The structural requirements for inhibition of proteasome function by the lactacystin-derived ?-lactone and synthetic analogs

Corey, E. J.; Li, Wei‐Dong Z.; Nagamitsu, Tohru; Fenteany, Gabriel

doi:10.1016/s0040-4020(98)01142-9

Cited by 51 publications

(39 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A similar result was obtained with clasto -lactacystin β-lactone, which also reacts with the hydroxyl group but not with the α-amino group (Table 1, experiment 9; Figure S2). The β-lactone forms an ester adduct analogous to the acyl intermediate in the proteasome reaction cycle (Corey et al, 1999;). Therefore, the AFM data argue against an acyl intermediate as a key allosteric effector for α-ring opening.…”

Section: Resultsmentioning

confidence: 99%

A Tetrahedral Transition State at the Active Sites of the 20S Proteasome Is Coupled to Opening of the α-Ring Channel

2009

View full text Add to dashboard Cite

Summary Intrinsic conformational transitions contribute to the catalytic action of many enzymes. Here we use a single-molecule approach to demonstrate how such transitions are linked to the catalytic sites of the eukaryotic proteasome, an essential protease of the ubiquitin pathway. The active sites of the cylindrical proteasomal core particle (CP) are located in a central chamber accessible through gated entry channels. By atomic force microscopy (AFM), we found continual alternation between open and closed gate conformations. We analyzed the relative abundance of these conformers in wild-type and mutated yeast CPs upon exposure to substrates or inhibitors. Our data indicate that the dynamic gate can be opened by allosteric coupling to a tetrahedral transition state at any of the working active centers. The results point to the Nα-amine of the N-terminal active site threonyl residue as the major effector group responsible for triggering the essential conformational switch.

show abstract

Section: Resultsmentioning

confidence: 99%

A Tetrahedral Transition State at the Active Sites of the 20S Proteasome Is Coupled to Opening of the α-Ring Channel

2009

View full text Add to dashboard Cite

show abstract

“…The structural features of omuralide that are responsible for its activity have been studied in detail by Corey and co-workers who demonstrated that the C-5 isopropyl group (see Scheme 1) is required for activity and that substitution with a phenyl ring at this position completely abolished activity. [9] The fact that salinosporamide A (1) incorporates a cyclohexene substituent at this position, yet retains activity, suggests that it may interact with the proteasome in a manner that is different from omuralide. Future studies on the structure±activity relationships of salinosporamide A derivatives, or co-crystallization of 1 with purified 20S proteasome, may help elucidate these differences.…”

Section: Methodsmentioning

confidence: 99%

Salinosporamide A: A Highly Cytotoxic Proteasome Inhibitor from a Novel Microbial Source, a Marine Bacterium of the New Genus Salinospora

Feling¹,

Buchanan²,

Mincer³

et al. 2003

Angew Chem Int Ed

962

316

View full text Add to dashboard Cite

We recently reported the cultivation and phylogenetic characterization of a new group of obligate marine actinomycete bacteria that is widely distributed in ocean sediments.[1] Analogous soil-derived actinomycetes have been the single most significant source of naturally occurring microbial antibiotics, [2] thus the discovery of a major new group of these bacteria in marine sediments suggests that the ocean represents an overlooked habitat from which to isolate these important microorganisms. Given that the rate of discovery of new biologically active compounds from common soil actinomycetes has been falling, [3] obligate marine actinomycetes represent a new resource for structurally diverse secondary metabolites.To date, we have isolated in excess of 2500 strains belonging to this new taxon for which we have proposed the genus name ™Salinospora∫ (a formal taxonomic description is in progress). ™Salinospora∫ strains, with previously undescribed 16S rRNA gene sequences, have been recovered from five distinct tropical/subtropical ocean systems [1] and from depths as great as À1100 m, which indicates that they represent a widely distributed and taxonomically diverse group of sediment bacteria. All isolates display an obligate requirement of ionic sodium for growth, thus indicating a high level of marine adaptation.In preliminary screening, a high percentage of the organic extracts of cultured ™Salinospora∫ strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery. Herein we report the results of our first chemical investigation of a member of the ™Salinospora∫ group and show that strain CNB-392 produces the chemically unique and highly bioactive metabolite salinosporamide A (1, Scheme 1). Salinosporamide A exhibits potent cancer cell cytotoxicity and appears to exert its cytotoxic effects through inhibition of the 20S proteasome.™Salinospora∫ strain CNB-392 was isolated from a heattreated marine sediment sample that was plated on a seawater-based agar nutrient medium. Liquid shake flask cultivation of this strain, followed by solid-phase extraction with Amberlite resin (XAD-16) and elution with acetone, resulted in a crude extract that was highly cytotoxic in vitro toward HCT-116 human colon carcinoma (IC 50 ca. 80 ng mL À1 ). Cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A (1) as a colorless crystalline solid (yield: 7 mg L À1 ). The complete structural assignment of 1 was accomplished by spectral analysis and by a single-crystal X-ray diffraction study.Analysis of the low-resolution mass spectrum of salinosporamide A showed a characteristic [Mþ2] þ peak indicative of the presence of a chlorine atom. High-resolution massspectral analysis provided the molecular formula Comprehensive analysis of 2D NMR data, including the results of COSY, HMQC, and HMBC experiments, enabled the complete planar structure of salinosporamide A to be assigned, as in 1, to a 2-aza-6-oxabicyclo[3.2.0]heptane-3,7...

