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
Multip ...
(
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. ...
-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, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
or
isopeptidase activities. MG132 activates
c-Jun N-terminal kinase (JNK1), which initiates
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes inclu ...
. 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 cellula ...
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 protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by wh ...
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 Chun ...
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