MG132

Last updated

MG132
MG132.svg
Names
Systematic IUPAC name
Benzyl [(2S)-4-methyl-1-{[(2S)-4-methyl-1-{[(2S)-4-methyl-1-oxopentan-2-yl]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
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • 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/s1 X mark.svgN
    Key: TZYWCYJVHRLUCT-VABKMULXSA-N X mark.svgN
  • CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Properties
C26H41N3O5
Molar mass 475.630 g·mol−1
AppearanceWhite solid
Solubility 100 mM in EtOH and DMSO
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

MG132 is a potent, reversible, and cell-permeable proteasome inhibitor [1] (Ki = 4 nM). It belongs to the class of synthetic peptide aldehydes. [2] [3] 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.

Contents

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). [1] These are substrate analogues and potent transition-state inhibitors of chymotrypsin like activity of proteasome machinery. [4] [5] 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. [4]

Related Research Articles

<span class="mw-page-title-main">Proteasome</span> Protein complexes which degrade ubiquitin-tagged proteins by proteolysis

Proteasomes are protein complexes which degrade ubiquitin-tagged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.

<span class="mw-page-title-main">Calpain</span> Protease enzyme present in mammals and other organisms

A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1, also known as CAPN4, and the endogenous calpain-specific inhibitor, calpastatin.

<span class="mw-page-title-main">Proteasome inhibitor</span>

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; three are approved for use in treating multiple myeloma.

The IκB kinase is an enzyme complex that is involved in propagating the cellular response to inflammation, specifically the regulation of lymphocytes.

<span class="mw-page-title-main">PSMC3</span> Enzyme found in humans

26S protease regulatory subunit 6A, also known as 26S proteasome AAA-ATPase subunit Rpt5, is an enzyme that in humans is encoded by the PSMC3 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMB4</span> Protein found in humans

Proteasome subunit beta type-4 also known as 20S proteasome subunit beta-7 is a protein that in humans is encoded by the PSMB4 gene.

<span class="mw-page-title-main">PSMB10</span> Protein found in humans

Proteasome subunit beta type-10 as known as 20S proteasome subunit beta-2i is a protein that in humans is encoded by the PSMB10 gene.

<span class="mw-page-title-main">PSMC5</span> Enzyme found in humans

26S protease regulatory subunit 8, also known as 26S proteasome AAA-ATPase subunit Rpt6, is an enzyme that in humans is encoded by the PSMC5 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMC2</span> Enzyme found in humans

26S protease regulatory subunit 7, also known as 26S proteasome AAA-ATPase subunit Rpt1, is an enzyme that in humans is encoded by the PSMC2 gene This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex. Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMB5</span> Protein found in humans

Proteasome subunit beta type-5 also known as 20S proteasome subunit beta-5 is a protein that in humans is encoded by the PSMB5 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.

<span class="mw-page-title-main">PSMC4</span> Enzyme found in humans

26S protease regulatory subunit 6B, also known as 26S proteasome AAA-ATPase subunit Rpt3, is an enzyme that in humans is encoded by the PSMC4 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMD7</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 7, also known as 26S proteasome non-ATPase subunit Rpn8, is an enzyme that in humans is encoded by the PSMD7 gene.

<span class="mw-page-title-main">PSME2</span> Protein found in humans

Proteasome activator complex subunit 2 is a protein that in humans is encoded by the PSME2 gene.

<span class="mw-page-title-main">PSMF1</span> Protein found in humans

Proteasome inhibitor PI31 subunit is a protein that in humans is encoded by the PSMF1 gene.

<span class="mw-page-title-main">PSMC6</span> Enzyme found in humans

26S protease regulatory subunit S10B, also known as 26S proteasome AAA-ATPase subunit Rpt4, is an enzyme that in humans is encoded by the PSMC6 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

<span class="mw-page-title-main">PSMD8</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 8 is an enzyme that in humans is encoded by the PSMD8 gene.

<span class="mw-page-title-main">PSMD3</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 3 is an enzyme that in humans is encoded by the PSMD3 gene.

<span class="mw-page-title-main">PSMD6</span> Enzyme found in humans

26S proteasome non-ATPase regulatory subunit 6 is an enzyme that in humans is encoded by the PSMD6 gene.

Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell. Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes, as well as aggregation-associated degenerative disorders. Therapeutic restoration of proteostasis may treat or resolve these pathologies.

Alfred Lewis Goldberg was an American cell biologist-biochemist and professor at Harvard University. His major discoveries have concerned the mechanisms and physiological importance of protein degradation in cells. Of wide impact have been his lab's demonstration that all cells contain a pathway for selectively eliminating misfolded proteins, his discoveries about the role of proteasomes in this process and of the enzyme systems catalyzing protein breakdown in bacteria, his elucidating the mechanisms for muscle atrophy and the role of proteasomes in antigen presentation to the immune system, and his introduction of proteasome inhibitors now widely used as research tools and in the treatment of blood cancers.

References

  1. 1 2 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. 1 2 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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