C-N-Coupled Metabolites Yield Insights into Dynemicin A Biosynthesis

Abstract

The biosynthesis of the three structural subclasses of enediyne antitumor antibiotics remains largely unknown beyond a common C₁₆ -hexaene precursor. For the anthraquinone-fused subtype, however, an unexpected iodoanthracene γ-thiolactone was established to be a mid-pathway intermediate to dynemicin A. Having deleted a putative flavin-dependent oxidoreductase from the dynemicin biosynthetic gene cluster, we can now report four metabolites that incorporate the iodoanthracene and reveal the formation of the C-N bond linking the anthraquinone and enediyne halves emblematic of this structural subclass. The coupling of an aryl iodide and an amine is familiar from organometallic chemistry, but has little or no precedent in natural product biosynthesis. These metabolites suggest further that enediyne formation occurs early in the overall biosynthesis, and that even earlier events might convert the C₁₆ -hexaene to a common C₁₅ intermediate that partitions to enediyne and anthraquinone building blocks for the heterodimerization.

Keywords: biosynthesis; dynemicin; enediyne; oxidoreductases; polyketides.