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

Abstract Echinocandins are an important group of cyclic non-ribosomal peptides with strong antifungal activity produced by filamentous fungi from Aspergillaceae and Leotiomycetes. Their structure is characterized by numerous hydroxylated non-proteinogenic amino acids. Biosynthetic clusters discovered in the last years contain up to six oxygenases, all of which are involved in amino acid modifications. Especially, variations in the oxidation pattern induced by these enzymes account for a remarkable structural diversity among the echinocandins. This review provides an overview of the current knowledge of echinocandin biosynthesis with a special focus on diversity-inducing oxidation steps. The emergence of metabolic diversity is further discussed on the basis of a comprehensive overview of the structurally characterized echinocandins, their producer strains and biosynthetic clusters. For the pneumocandins, echinocandins produced by Glarea lozoyensis, the formation of metabolic diversity in a single organism is analyzed. It is compared to two common models for the evolution of secondary metabolism: the ‘target-based’ approach and the ‘diversity-based’ model. Whereas the early phase of pneumocandin biosynthesis supports the target-based model, the diversity-inducing late steps and most oxidation reactions best fit the diversity-based approach. Moreover, two types of diversity-inducing steps can be distinguished. Although incomplete hydroxylation is a common phenomenon in echinocandin production and secondary metabolite biosynthesis in general, the incorporation of diverse hydroxyprolines at position 6 is apparently a unique feature of pneumocandin biosynthesis, which stands in stark contrast to the strict selectivity found in echinocandin biosynthesis by Aspergillaceae. The example of echinocandin biosynthesis shows that the existing models for the evolution of secondary metabolism can be well applied to parts of the pathway; however, thus far, there is no comprehensive theory that could explain the entire biosynthesis.