Activation, structure, biosynthesis and bioactivity of glidobactin-like 
proteasome inhibitors from Photorhabdus laumondii

Zhao, Lei; Le Chapelain, Camille; Brachmann, Alexander O.; Kaiser, Marcel; Groll, Michael; Bode, Helge B.

doi:10.1002/cbic.202100014

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Activation, structure, biosynthesis and bioactivity of glidobactin-like proteasome inhibitors from Photorhabdus laumondii

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Bode, Helge B.
Natural Product Function and Engineering, Department of Natural Products in Organismic Interactions, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;

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https://doi.org/10.1002/cbic.202100014
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Citation

Zhao, L., Le Chapelain, C., Brachmann, A. O., Kaiser, M., Groll, M., & Bode, H. B. (2021). Activation, structure, biosynthesis and bioactivity of glidobactin-like proteasome inhibitors from Photorhabdus laumondii. ChemBioChem, 22(9), 1582-1588. doi:10.1002/cbic.202100014.

Cite as: https://hdl.handle.net/21.11116/0000-0008-BDF2-2

Abstract

The glidobactin-like natural products (GLNPs) glidobactin A and
cepafungin I have been reported to be potent proteasome inhibitors and
are regarded as promising candidates for anticancer drug development.
Their biosynthetic gene cluster (BGC) plu1881-1877 is present in
entomopathogenic Photorhabdus laumondii but silent under standard
laboratory conditions. Here we show the largest subset of GLNPs, which
are produced and identified after activation of the silent BGC in the
native host and following heterologous expression of the BGC in
Escherichia coli. Their chemical diversity results from a relaxed
substrate specificity and flexible product release in the assembly line
of GLNPs. Crystal structure analysis of the yeast proteasome in complex
with new GLNPs suggests that the degree of unsaturation and the length
of the aliphatic tail are critical for their bioactivity. The results in
this study provide the basis to engineer the BGC for the generation of
new GLNPs and to optimize these natural products resulting in potential
drugs for cancer therapy.