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MG132

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MG132
Names
Systematic IUPAC name Benzyl amino}-1-oxopentan-2-yl]amino}-1-oxopentan-2-yl]carbamate
Other names N-Benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal
Z-Leu-Leu-Leu-al
Identifiers
CAS Number
3D model (JSmol)
ChemSpider
PubChem CID
UNII
CompTox Dashboard (EPA)
InChI
  • InChI=1S/C26H41N3O5/c1-17(2)12-21(15-30)27-24(31)22(13-18(3)4)28-25(32)23(14-19(5)6)29-26(33)34-16-20-10-8-7-9-11-20/h7-11,15,17-19,21-23H,12-14,16H2,1-6H3,(H,27,31)(H,28,32)(H,29,33)/t21-,22-,23-/m0/s1Key: TZYWCYJVHRLUCT-VABKMULXSA-N
SMILES
  • CC(C)C(C=O)NC(=O)(CC(C)C)NC(=O)(CC(C)C)NC(=O)OCc1ccccc1
Properties
Chemical formula C26H41N3O5
Molar mass 475.630 g·mol
Appearance White solid
Solubility 100 mM in EtOH and DMSO
Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). ☒N verify (what is  ?) Infobox references
Chemical compound

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-conjugated proteins in mammalian cells and permeable strains of yeast by the 26S complex without affecting its ATPase or isopeptidase activities. MG132 activates c-Jun N-terminal kinase (JNK1), which initiates apoptosis. MG132 also inhibits NF-κB 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 cysteine proteases and the calpains hence MG132 may not be exclusive inhibitor of proteasomal pathway.

References

  1. ^ Lee, Do Hee; Goldberg, Alfred L (October 1998). "Proteasome inhibitors: valuable new tools for cell biologists". Trends in Cell Biology. 8 (10): 397–403. doi:10.1016/S0962-8924(98)01346-4. PMID 9789328.
  2. Ito A, Takahashi R, Muira C, Baba Y (1975). "Synthetic Study of Peptide Aldehydes". Chemical and Pharmaceutical Bulletin. 12 (23): 3106–3113. doi:10.1248/cpb.23.3106.
  3. Hayashi M, Saito Y, Kawashima S (31 January 1992). "Calpain activation is essential for membrane fusion of erythrocytes in the presence of exogenous Ca2+". Biochem Biophys Res Commun. 182 (2): 939–946. doi:10.1016/0006-291x(92)91822-8. PMID 1734892.
  4. ^ Rock, Kenneth L.; Gramm, Colette; Rothstein, Lisa; Clark, Karen; Stein, Ross; Dick, Lawrence; Hwang, Daniel; Goldberg, Alfred L. (September 1994). "Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules". Cell. 78 (5): 761–771. doi:10.1016/s0092-8674(94)90462-6. ISSN 0092-8674. PMID 8087844. S2CID 22262916.
  5. Lee, Do Hee; Goldberg, Alfred L. (1 November 1996). "Selective Inhibitors of the Proteasome-dependent and Vacuolar Pathways of Protein Degradation in Saccharomyces cerevisiae". Journal of Biological Chemistry. 271 (44): 27280–27284. doi:10.1074/jbc.271.44.27280. ISSN 0021-9258. PMID 8910302. S2CID 40396862.

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