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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.

Ikarugamycin is a member of the polycyclic tetramate macrolactams (PTMs) family of natural products with diverse biological activities. The biochemical mechanisms for the formation of polycyclic ring systems in PTMs remain elusive. The enzymatic mechanism of constructing an inner five-membered ring in ikarugamycin is reported. A three-gene-cassette ikaABC from the marine-derived Streptomyces sp. ZJ306 is sufficient for conferring ikarugamycin production in a heterologous host. IkaC catalyzes a reductive cyclization reaction to form the inner five-membered ring by a Michael addition-like reaction. This study provides the first biochemical evidence for polycycle formation in PTMs and suggests a reductive cyclization strategy which may be potentially applicable in general to the corresponding ring formation in other PTMs.

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.

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.

The structure and configuration of an antibiotic, ikarugamycin, have been established to be 1e on the basis of chemical reactions, especially of oxidative degradation. It is suggested that the as-hydrindacene skeleton arises biogenetically via an intramolecular Diels-Alder reaction.

Synthese du cyclopenta [b] indocene-cis diol-7,8-endo intermediaire potentiel pour la synthese de l'ikarugamycine a partir du bicyclo [3.3.0] octadiene-2,6 carboxylate-2 de methyle

The four 3,4-cis-stereoisomers of dimethyl dl-3-ethyl-4-methyl-1,2-cyclopentanedicarboxylates (1a, 1b, 1c, and 1d) have been synthesized and their configurations established. A comparison of the spectral data and the GLC behaviors has shown that the corresponding ester, one of the key degradation products of ikarugamycin, has the r-1, t-2, c-3, c-4-configuration (1a). The r-1, t-2, c-3, t-4-stereoisomer (1f) has also been prepared.

The five trimethyl dl-3-methoxycarbonylmethyl-1,2,4-cyclopentanetricarboxylates have been synthesized and their configurations determined. A comparison of their spectral properties with those of the corresponding ester obtained from ikarugamycin indicates that the latter has a cis, trans, trans configuration.