Different polyketide folding modes converge to an identical molecular architecture

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Abstract

Metabolic diversity is being studied intensively by evolutionary biologists, but so far there has been no comparison of biosynthetic pathways leading to a particular secondary metabolite in both prokaryotes and eukaryotes. We have detected the bioactive anthraquinone chrysophanol, which serves as a chemical defense in diverse eukaryotic organisms, in a bacterial Nocardia strain, thereby permitting the first comparative biosynthetic study. Two basic modes of folding a polyketide chain to fused-ring aromatic structures have so far been described1: mode F (referring to fungi) and mode S (from Streptomyces). We have demonstrated that in eukaryotes (fungi, higher plants and insects), chrysophanol is formed via folding mode F. In actinomycetes, by contrast, the cyclization follows mode S. Thus, chrysophanol is the first polyketide synthase product that is built up by more than one polyketide folding mode.

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Figure 1
Figure 2: The four biosynthetic folding modes that might lead from acetyl coenzyme A to chrysophanol (1) in nature, with their joint (4) and individually different (5a5d) hypothetical intermediates, with the expected characteristic 13C labeling patterns for 1.
Figure 3
Figure 4: 2D INADEQUATE NMR spectrum of 1 from Nocardia strain Acta 1057 after feeding sodium [1,2-13C2]acetate; the labeling pattern with its pairwise 13C-13C correlations of incorporated intact [13C2] units indicates the presence of mode S folding.

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Acknowledgements

This work is dedicated to Burchard Franck on the occasion of his 80th birthday. Financial support from the Fonds der Chemischen Industrie, the European Commission (grant QLK3-CT-2001-01783; project ACTAPHARM), and the German Research Foundation (DFG Hi 416/16-2) are gratefully acknowledged. We thank D. Moskau (Bruker Biospin AG, Fällanden, Switzerland) for the acquisition of a 2D INADEQUATE spectrum with a cryoprobe and F. Meyer for technical support.

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Correspondence to Gerhard Bringmann.

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