- MG132 (carbobenzoxy-Leu-Leu-leucinal) is a synthetic peptide aldehyde that functions as a potent, reversible, and cell-permeable inhibitor of the proteasome.
- It was originally developed as part of a series of tripeptide aldehyde inhibitors designed to block proteolytic enzymes, and it is now widely used in molecular and cellular biology to study the ubiquitin–proteasome system.
- By inhibiting the 26S proteasome, MG132 prevents the degradation of ubiquitinated proteins, leading to their intracellular accumulation. This property makes it a valuable tool for dissecting protein turnover, signaling pathways, and regulatory processes that depend on controlled proteolysis.
- The mechanism of action of MG132 centers on its ability to inhibit the chymotrypsin-like activity of the proteasome’s catalytic β5 subunit, though at higher concentrations it can also interfere with trypsin-like and caspase-like proteolytic activities. The aldehyde group of MG132 forms a reversible covalent bond with the active site threonine of the proteasome, effectively blocking substrate access. Because of its relative stability and cell permeability, MG132 has become one of the most widely used experimental proteasome inhibitors in laboratory research. However, its lack of complete selectivity means that MG132 can also inhibit other cysteine proteases, such as calpains and cathepsins, at elevated doses, which must be considered when interpreting results.
- Biologically, MG132 has been extensively used to probe the role of the proteasome in diverse cellular processes. It stabilizes short-lived proteins such as transcription factors (e.g., p53, HIF-1α, c-Jun, and NF-κB inhibitors like IκBα), allowing researchers to study their regulation and downstream effects. Treatment with MG132 can induce apoptosis, cell cycle arrest, or stress responses depending on the cell type, reflecting the central role of proteasomal degradation in maintaining protein homeostasis. In cancer research, MG132 and related compounds have been applied to model the effects of proteasome inhibition on tumor cell survival, angiogenesis, and sensitivity to chemotherapy. These studies laid the groundwork for the development of clinically approved proteasome inhibitors such as bortezomib.
- Despite its usefulness in research, MG132 is not suitable as a therapeutic drug due to its instability in vivo, limited bioavailability, and off-target effects. Nevertheless, it remains an essential laboratory reagent for mechanistic studies of protein degradation, signaling dynamics, and cellular stress pathways. Its ability to block proteasomal activity quickly and reversibly makes it a standard choice in experiments aimed at revealing the consequences of impaired proteostasis.
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