MG132

{{Chembox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 446613982 | ImageFile = MG132.svg | ImageSize = 250px | SystematicName = Benzyl [(2''S'')-4-methyl-1-{[(2''S'')-4-methyl-1-{[(2''S'')-4-methyl-1-oxopentan-2-yl]amino}-1-oxopentan-2-yl]amino}-1-oxopentan-2-yl]carbamate | OtherNames = ''N''-Benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Z-Leu-Leu-Leu-al

| Section1 = {{Chembox Identifiers | CASNo_Ref = {{cascite|correct|??}} | CASNo = 133407-82-6 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = RF1P63GW3K | PubChem = 462382 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 406728 | SMILES = CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1 | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = TZYWCYJVHRLUCT-VABKMULXSA-N}}

| Section2 = {{Chembox Properties | C=26 | H=41 | N=3 | O=5 | Appearance = White solid | SolubleOther = 100 mM in EtOH and DMSO}} }}

'''MG132''' is a potent, reversible, and cell-permeable proteasome inhibitor<ref name=":0">{{Cite journal|last1=Lee|first1=Do Hee|last2=Goldberg|first2=Alfred L|date=October 1998|title=Proteasome inhibitors: valuable new tools for cell biologists|journal=Trends in Cell Biology|language=en|volume=8|issue=10|pages=397–403|doi=10.1016/S0962-8924(98)01346-4|pmid=9789328}}</ref> (Ki = 4 nM). It belongs to the class of synthetic peptide aldehydes.<ref name="Ito">{{cite journal | vauthors = Ito A, Takahashi R, Muira C, Baba Y | title = Synthetic Study of Peptide Aldehydes | journal = Chemical and Pharmaceutical Bulletin | volume = 12 | issue = 23 | pages = 3106–3113 | date = 1975 | doi = 10.1248/cpb.23.3106 | doi-access = free }}</ref><ref name="Hayashi">{{cite journal | vauthors = Hayashi M, Saito Y, Kawashima S | title = Calpain activation is essential for membrane fusion of erythrocytes in the presence of exogenous Ca2+. | journal = Biochem Biophys Res Commun | volume = 182 | issue = 2 | pages = 939–946 | date = 31 January 1992 | pmid = 1734892 | doi=10.1016/0006-291x(92)91822-8}}</ref> 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).<ref name=":0" /> These are substrate analogues and potent transition-state inhibitors of chymotrypsin like activity of proteasome machinery.<ref name=":1">{{Cite journal|last1=Rock|first1=Kenneth L.|last2=Gramm|first2=Colette|last3=Rothstein|first3=Lisa|last4=Clark|first4=Karen|last5=Stein|first5=Ross|last6=Dick|first6=Lawrence|last7=Hwang|first7=Daniel|last8=Goldberg|first8=Alfred L.|date=September 1994|title=Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules|journal=Cell|volume=78|issue=5|pages=761–771|doi=10.1016/s0092-8674(94)90462-6|pmid=8087844|s2cid=22262916|issn=0092-8674}}</ref><ref>{{Cite journal|last1=Lee|first1=Do Hee|last2=Goldberg|first2=Alfred L.|date=1996-11-01|title=Selective Inhibitors of the Proteasome-dependent and Vacuolar Pathways of Protein Degradation in Saccharomyces cerevisiae|journal=Journal of Biological Chemistry|language=en|volume=271|issue=44|pages=27280–27284|doi=10.1074/jbc.271.44.27280|pmid=8910302|s2cid=40396862|issn=0021-9258|doi-access=free}}</ref> 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.<ref name=":1" />

==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 inhibitors [https://www.sciencedirect.com/science/article/pii/S1074552101000564 review]

Category:Peptide therapeutics Category:Proteasome inhibitors Category:Aldehydes Category:Carbamates