kitasatospora sp. MK993-dF2, were determined by analysis of various NMR experiments. The 1H and 13C NMR of tyropeptins were complicated due to the presence of an aldehyde group. Therefore, tyropeptins were converted to their alcohols by sodium borohydride. These alcohol derivatives gave assignable NMR spectra. The ster...

The nuclear proteasome activator REGgamma/PA28gamma is an ATP- and ubiquitin-independent activator of the 20S proteasome and has been proposed to degrade and thereby regulate both a key human oncogene, encoding the coactivator SRC-3/AIB1, and the cyclin-dependent kinase inhibitor p21 (Waf/Cip1). We report the identification and characterization of a PA28/REG homolog in Dictyostelium. Associatio...

The proteasome is a validated target for anticancer therapy, and proteasome inhibition is employed in the clinic for the treatment of tumors and hematological malignancies. Here, we describe crystal structures of the native human 20S proteasome and its complexes with inhibitors, which either are drugs approved for cancer treatment or are in clinical trials. The structure of the native human 20S...

Numerous studies suggest that proteasome inhibition may play a causal role in mediating the increased levels of protein oxidation and neuron death observed in conditions associated with oxidative stress. In the present study we demonstrate that administration of non-toxic levels of oxidative stress does not result in impairment of 20S/26S proteasome activity, and actually increases the expressi...

We examined the mechanisms by which two different types of photonic radiation, short wavelength UV (UV-C) and gamma radiation, activate transcription factor NF-kappaB. Exposure of mammalian cells to either form of radiation resulted in induction with similar kinetics of NF-kappaB DNA binding activity, nuclear translocation of its p65(RelA) subunit, and degradation of the major NF-kappaB inhibit...

PURPOSE Increase in intracellular chymotrypsin activity was reported during acute pancreatitis. Beside chymotrypsin, there are at least two enzymes with chymotrypsin-like activity: proteasome and lysosomal cathepsin A. Until now it is not known whether and to what extent they contribute to increases in chymotrypsin activity in acute pancreatitis. Our aim was to study organ chymotrypsin-like act...