Activation, Structure, Biosynthesis and Bioactivity of Glidobactin‐like Proteasome Inhibitors from Photorhabdus laumondii
Autor: | Marcel Kaiser, Lei Zhao, Alexander O. Brachmann, Helge B. Bode, Michael Groll, Camille Le Chapelain |
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Rok vydání: | 2020 |
Předmět: |
drug design
proteasome inhibitors 010402 general chemistry Glidobactin A Peptides Cyclic 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Bacterial Proteins Biosynthesis Very Important Paper Gene cluster Escherichia coli Molecular Biology Full Paper biology 010405 organic chemistry Chemistry Organic Chemistry Full Papers biology.organism_classification glidobactins Yeast 3. Good health 0104 chemical sciences ddc Drug development Proteasome Multigene Family Molecular Medicine structure–activity relationships Heterologous expression biosynthesis Photorhabdus |
Zdroj: | ChemBioChem Chembiochem |
Popis: | 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. The silent treatment: Glidobactin‐like proteasome inhibitors are regarded as promising candidates for anticancer drug development. We report the largest subset of glidobactin‐like proteasome inhibitors, which are produced and identified after the silent biosynthetic gene cluster plu1881–1877 is activated in the native host P. laumondii. |
Databáze: | OpenAIRE |
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