Activation of Natural Products Biosynthetic Pathways via a Protein Modification Level Regulation
Citations Over TimeTop 10% of 2017 papers
Abstract
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.
Related Papers
- → The merger of natural product synthesis and medicinal chemistry: on the chemistry and chemical biology of epothilones(2004)89 cited
- → Chemical Biology of Natural Products on the Basis of Identification of Target Proteins(2012)84 cited
- → Chemical biology—identification of small molecule modulators of cellular activity by natural product inspired synthesis(2008)69 cited
- → Natural Product Synthesis at the Interface of Chemistry and Biology(2014)49 cited
- → Natural Product Synthesis for Drug Discovery and Chemical Biology(2018)