The substrate lends a hand

Duramycin is a small post-translationally modified peptide with antibody-like affinity for phosphatidylethanolamine. As it turns out, the same functionality that is essential for duramycin activity helps to catalyze the formation of its conformationally constrained and compact polycyclic architecture

Methylating mushrooms

Peptide N-methylation is an important strategy used by medicinal chemists to improve cell permeability, oral bioavailability, and target affinity of peptide-based inhibitors. Correspondingly, N-methyl amides appear extensively in bioactive natural products. In the case of the immunosuppressant cyclosporine, for example, specific N-methylation of seven out of ten backbone amide nitrogens in the cyclic decapeptide is thought to allow a conformational ‘shapeshifting’ that hides polar N–H moieties and facilitates passive diffusion across cell membranes. Until now, N-methylation has primarily been the mark of peptide natural products from complex nonribosomal peptide synthetase (NRPS) assembly lines, and has not previously been found among their cousins, the ribosomally synthesized and post-translationally modified peptide (RiPP) natural products. In this issue, van der Velden et al. uncover the biosynthetic origins of the omphalotins, peptide natural products from the bioluminescent fungus O. olearius (Fig. 1a), and bring peptide backbone N-methylation into the realm of peptide post-translational modifications

Comparative genomics reveals phylogenetic distribution patterns of secondary metabolites in Amycolatopsis species

Background Genome mining tools have enabled us to predict biosynthetic gene clusters that might encode compounds with valuable functions for industrial and medical applications. With the continuously increasing number of genomes sequenced, we are confronted with an overwhelming number of predicted clusters. In order to guide the effective prioritization of biosynthetic gene clusters towards finding the most promising compounds, knowledge about diversity, phylogenetic relationships and distribution patterns of biosynthetic gene clusters is necessary. Results Here, we provide a comprehensive analysis of the model actinobacterial genus Amycolatopsis and its potential for the production of secondary metabolites. A phylogenetic characterization, together with a pan-genome analysis showed that within this highly diverse genus, four major lineages could be distinguished which differed in their potential to produce secondary metabolites. Furthermore, we were able to distinguish gene cluster families whose distribution correlated with phylogeny, indicating that vertical gene transfer plays a major role in the evolution of secondary metabolite gene clusters. Still, the vast majority of the diverse biosynthetic gene clusters were derived from clusters unique to the genus, and also unique in comparison to a database of known compounds. Our study on the locations of biosynthetic gene clusters in the genomes of Amycolatopsis’ strains showed that clusters acquired by horizontal gene transfer tend to be incorporated into non-conserved regions of the genome thereby allowing us to distinguish core and hypervariable regions in Amycolatopsis genomes. Conclusions Using a comparative genomics approach, it was possible to determine the potential of the genus Amycolatopsis to produce a huge diversity of secondary metabolites. Furthermore, the analysis demonstrates that horizontal and vertical gene transfer play an important role in the acquisition and maintenance of valuable secondary metabolites. Our results cast light on the interconnections between secondary metabolite gene clusters and provide a way to prioritize biosynthetic pathways in the search and discovery of novel compounds