4 years ago

Activation of Natural Products Biosynthetic Pathways via a Protein Modification Level Regulation

Activation of Natural Products Biosynthetic Pathways via a Protein Modification Level Regulation
Benyin Zhang, Zixin Deng, Xudong Qu, Hongmin Ma, Xiaoli Yan, Xinying Jia, Shuwen Wang, Wenqing Chen, Gregory K. Pierens, Wenya Tian
Natural products are critical for drug discovery and development; however their discovery is challenged by the wide inactivation or silence of microbial biosynthetic pathways. Currently strategies targeting this problem are mainly concentrated on chromosome dissembling, transcription, and translation-stage regulations as well as chemical stimulation. In this study, we developed a novel approach to awake cryptic/silenced microbial biosynthetic pathways through augmentation of the conserved protein modification step-phosphopantetheinylation of carrier proteins. Overexpression of phosphopantetheinyl transferase (Pptase) genes into 33 Actinomycetes achieved a significantly high activation ratio at which 23 (70%) strains produced new metabolites. Genetic and biochemical studies on the mode-of-action revealed that exogenous PPtases triggered the activation of carrier proteins and subsequent production of metabolites. With this approach we successfully identified five oviedomycin and halichomycin-like compounds from two strains. This study provides a novel approach to efficiently activate cryptic/silenced biosynthetic pathways which will be useful for natural products discovery.

Publisher URL: http://dx.doi.org/10.1021/acschembio.7b00225

DOI: 10.1021/acschembio.7b00225

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