A New Cyclase Family Catalyzing Head-to-Tail Macrolactamization of Non-ribosomal Peptides

Abstract

Macrolactamization is one of the most important peptide-modifying reactions. However, chemical macrocyclization is often hampered by several technical problems such as epimerization at the C-terminal residue, and a requirement for high dilution conditions, as well as for protective groups. In contrast, natural cyclopeptides are biosynthesized by efficient cyclases under mild conditions, suggesting these enzymes have potential as biocatalysts. However, the versatility of natural cyclases has not been fully exploited, mainly due to their strict substrate specificity. During the course of our synthetic and biosynthetic studies on surugamides, we have discovered a new family of cyclases showing broad substrate specificity. The new cyclase SurE, which is homologous to penicillin binding protein, offloads two assembly lines of non-ribosomal peptide synthetase, and remarkably, catalyzes the head-to-tail macrolactamization of two distinct peptides, thereby offering a new platform for the development of biocatalysts for macrolactamization.