Macrocyclization of peptides confer protection to proteolytic degradation, improve their membrane solubility and target specificity. In case of non-ribosomal peptide (NRP) biosynthesis, this key step is generally mediated by chain terminating domains such as TE or CT domain located at C terminus of synthetases. Surugamides are simultaneously synthesized but structurally unrelated two groups of NRPs produced by several Streptomyces strains. Cyclic octapeptide surugamide A exhibit catepsin B inhibitory activity, while the activity of decapeptides cyclosurugamide F and its linear derivative remain elusive. Their biosynthetic genes are clustered in a single genomic locus. None of the NRPS encoded in this cluster possesses canonical chain-terminating domain at its C-terminus.
We established the total synthetic route of surugamide B for the first time though macrolactamization at biomimetic position. This led to the identification of a new peptide cyclase, SurE that is responsible for chain-termination and macrolactamization in biosynthesis of surugamides (1). Our biochemical analyses showed that SurE is a trans-acting peptide cyclase with broad substrate specificity, acting on two distinct peptide assembly-lines to cyclize structurally unrelated peptides (2).