Competitive Metabolite Profiling of Natural Products Reveals Subunit Specific Inhibitors of the 20S Proteasome
Competitive Metabolite Profiling of Natural Products Reveals Subunit Specific Inhibitors of the 20S Proteasome
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2020
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ACS Central Science ; 6 (2020), 2. - pp. 241-246. - American Chemical Society (ACS). - ISSN 2374-7943. - eISSN 2374-7951
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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540 Chemistry
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Rodent models, Cells, Inhibitors, Peptides and proteins, Probes
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PAWAR, 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). 6(2), pp. 241-246. ISSN 2374-7943. eISSN 2374-7951. Available under: doi: 10.1021/acscentsci.9b01170BibTex
@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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