MG132 is a potent, reversible, and cell-permeable
proteasome inhibitor
Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins. They are being studied in the treatment of cancer; and three are approved for use in treating multiple myeloma.
Mechanism
Multipl ...
(
Ki = 4 nM). It belongs to the class of synthetic peptide aldehydes.
It reduces the degradation of
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
-conjugated proteins in mammalian cells and permeable strains of yeast by the 26S complex without affecting its
ATPase or
isopeptidase An isopeptidase is a protease enzyme that hydrolyzes isopeptide bonds, or amide bonds that occur outside the main chain in a polypeptide chain.
In protein degradation
Isopeptide bonds occur in the linkage of protein amino acid side chains to pro ...
activities. MG132 activates
c-Jun N-terminal kinase
c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are ...
(JNK1), which initiates
apoptosis. MG132 also inhibits
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
activation with an
IC50 of 3 μM and prevents
β-secretase cleavage.
Molecular mechanism
There are several inhibitors that can readily enter cell and selectively inhibit degradative pathway. It includes
peptide aldehydes, such as Cbz-leu-leu-leucinal (MG132), Cbz-leu-leu-norvalinal (
MG115) and acetyl-leu-leu-norleucinal (
ALLN).
These are substrate analogues and potent
transition-state inhibitors of
chymotrypsin like activity of
proteasome machinery.
The peptide aldehydes are also known to inhibit certain
lysosomal
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pro ...
cysteine protease
Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.
Discovered by Gopal Ch ...
s and the
calpain
A calpain (; , ) is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases ( proteolytic enzymes) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan C ...
s hence MG132 may not be exclusive inhibitor of proteasomal pathway.
References
External links
*{{cite web , url = http://www.merck-chemicals.com/germany/life-science-research/mg-132/EMD_BIO-474790/p_w_.b.s1LzxMAAAEW02EfVhTm , publisher = merck-chemicals.com , title = MG-132
* Proeasome inhibitor
review
Peptides
Proteasome inhibitors
Aldehydes
Carbamates