Abstract
To face the current antibiotic resistance crisis, novel strategies are urgently required. Indeed, in the last 30 years, despite considerable efforts involving notably high-throughput screening and combinatorial libraries, only few antibiotics have been launched to the market. Natural products have markedly contributed to the discovery of novel antibiotics, chemistry and drug leads, with more than half anti-infective and anticancer drugs approved by the FDA being of natural origin or inspired by natural products. Among them, thanks to their modular structure and simple biosynthetic logic, ribosomally synthesized and posttranslationally modified peptides (RiPPs) are promising scaffolds. In addition, recent studies have highlighted the pivotal role of RiPPs in the human microbiota which remains an untapped source of natural products. In this review, we report on recent developments in radical SAM enzymology and how these unique biocatalysts have been shown to install complex and sometimes unprecedented posttranslational modifications in RiPPs with a special focus on microbiome derived enzymes.
Highlights
Reviewed by: Satish Nair, University of Illinois at UrbanaChampaign, United States Natalia Miguel Vior, John Innes Centre, United Kingdom Myco Umemura, National Institute of Advanced Industrial Science and Technology (AIST), Japan
Natural products have markedly contributed to the discovery of novel antibiotics, chemistry and drug leads, with more than half anti-infective and anticancer drugs approved by the FDA being of natural origin or inspired by natural products
We report on recent developments in radical SAM enzymology and how these unique biocatalysts have been shown to install complex and sometimes unprecedented posttranslational modifications in ribosomally synthesized and posttranslationally modified peptides (RiPPs) with a special focus on microbiome derived enzymes
Summary
While the biosynthesis of RiPPs follows a common logic with the translation of a precursor peptide containing a leader (or a follower) sequence, the installation of posttranslational modifications and the cleavage of the leader peptide (Figures 1A,B) (Arnison et al, 2013; Ortega and van der Donk, 2016; Funk and van der Donk, 2017; Montalban-Lopez et al, 2021), RiPPs display an extraordinary structural diversity largely due to the various posttranslational modifications installed by diverse and unrelated enzymes (Montalban-Lopez et al, 2021). There has been a tremendous increase in the discovery of radical SAM enzymes involved in RiPP biosynthetic pathways (Wang and Frey, 2007; Fluhe et al, 2012; Pierre et al, 2012; Allen and Wang, 2014; Benjdia et al, 2015; Benjdia et al, 2017a; Parent et al, 2018; Balty et al, 2019; Imai et al, 2019; Balty et al, 2020) Despite catalyzing such diverse reactions, radical SAM enzymes share common structural and mechanistic features. In the last five years, a new picture has emerged regarding mechanistic evolution within the radical SAM enzyme superfamily and how they have evolved to catalyze RiPP post-translational modifications
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