Radical SAM enzymes are emerging as a major superfamily of biological catalysts involved in the biosynthesis of the broad family of bioactive peptides called ribosomally synthesized and post-translationally-modified peptides (RiPPs). These enzymes have been shown to catalyze unconventional reactions such as methyl transfer to electrophilic carbon atoms, sulfur to Cα-atom thioether bonds or carbon-carbon bond formation. Recently, a novel radical SAM enzyme catalyzing the formation of a lysine-tryptophan bond has been identified in Streptococcus thermophilus and a reaction mechanism has been proposed. By combining site-directed mutagenesis, biochemical assays and spectroscopic analyses, we show here that this enzyme, belonging to the emerging family of SPASM-domain radical SAM enzymes, likely contains three [4Fe-4S] clusters. Notably, our data support that the seven conserved cysteine residues, present within the SPASM-domain, are critical for enzyme activity. In addition, we uncovered the minimum substrate requirements and demonstrate that KW-cyclic peptides are more widespread than anticipated, notably in pathogenic bacteria. Finally, we show a strict specificity of the enzyme for lysine and tryptophan residues and the dependence of an eight-amino acids leader peptide, for activity. Altogether, our study suggests novel mechanistic links among SPASM-domain radical SAM enzymes and supports the involvement of non-cysteinly ligands in the coordination of auxiliary clusters.
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