Activation, Structure, Biosynthesis and Bioactivity of Glidobactin‐like Proteasome Inhibitors from Photorhabdus laumondii. (3rd March 2021)

• Record Type: Journal Article
• Authors: Zhao, Lei; Le Chapelain, Camille; Brachmann, Alexander O.; Kaiser, Marcel; Groll, Michael; Bode, Helge B.
• Is Part Of: Chembiochem. Volume 22:Number 9(2021)
• Page Start: 1582
• Page End: 1588
• Publication Date: 2021-03-03
• Subjects: biosynthesis -- drug design -- glidobactins -- proteasome inhibitors -- structure–activity relationships; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.202100014
• Languages: English
• ISSNs: 1439-4227

Abstract

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. Abstract : 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 .