"Natural products are a constant source of inspiration in chemistry and have played a key role in the development of medicine. Recently, thanks to the progress in genomics and metagenomics, it has appeared that the biosynthetic potential of microorganisms and the complexity of the reactions catalyzed have been largely underestimated. Notably, enzymes using radical-based chemistry have been shown to be present in a very-large amount of biosynthetic pathways and to be widely distributed among all living organisms. The highly reactive radical species they generate give access to chemistries not accessible otherwise and allow them to catalyze unique and diverse reactions. Among them, the so-called ""radical SAM enzymes"" have attracted considerable attention in recent years. While, initially hypothesized to be a family with several hundreds of members, recent genomic analyses have revealed that there are several tens of thousands of radical SAM enzymes catalyzing more than sixty distinct biochemical processes.
Very recently, an ever increasing number of radical SAM enzymes has been discovered in the biosynthetic pathways of natural compounds. In several cases, it has been shown that, instead of involving non-ribosomal or polyketide synthases, microorganisms use radical SAM enzymes to extensively modify ribosomally synthesized peptides producing highly complex bioactive molecules. In the present project, we propose to develop a multidisciplinary approach to investigate promising radical SAM enzymes catalyzing peptide modifications and elucidate their unique mechanisms which, in many cases, have no counterparts in biochemistry and synthetic chemistry. Based on the unique and highly conserved radical SAM domain and the mechanistic insights gained, we will develop novel radical SAM enzymes as catalysts for the synthesis of new chemicals with original structures and properties using a synthetic biology approach."
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