The human microbiome plays a central role in human physiology. This complex ecosystem is composed of thousands of bacterial species and has a remarkable biosynthetic potential. However, we still have a limited knowledge of its biosynthetic potential and the enzymes that support its functions. In the ChemSyBio team, we have shown that an emerging superfamily of enzymes called “radical SAM enzymes” play a key role in the human microbiome from host colonization to the production of bioactive compounds including antibiotics. These metalloenzymes catalyze chemically challenging reactions using a central radical-based mechanism. Although broadly distributed, the importance of these enzymes has been recently recognized. They are major biocatalysts in the biosynthesis of natural products from small organic compounds to antimicrobial peptides and in the post-translational modification of proteins.
Our laboratory has conducted pioneer studies in the field. By combining a broad range of approaches from biochemistry, analytical chemistry, spectroscopy to structural biology, we have unraveled novel reactions and post-translational modifications catalyzed by radical SAM enzymes, unprecedented mechanisms and protein architectures. Our research aims at obtaining a comprehensive picture of the major enzymes of the microbiome and to develop novel therapeutic strategies targeting the microbiome. Our research is focused on two main axes:
The ChemSyBio team explores the biosynthetic potential of the gut microbiota and their capacity to produce innovative natural products called RiPPs (Ribosomally synthesized and Post-translationally modified Peptides). In the last decade, research on RiPPs has demonstrated the extraordinary structural and functional diversity of these molecules. Notably, work from our team and others has shown that RiPPs play a key role within the human microbiota. In the biosynthesis of RiPPs, we have demonstrated that metalloenzymes, including the so-called radical SAM enzymes, are key players by catalyzing the installation of a myriad of post-translational modifications, many of which being not accessible by synthetic chemistry, and essential for the biological activities of RiPPs. By combining structural biology and biochemistry, our team is seeking to develop innovative RiPP antibiotics targeting the human microbiome.
Enzymes play a central but ill-investigated role in the human microbiome. Indeed, we have a limited knowledge of the structural and functional diversity of the enzymes that support the main functions of the microbiome. Our team is focused mainly on the investigation of metalloenzymes using iron-sulfur clusters and vitamin B12 (cobalamin) as co-factors. Our Work aims at gaining a better mechanistic understanding of the enzymes from the microbiome by combining advanced approaches in biochemistry, structural biology and spectroscopy. In addition to a better fundamental knowledge of the microbiome, we also ambition to develop innovative biocatalysts in the frame of synthetic biology and sustainable development.
All the team publications are available in the CHEMSYBIO-MICALIS HAL collection.
