Competitive Metabolite Profiling of Natural Products Reveals Subunit Specific Inhibitors of the 20S Proteasome

  • ACS Cent Sci. 2020 Feb 26;6(2):241-246. doi: 10.1021/acscentsci.9b01170.
Atul Pawar  1 ,  Michael Basler  2  3 ,  Heike Goebel  2  3 ,  Gerardo Omar Alvarez Salinas  2  3 ,  Marcus Groettrup  2  3 ,  Thomas Böttcher  1
Affiliations
  • 1. Department of Chemistry, Zukunftskolleg, Konstanz Research School Chemical Biology, University of Konstanz, 78457 Konstanz, Germany.
  • 2. Division of Immunology, Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
  • 3. Biotechnology Institute Thurgau, 8280 Kreuzlingen, Switzerland.
PMID: 32123742 DOI: 10.1021/acscentsci.9b01170
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.

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