Back to Search
Start Over
Competitive Metabolite Profiling of Natural Products Reveals Subunit Specific Inhibitors of the 20S Proteasome
- Source :
- ACS Central Science, Vol 6, Iss 2, Pp 241-246 (2020), ACS Central Science
- Publication Year :
- 2020
- Publisher :
- American Chemical Society, 2020.
-
Abstract
- 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.<br />Competitive profiling with a syringolin A probe allows us to find subunit specific proteasome inhibitors “in the haystack” of complex metabolite extracts.
- Subjects :
- General Chemical Engineering
Protein subunit
Metabolite
Cell
010402 general chemistry
01 natural sciences
20s proteasome
Rodent models, Cells, Inhibitors, Peptides and proteins, Probes
chemistry.chemical_compound
medicine
Potency
QD1-999
biology
010405 organic chemistry
Chemistry
General Chemistry
biology.organism_classification
0104 chemical sciences
Burkholderiales
medicine.anatomical_structure
Biochemistry
Metabolite profiling
ddc:540
Proteasome inhibitor
Research Article
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 23747951
- Volume :
- 6
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- ACS Central Science
- Accession number :
- edsair.doi.dedup.....201506c2a907bf52fd2c9636247fecab