The Experts below are selected from a list of 27 Experts worldwide ranked by ideXlab platform
Louis Grenier - One of the best experts on this subject based on the ideXlab platform.
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a novel and efficient synthesis of a highly active analogue of clasto Lactacystin Beta Lactone
Journal of the American Chemical Society, 1999Co-Authors: Francois Soucy, Louis Grenier, Mark L Behnke, Antonia T Destree, Teresa A Mccormack, Julian Adams, Louis PlamondonAbstract:Herein, we describe a new convergent synthesis of a more potent analogue of clasto-Lactacystin β-Lactone (2), PS-519 compound 4, which is currently in preclinical development for the treatment of i...
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Mechanistic studies on the inactivation of the proteasome by Lactacystin: a central role for clasto-Lactacystin Beta-Lactone.
The Journal of biological chemistry, 1996Co-Authors: Lawrence R. Dick, Amy A. Cruikshank, Louis Grenier, Francesco D. Melandri, Sandra L. Nunes, Ross L. SteinAbstract:Lactacystin is a Streptomyces metabolite that inhibits cell cycle progression and induces differentiation in a murine neuroblastoma cell line. The cellular target of Lactacystin is the 20 S proteasome, also known as the multicatalytic proteinase complex, an essential component of the ubiquitin-proteasome pathway for intracellular protein degradation. In aqueous solution at pH 8, Lactacystin undergoes spontaneous hydrolysis to yield N-acetyl-L-cysteine and the inactive Lactacystin analog, clasto-Lactacystin dihydroxy acid. We have studied the mechanism of Lactacystin hydrolysis under these conditions and found that it proceeds exclusively through the intermediacy of the active Lactacystin analog, clasto-Lactacystin Beta-Lactone. Conditions that stabilize Lactacystin (and thus prevent the transient accumulation of the intermediate Beta-Lactone) negate the ability of Lactacystin to inactivate the proteasome. Together these findings suggest that Lactacystin acts as a precursor for clasto-Lactacystin Beta-Lactone and that the latter is the sole species that interacts with the proteasome.
Ross L. Stein - One of the best experts on this subject based on the ideXlab platform.
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Mechanistic studies on the inactivation of the proteasome by Lactacystin: a central role for clasto-Lactacystin Beta-Lactone.
The Journal of biological chemistry, 1996Co-Authors: Lawrence R. Dick, Amy A. Cruikshank, Louis Grenier, Francesco D. Melandri, Sandra L. Nunes, Ross L. SteinAbstract:Lactacystin is a Streptomyces metabolite that inhibits cell cycle progression and induces differentiation in a murine neuroblastoma cell line. The cellular target of Lactacystin is the 20 S proteasome, also known as the multicatalytic proteinase complex, an essential component of the ubiquitin-proteasome pathway for intracellular protein degradation. In aqueous solution at pH 8, Lactacystin undergoes spontaneous hydrolysis to yield N-acetyl-L-cysteine and the inactive Lactacystin analog, clasto-Lactacystin dihydroxy acid. We have studied the mechanism of Lactacystin hydrolysis under these conditions and found that it proceeds exclusively through the intermediacy of the active Lactacystin analog, clasto-Lactacystin Beta-Lactone. Conditions that stabilize Lactacystin (and thus prevent the transient accumulation of the intermediate Beta-Lactone) negate the ability of Lactacystin to inactivate the proteasome. Together these findings suggest that Lactacystin acts as a precursor for clasto-Lactacystin Beta-Lactone and that the latter is the sole species that interacts with the proteasome.
Louis Plamondon - One of the best experts on this subject based on the ideXlab platform.
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a novel and efficient synthesis of a highly active analogue of clasto Lactacystin Beta Lactone
Journal of the American Chemical Society, 1999Co-Authors: Francois Soucy, Louis Grenier, Mark L Behnke, Antonia T Destree, Teresa A Mccormack, Julian Adams, Louis PlamondonAbstract:Herein, we describe a new convergent synthesis of a more potent analogue of clasto-Lactacystin β-Lactone (2), PS-519 compound 4, which is currently in preclinical development for the treatment of i...
Stuart L. Schreiber - One of the best experts on this subject based on the ideXlab platform.
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A Beta-Lactone related to Lactacystin induces neurite outgrowth in a neuroblastoma cell line and inhibits cell cycle progression in an osteosarcoma cell line.
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Gabriel Fenteany, Gregory A. Reichard, Ellas J. Corey, Robert F. Standaert, Stuart L. SchreiberAbstract:Abstract Lactacystin, a microbial natural product, induces neurite outgrowth in Neuro 2A mouse neuroblastoma cells and inhibits progression of synchronized Neuro 2A cells and MG-63 human osteosarcoma cells beyond the G1 phase of the cell cycle. A related Beta-Lactone, clasto-Lactacystin Beta-Lactone, formally the product of elimination of N-acetylcysteine from Lactacystin, is also active, whereas the corresponding clastoLactacystin dihydroxy acid is completely inactive. Structural analogs of Lactacystin altered only in the N-acetylcysteine moiety are active, while structural or stereochemical modifications of the gamma-lactam ring or the hydroxyisobutyl group lead to partial or complete loss of activity. The inactive compounds do not antagonize the effects of Lactacystin in either neurite outgrowth or cell cycle progression assays. The response to Lactacystin involves induction of a predominantly bipolar morphology that is maximal 16-32 h after treatment and is distinct from the response to several other treatments that result in morphological differentiation. Neurite outgrowth in response to Lactacystin appears to be dependent upon microtubule assembly, actin polymerization, and de novo protein synthesis. The observed structure-activity relationships suggest that Lactacystin and its related Beta-Lactone may act via acylation of one or more relevant target molecule(s) in the cell.
Lawrence R. Dick - One of the best experts on this subject based on the ideXlab platform.
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Mechanistic studies on the inactivation of the proteasome by Lactacystin: a central role for clasto-Lactacystin Beta-Lactone.
The Journal of biological chemistry, 1996Co-Authors: Lawrence R. Dick, Amy A. Cruikshank, Louis Grenier, Francesco D. Melandri, Sandra L. Nunes, Ross L. SteinAbstract:Lactacystin is a Streptomyces metabolite that inhibits cell cycle progression and induces differentiation in a murine neuroblastoma cell line. The cellular target of Lactacystin is the 20 S proteasome, also known as the multicatalytic proteinase complex, an essential component of the ubiquitin-proteasome pathway for intracellular protein degradation. In aqueous solution at pH 8, Lactacystin undergoes spontaneous hydrolysis to yield N-acetyl-L-cysteine and the inactive Lactacystin analog, clasto-Lactacystin dihydroxy acid. We have studied the mechanism of Lactacystin hydrolysis under these conditions and found that it proceeds exclusively through the intermediacy of the active Lactacystin analog, clasto-Lactacystin Beta-Lactone. Conditions that stabilize Lactacystin (and thus prevent the transient accumulation of the intermediate Beta-Lactone) negate the ability of Lactacystin to inactivate the proteasome. Together these findings suggest that Lactacystin acts as a precursor for clasto-Lactacystin Beta-Lactone and that the latter is the sole species that interacts with the proteasome.
