Competitive Metabolite Profiling of Natural Products Reveals Subunit Specific Inhibitors of the 20S Proteasome.
Journal
ACS central science
ISSN: 2374-7943
Titre abrégé: ACS Cent Sci
Pays: United States
ID NLM: 101660035
Informations de publication
Date de publication:
26 Feb 2020
26 Feb 2020
Historique:
received:
12
11
2019
entrez:
4
3
2020
pubmed:
4
3
2020
medline:
4
3
2020
Statut:
ppublish
Résumé
We have developed a syringolin-based chemical probe and explored its utility for the profiling of metabolite extracts as potent inhibitors of the 20S proteasome. Activity-guided fractionation by competitive labeling allowed us to isolate and identify glidobactin A and C as well as luminmycin A from a Burkholderiales strain. The natural products exhibited unique subunit specificities for the proteolytic subunits of human and mouse constitutive and immunoproteasome in the lower nanomolar range. In particular, glidobactin C displayed an unprecedented β2/β5 coinhibition profile with single-digit nanomolar potency in combination with sufficiently high cell permeability. These properties render glidobactin C a promising live cell proteasome inhibitor with potent activity against human breast cancer cell lines and comparably low immunotoxicity.
Identifiants
pubmed: 32123742
doi: 10.1021/acscentsci.9b01170
pmc: PMC7047272
doi:
Types de publication
Journal Article
Langues
eng
Pagination
241-246Informations de copyright
Copyright © 2020 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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