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

Abstract

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.

Evolution of Chemical Diversity in Echinocandin Lipopeptide Antifungal Metabolites

“…The functional similarities among the different echinocandin chemistries in combination with the conserved architecture of their physically linked core genes ( Fig. 1) suggested the hypothesis that the echinocandin NRPS genes may have arisen only once, possibly through tandem gene duplication and recruitment (21). Subsequently, selection pressures and pathway reorganizations acting on a beneficial suite of pathway elements likely have driven further functional chemical evolution.…”

“…In both, maturation requires a lipoinitiation step, peptide chain elongation and cyclization, and a cascade of hydroxylation reactions (17)(18)(19)(20) resulting in six (echinocandin) or seven (pneumocandin) hydroxyl groups on five amino acid residues of the cyclic hexapeptide core. Additional differences and similarities between the two pathways have been detailed previously (19)(20)(21)(22). The genomic sequencing of rep- (5).…”

“…See reference 7. resentative strains of most of the echinocandin variants ( Fig. 2 and Table 1), including the parent wild-type strains of the fungi employed for production of the antifungal drugs caspofungin, micafungin, and anidulafungin, has enabled characterization of the basic genomic architecture of the echinocandin pathways (21). Thus, a global perspective of how pathway genes interact to produce different forms of lipoinitiation, biosynthesis of nonproteinogenic amino acids, amino acid selection and hydroxylation, and sulfation of the core peptide is now evident.…”

Structural diversity in echinocandin biosynthesis: the impact of oxidation steps and approaches toward an evolutionary explanation

“…The history of exploring echinocandin biosynthesis has been featured in previous review articles [1,2,[7][8][9]. In brief, the biosynthetic origin of the non-proteinogenic amino acids and the dimethylmyristate side chain was elucidated in the early 1990s by groups of Tang and Walsh disclosed the genes encoding echinocandin B biosynthesis in the genome of Aspergillus pachycristatus NRRL 11440 (formerly Emericella rugulosa) [13].…”

Echinocandins Versus Dated Antifungals in Combination Against Opportunistic Mycotic Infections

“…Genetic mapping of these gene assemblies has been done and characterization of their function is still in progress. Genomic sequencing of wild type and variants of echinocandin family has made it possible to understand the fundamental architecture of echinocandin NRPS pathways [54].…”