Morphing peptide backbones into heterocycles

Microbes employ several catalytic strategies to transform conformationally flexible peptide chains into rigidified scaffolds that possess antibiotic or toxin activity. Prominent examples include the biosynthesis of the β-lactam antibiotics of the penicillin and cephalosporin families (1) and the maturation of vancomycin (2) where distinct structural modifications to the nascent peptide chains confer physiological function. In this issue of PNAS, Lee et al. (3) provide the first insight into the chemical structure of streptolysin S (SLS), a hemolytic toxin produced by the human pathogen Streptococcus pyogenes. Its peptide backbone undergoes remarkable posttranslational tailoring, resulting in heterocycle formation and cytolytic activity. Lee et al. further show that a variety of prokaryotes harbor analogous maturation machinery, which suggests widespread use of heterocyclization for altering peptide shape/flexibility and creating functional toxins. This work builds on previous examples where enzymes morph peptide frameworks of both ribosomal and nonribosomal origin.