MG132 is a potent, reversible, and cell-permeable
proteasome inhibitor (
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 19 ...
-conjugated proteins in mammalian cells and permeable strains of yeast by the 26S complex without affecting its
ATPase
ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, ATP hydrolase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or ...
or
isopeptidase activities. MG132 activates
c-Jun N-terminal kinase (JNK1), which initiates
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
. MG132 also inhibits
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
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
Chymotrypsin (, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme component of pancreatic juice acting in the duodenu ...
like activity of
proteasome
Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...
machinery.
The peptide aldehydes are also known to inhibit certain
lysosomal
A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...
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 Chu ...
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
Peptide therapeutics
Proteasome inhibitors
Aldehydes
Carbamates