Structures and biological activities of cycloheptamycins A and B.

The heptadepsipeptide cycloheptamycin A was isolated from the terrestrial Streptomyces sp. Tü 6314. Its constitution was elucidated on the basis of NMR spectroscopic experiments and mass spectrometric analysis. Its stereostructure was investigated by peptide hydrolysis and derivatization and firmly established by X-ray structure analysis. In addition to the parent compound, a new cycloheptamycin analog, cycloheptamycin B, was discovered and structurally assigned using comparative MS/MS experiments and NMR. The biological profile of both compounds was investigated, revealing a selective inhibitory potential of cycloheptamycins against Propionibacterium acnes.

Biocatalytic Total Synthesis of Ikarugamycin.

Nature provides an inexhaustible diversity of small organic molecules with beautiful molecular architectures that have strong and selective inhibitory activities. However, this tremendous biomedical potential often remains inaccessible, as the structural complexity of natural products can render their synthetic preparation extremely challenging. This problem is addressable by harnessing the biocatalytic procedures evolved by nature. In this work, we present an enzymatic total synthesis of ikarugamycin. The use of an iterative PKS/NRPS machinery and two reductases has allowed the construction of 15 carbon-carbon and 2 carbon-nitrogen bonds in a biocatalytic one-pot reaction. By scaling-up this method we demonstrate the applicability of biocatalytic approaches for the ex vivo synthesis of complex natural products.

Promiscuous hydroxylases for the functionalization of polycyclic tetramate macrolactams--conversion of ikarugamycin to butremycin.

Polycyclic tetramate macrolactams (PTMs) are a structurally, biomedically and biosynthetically intriguing class of bacterial metabolites. By combining parts of the machineries of different PTM biosynthetic pathways, we demonstrate for the first time the substrate promiscuity of a class of PTM tailoring enzymes, thereby facilitating the (bio)synthesis of butremycin.

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.