Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin

  title={Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin},
  author={Gabriel Fenteany and Robert F Standaert and William Arbuthnot Sir Lane and S W Choi and E. J. Corey and Stuart L. Schreiber},
  pages={726 - 731}
Lactacystin is a Streptomyces metabolite that inhibits cell cycle progression and induces neurite outgrowth in a murine neuroblastoma cell line. Tritium-labeled lactacystin was used to identify the 20S proteasome as its specific cellular target. Three distinct peptidase activities of this enzyme complex (trypsin-like, chymotrypsin-like, and peptidylglutamyl-peptide hydrolyzing activities) were inhibited by lactacystin, the first two irreversibly and all at different rates. None of five other… 

Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for gamma-glutamylcysteine synthetase.

These studies have identified 26S proteasome activity as a central regulatory pathway for glutathione synthesis and Gel mobility shift assays and expression of CAT activity from heterologous reporter vectors identified Nrf2 mediation of the GLCLC antioxidant response element, ARE4, as the mechanism by which lactacystin inducedGLCLC.

Covalent modification of the active site threonine of proteasomal beta subunits and the Escherichia coli homolog HslV by a new class of inhibitors.

125I-NIP-L3VS covalently modifies the HSlV subunit of the Escherichia coli protease complex HslV/HslU, a reaction that requires ATP, and supports a catalytic mechanism shared with that of the eukaryotic proteasome.

Lactacystin and clasto-Lactacystin β-Lactone Modify Multiple Proteasome β-Subunits and Inhibit Intracellular Protein Degradation and Major Histocompatibility Complex Class I Antigen Presentation*

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Mechanistic Studies on the Inactivation of the Proteasome by Lactacystin in Cultured Cells*

It is shown that when the β-lactone is added to mammalian cells in culture, it rapidly enters the cells, where it can react with the sulfhydryl of glutathione to form a thioester adduct that is both structurally and functionally analogous to lactacystin.

Active Site-directed Inhibitors of Rhodococcus 20 S Proteasome

Using peptide mapping of tryptic digests, LC/MS, and amino acid sequence analysis, it is established that the Oγ of the hydroxyl group on the N-terminal threonine of the β-subunit is the sole modification made by theβ-lactone.

Catalytic activities of the 20 S proteasome, a multicatalytic proteinase complex.

This minireview focuses on the three classical catalytic activities of the proteasome, designated chymotrypsin-like, trypsin -like, and peptidyl-glutamyl-peptide hydrolyzing in eukaryotes and also the Activities of the more simple Archaebacteria and Eubacteria proteasomes.

The human 26S proteasome is a target of antiretroviral agents

The human 26S proteasome is a target of antiretroviral agents, suggesting that the antiviral action and some clinical and immunological benefits of combined antireTroviral therapy rely not only on its known effects on viral enzymes, but also on host cell components.

Peptide vinyl sulfones : inhibitors and active site probes for the study of proteasome function in vivo

In vivo application of the peptide vinyl sulfones and their use in uncovering the role of the proteasome in the Human cytomegalovirus (HCMV)-mediated destruction of MHC class I heavy chains are described.



Proteasome from Thermoplasma acidophilum: a threonine protease.

The catalytic mechanism of the 20S proteasome from the archaebacterium Thermoplasma acidophilum has been analyzed by site-directed mutagenesis of the beta subunit and by inhibitor studies, and data show that the nucleophilic attack is mediated by the amino-terminal threonine of processed beta subunits.

Homology of proteasome subunits to a major histocompatibility complex-linked LMP gene

The isolation of a complementary DNA corresponding to one of the subunits of the LMP complex, LMP-2, closely matches the amino-terminal peptide sequence of a rat proteasome subunit, confirming that the proteasomesome and the L MP complex share polypeptide subunits.

Nucleotide sequence of PUP1 encoding a putative proteasome subunit in Saccharomyces cerevisiae.

Proteasomes are ring-shaped 20 S particles that exhibit multiple proteolytic activities and are composed of several protein subunits and small RNAs (1 —4). They have been found in archaebacteria and

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Evidence obtained by genetic analyses in yeast and studies on the levels of proteasome expression in various eukaryotic cells indicates that proteasomes have essential roles in the cell.

Primary structure of the Thermoplasma proteasome and its implications for the structure, function, and evolution of the multicatalytic proteinase.

It is suggested that the alpha-subunits have regulatory and targeting functions, while the beta-subunit carry the active sites in the archaebacterial proteasome.