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

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2020
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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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Fachgebiet (DDC)
540 Chemie
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Rodent models, Cells, Inhibitors, Peptides and proteins, Probes
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ISO 690PAWAR, Atul, Michael BASLER, Heike GOEBEL, Gerardo Omar ALVAREZ SALINAS, Marcus GRÖTTRUP, Thomas BÖTTCHER, 2020. Competitive Metabolite Profiling of Natural Products Reveals Subunit Specific Inhibitors of the 20S Proteasome. In: ACS Central Science. American Chemical Society (ACS). 2020, 6(2), pp. 241-246. ISSN 2374-7943. eISSN 2374-7951. Available under: doi: 10.1021/acscentsci.9b01170
BibTex
@article{Pawar2020-02-26Compe-48520,
  year={2020},
  doi={10.1021/acscentsci.9b01170},
  title={Competitive Metabolite Profiling of Natural Products Reveals Subunit Specific Inhibitors of the 20S Proteasome},
  number={2},
  volume={6},
  issn={2374-7943},
  journal={ACS Central Science},
  pages={241--246},
  author={Pawar, Atul and Basler, Michael and Goebel, Heike and Alvarez Salinas, Gerardo Omar and Gröttrup, Marcus and Böttcher, Thomas}
}
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