Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

Abstract

SummaryThis review highlights the biosynthesis of heterocycles in polyketide natural products with a focus on oxygen and nitrogen-containing heterocycles with ring sizes between 3 and 6 atoms. Heterocycles are abundant structural elements of natural products from all classes and they often contribute significantly to their biological activity. Progress in recent years has led to a much better understanding of their biosynthesis. In this context, plenty of novel enzymology has been discovered, suggesting that these pathways are an attractive target for future studies.

Insights into the Dual Activity of a Bifunctional Dehydratase‐Cyclase Domain

“…Despite their importance, relatively little is known about the enzymes involved in their biosynthesis. Ring formation occurs by reductive processing of acetals, direct oxidative cyclization, epoxide opening, and oxa‐conjugate 1,4‐addition …”

“…Enzymes that act via oxa‐conjugate 1,4‐addition have been proposed in several biosynthetic pathways based on gene cluster analysis and a few examples have been biochemically studied: The enoyl‐CoA hydratase homologue NonS from nonactin biosynthesis and the pyran synthase PedPS7 from pederin biosynthesis have been demonstrated to catalyze the formation of tetrahydrofuran and tetrahydropyran (THP) rings, respectively ,. These monofunctional enzymes form separate phylogenetic clades (Figure S2).…”

β-Lactone Synthetase Found in the Olefin Biosynthesis Pathway

“…Other polyketide-type β-lactone gene clusters, such as those for salinosporamide A, cinnabaramide, and oxazolomycin, do not encode an OleC homologue with high sequence similarity (>35%). Polyketide-derived β-lactones are thought to form by the cyclization of the final thioester, enzyme-linked intermediate, but this has never been characterized 2,17–19 . It is reasonable to hypothesize that specialized polyketide synthase domains represent a second mechanism of β-lactone formation.…”

Chemical probing of thiotetronate bio-assembly

“…1 The presence of heterocyclic moieties in polyketides, such as pyran and furan rings in ionophore antibiotics, is common and often decisive for the physical properties and biological activity of the compound. 2 Although sulphur-ring based structures are relatively common in peptides of both ribosomal and nonribosomal origin, 3 polyketides bearing sulphur-containing rings are rare. They include potent antitumor agents such as leinamycin 4 and the family of thiotetronate antibiotics (Fig.…”

“…11 TLM constitutes a promising lead structure for the development of novel anti-tuberculosis, anti-malarial and antitrypanosomal agents. [12][13][14] The closely structurally related Tü 3010 (2) has been reported to be the most potent antibacterial tetronate to date, capable of targeting FabH/FabF in Staphylococcus aureus at lower doses in comparison to TLM and other known FabH/FabF inhibitors. 15 Only very recently these medicinally promising molecules were unequivocally established to be of polyketide origin.…”