Radical SAM enzymes involved in modifications of RiPP natural products

Most natural products are not essential for basic survival; instead, they provide a competitive edge for the biological niche the producing organisms occupy. Peptide-based compounds are an important family of natural products with a wide array of structural features and biological activities. These generally fall into two classes based upon the origin of the peptide backbone. Members of the first class are synthesized by non-ribosomal peptide synthetases (NRPSs), which are large protein megasynthases that carry out the sequential amino acid incorporation and tailoring steps, as necessary, to assemble the complex natural product.¹ Examples that highlight industrially and therapeutically significant NRPS derived natural products are shown in Fig. 1. Members of the second class use a genetically encoded peptide as the starting point for subsequent tailoring to reach the matured natural products. These ribosomally synthesized and post-translationally modified polypeptides (RiPPs) have been of interest for decades. Members of this class include notable examples such as nisin, which has been used commonly as a food preservative. The co-localization of genes encoding the substrate peptide and the tailoring enzymes has led to the rapid discovery of large numbers of these putative natural products in the expanding genome databases (for a recent review see²). RiPP biosynthetic gene clusters (BGCs), at a minimum, encode a precursor peptide and a maturase (see Fig. 2A). The precursor peptide often contains a leader sequence, which is generally removed in the course of maturation. In addition, these clusters also sometimes encode protein transporters or proteases, which may be responsible....