Heterologous Reconstitution of Ikarugamycin Biosynthesis in E. coli

Polycyclic tetramate macrolactams (PTMs) are a family of biomedically promising natural products with challenging molecular frameworks. Despite these interesting properties, so far only relatively little is known about the biosynthetic origin of PTMs, in particular concerning the mechanism by which their ring systems are formed. Herein we present the first insights into these processes by using the biosynthesis of ikarugamycin as an example. This has been facilitated by the first heterologous expression of a PTM biosynthetic gene cluster in Escherichia coli. With this approach it will not only become possible to mechanistically investigate already known PTM biosynthetic pathways in more detail in the future, but also to interrogate cryptic PTM biosynthetic pathways chemically and biochemically. Small cluster, big molecule: Polycyclic tetramate macrolactams (PTMs) are a family of structurally diverse, bioactive natural products. Valuable insight into the compact biosynthesis of PTMs has been obtained by heterologous expression of the newly identified ikarugamycin biosynthetic gene cluster in E. coli. The heterologous production of PTMs with the established method will allow many cryptic PTM gene clusters to be chemically unlocked in the future.