New insights into the echinocandins and other fungal non-ribosomal peptides and peptaibiotics.

Non-ribosomal peptide synthetases (NRPSs) are a primary modality for fungal peptidic natural product assembly and are responsible for some of the best known, most useful, and most destructive fungal metabolites. Through genome sequencing and computer-assisted recognition of modular motifs of catalytic domains, one can now confidently identify most NRPS biosynthetic genes of a fungal strain. The biosynthetic gene clusters responsible for two of the most important classes of NRP fungal derived drugs, cyclosporine and the echinocandins, have been recently characterized by genomic sequencing and annotation. Complete biosynthetic gene clusters for the pneumocandins and echinocandins have been mapped at the genetic level and functionally characterized to some extent. Genomic sequencing of representative strains of most of the variants in the echinocandin family, including the wild-type of the three fungal strains employed for industrial-scale production of caspofungin, micafungin and anidulofungin, has enabled characterization of the basic architecture of the echinocandin NRPS pathways. A comparative analysis of how pathway genes cause variations in lipoinitiation, biosynthesis of the non-proteinogenic amino acids, amino acid substitutions, and hydroxylations and sulfonations of the core peptide and contribute to the molecular diversity of the family is presented. We also review new information on the natural functions of NRPs, the differences between fungal and bacterial NRPSs, and functional characterization of selected NRPS gene clusters. Continuing discovery of the new fungal nonribosomal peptides has contributed new structural diversity and potential insights into their biological functions among other natural peptides and peptaibiotics. We therefore provide an update on new peptides, depsipeptides and peptaibols discovered in the Fungi since 2009.