TMC-86A, B and TMC-96, New Proteasome Inhibitors from Streptomyces sp. TC 1084 and Saccharothrix sp. TC 1094: I. Taxonomy, Fermentation, Isolation, and Biological Activities

TMC-86A, B and TMC-96, new 20S proteasome inhibitors with an epoxy-β-aminoketone moiety, were isolated from the fermentation broth of Streptomyces sp. TC 1084 and Saccharothrix sp. TC 1094, respectively. TMC-86A, B and TMC-96 inhibited the chymotrypsin-like and peptidylglutamyl-peptide hydrolyzing a...

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Bibliographic Details
Published in:Journal of antibiotics 1999/12/25, Vol.52(12), pp.1069-1076
Main Authors: KOGUCHI, YUTAKA, KOHNO, JUN, SUZUKI, SHIN-ICHI, NISHIO, MAKI, TAKAHASHI, KOHEI, OHNUKI, TETSUO, KOMATSUBARA, SABURO
Format: Article
Language:English
Subjects:
Actinomycetales - metabolism
Animals
Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents
Antineoplastic agents
Applied microbiology
Biological and medical sciences
Chemotherapic agents
Cysteine Endopeptidases - drug effects
Dipeptides - isolation & purification
Dipeptides - pharmacology
Fermentation
Fundamental and applied biological sciences. Psychology
General aspects
Humans
Medical sciences
Mice
Microbiology
Multienzyme Complexes - drug effects
Pharmacology. Drug treatments
Protease Inhibitors - isolation & purification
Protease Inhibitors - pharmacology
Proteasome Endopeptidase Complex
proteasome inhibitors
Saccharothrix
Streptomyces
Streptomyces - classification
Streptomyces - metabolism
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Summary:TMC-86A, B and TMC-96, new 20S proteasome inhibitors with an epoxy-β-aminoketone moiety, were isolated from the fermentation broth of Streptomyces sp. TC 1084 and Saccharothrix sp. TC 1094, respectively. TMC-86A, B and TMC-96 inhibited the chymotrypsin-like and peptidylglutamyl-peptide hydrolyzing activities of 20S proteasome with the following IC50 values: TMC-86A, 5.1 μM and 3.7 μM; TMC-86B, 1.1 μM and 31 μM; TMC96, 2.9 μM and 3.5μM, respectively. TMC-86A, B and TMC-96 exhibited the weak inhibitory activity against the trypsin-like activity of 20S proteasome with IC50 values of 51 μM, 250μM, and 36μM, respectively. They did not inhibit m-calpain, cathepsin L, and trypsin at 100 μM, suggesting their high specificity for proteasome. Taxonomy of the producing strains is also described.
ISSN:0021-8820
1881-1469
DOI:10.7164/antibiotics.52.1069