show abstract

“…Structure activity relationship studies indicate the requirement of the hydroxyl functionality cis to the carboxylic group for the formation of the reactive β-lactone intermediate (Fig. (5)) [190][191][192]. Not surprisingly, the hydrolyzed product of lactacystin, clastolactacystin dihydroxy acid, was found to be inactive in forming a covalent adduct to the proteasome [168].…”

Section: Inhibition Of I B Degradation and The Ubiquitinproteasomementioning

confidence: 99%

Enhancement of Chemotherapeutic Efficacy by Small Molecule Inhibition of NF-κ B and Checkpoint Kinases

Sharma¹,

Hupp²,

Tepe³

2007

CMC

View full text Add to dashboard Cite

Apoptosis or programmed cell death is a cellular mechanism used to regulate cell number and eliminate damaged or mutated cells. Many chemotherapeutic agents and ionizing radiation induce not only apoptotic signaling pathways, but also survival responses such as DNA damage responses and cell cycle arrest, which allow for DNA repair. These survival responses determine the toxicity as well as the efficacy of the cancer treatment. Two main DNA damage responses include the activation of the anti-apoptotic transcription factor NF-kappaB and the activation of cell cycle checkpoint kinases. Strategies of combining chemotherapeutics with (a) inhibitors of NF-kappaB or (b) inhibitors of checkpoint kinases, may therefore enhance the efficacy of current cancer therapies. This review will be focused on recent progress made in combining traditional chemotherapeutic drugs with small molecule inhibitors of NF-kappaB and the checkpoint kinases, Chk1 and Chk2.

show abstract

The structural requirements for inhibition of proteasome function by the lactacystin-derived ?-lactone and synthetic analogs

Cited by 51 publications

References 19 publications

A Tetrahedral Transition State at the Active Sites of the 20S Proteasome Is Coupled to Opening of the α-Ring Channel

A Tetrahedral Transition State at the Active Sites of the 20S Proteasome Is Coupled to Opening of the α-Ring Channel

Salinosporamide A: A Highly Cytotoxic Proteasome Inhibitor from a Novel Microbial Source, a Marine Bacterium of the New Genus Salinospora

Enhancement of Chemotherapeutic Efficacy by Small Molecule Inhibition of NF-κ B and Checkpoint Kinases

Contact Info

Product

Resources

About

The structural requirements for inhibition of proteasome function by the lactacystin-derived ?-lactone and synthetic analogs

Cited by 51 publications

References 19 publications

A Tetrahedral Transition State at the Active Sites of the 20S Proteasome Is Coupled to Opening of the α-Ring Channel

A Tetrahedral Transition State at the Active Sites of the 20S Proteasome Is Coupled to Opening of the α-Ring Channel

Salinosporamide A: A Highly Cytotoxic Proteasome Inhibitor from a Novel Microbial Source, a Marine Bacterium of the New Genus Salinospora

Enhancement of Chemotherapeutic Efficacy by Small Molecule Inhibition of NF-&#954; B and Checkpoint Kinases

Contact Info

Product

Resources

About

Enhancement of Chemotherapeutic Efficacy by Small Molecule Inhibition of NF-κ B and Checkpoint Kinases