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.

One famous strategy for constraining peptide flexibility and supplying antibiotic function is the bis-cyclization of the l-δ-(α-aminoadipoyl)–l-cysteinyl–d-valine (ACV) tripeptide to isopenicillin N by isopenicillin N synthetase (IPNS) in penicillin/cephalosporin biosynthesis (1). IPNS, a mononuclear nonheme Fe(II) oxygenase, creates the four–five fused ring system of isopenicillin N (Fig. 1) in one catalytic cycle. Formation of the five-membered thiolane and four-membered β-lactam rings rigidifies the ACV tripeptide scaffold and affords a suicide substrate for peptidogylcan cross-linking transpeptidases that inhibits bacterial cell wall biosynthesis. Further tailoring of the isopenicillin N core provides the various penicillin and cephalosporin family members.

*To whom correspondence should be addressed. E-mail: christopher_walsh{at}hms.harvard.edu