Indole diterpenes (IDT) are a large and structurally complex class of secondary metabolites produced by filamentous fungi that have a wide variety of bioactivities, including potent insecticidal and anti-cancer activity, making them enticing candidates for agrichemical or pharmaceutical development. Recent advances in molecular and synthetic biology have provided the tools to produce these previously inaccessible complex compounds in heterologous hosts through reconstitution of their biosynthetic pathways.
We identified IDT clusters in Aspergillus alliaceus (ACE cluster) and Aspergillus nomiae (NOM cluster), which are the first to contain genes encoding an unusual non-ribosomal peptide synthetase (NRPS)-like enzymes. Through heterologous pathway reconstruction, we have illuminated the genetic and biochemical basis for the only reported examples of aminoacylation in IDT biosynthesis, demonstrating the unusual involvement of monomodular non-ribosomal peptide synthetase (NRPS)-like enzymes, catalysing ester formation with a non-tethered acceptor.1 This cross-over in biosynthetic machinery between peptide and indole terpenoid biosynthesis creates new opportunities for the preparation of complex, tailored aminoacylated bioactive secondary metabolites.