Expanding molecular diversity of RiPP natural products by radical SAM enzymes: recent advances and mechanistic insights

Ribosomally synthesized and post-translationally modified peptides (RiPPs) represent a vast and diverse family of bioactive peptides. These peptides are synthesized by ribosomes and subsequently modified by various tailoring enzymes, endowing RiPPs with a wide chemical space. Among them, radical S-adenosylmethionine (rSAM) enzymes utilize unique radical chemistry to introduce a variety of novel peptide structures, which are crucial for their activity. With the advancement of protein structure analysis techniques and computational methods, we herein review the major types of modifications in RiPPs catalyzed by rSAM enzymes, combining with the latest crystal structures to elucidate their diverse catalytic mechanisms and substrate selectivity.