Activation and inhibition of the proteasome by betulinic acid and its derivatives.
This study discovered that betulinic acid (BA) is a potent proteasome activator that preferentially activates the chymotrypsin-like activity of the proteasome. Chemical modifications can transform BA into proteasome inhibitors. Chemical modifications at the C-3 position of BA resulted in compounds, such as dimethylsuccinyl BA (DSB), with various inhibitory activities against the human 20S proteasome. Interestingly, the proteasomal activation by BA and the inhibitory activity of DSB could be abrogated by introducing a side chain at the C-28 position. In summary, this study discovered a class of small molecules that can either activate or inhibit human proteasome activity depending on side chain modifications.
Huang
Li
L
Department of Surgery, Duke University Medical Center, P.O. Box 2926, Durham, NC 27710-2926, USA.
Ho
Phong
P
Chen
Chin-Ho
CH
D045744:Cell Line, Tumor; D002918:Chymotrypsin / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D053978:Pentacyclic Triterpenes; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors; D013386:Succinates / Q000737:chemistry / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D000094062:Betulinic Acid
D053978:Pentacyclic Triterpenes; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D013386:Succinates; D014315:Triterpenes; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex; C479935:bevirimat; D000094062:Betulinic Acid