Comparison of Multicyclic Polyketides by Folding Analysis: A Novel Approach to Recognize Biosynthetic and/or Evolutionary Interrelationships of the Natural Products or Intermediates and its Exemplification on hepta-, octa-, and Decaketides

A folding code—using an analogous E/Z-terminology as known for the description of the stereoisomers of alkenes—is suggested as a helpful tool for the comparison of multicyclic polyketides and is applied in this paper to selected subgroups, such as tetracyclic decaketides as well as to tricyclic hepta-and octaketides. The result is that in contrast to structural similarities, a biosynthesis relationship regarding the polyketide synthases (PKS) can be proposed between the tetracyclines, the anthracyclines, and the angucyclines, while the biosynthesis of the tetracenomycins and the aureolic acid antibiotics must be performed via a differently operating polyketide synthase. This also leads consequently to a new biosynthetic hypothesis including the same bicyclic intermediate for the tetracyclines, anthracyclines and angucyclines. A biosynthetic relationship between the tetracenomycins and the aureolic acid antibiotics can be deduced from the folding analysis of these two antibiotic groups leading to a novel biosynthesis hypothesis for the latter group. In addition, the application of the folding code system to hepta-and octaketides shows that this concept can be used in general as a simple, but predictive approach to visualize biosynthetic interrelationships of multicyclic polyketides including their putative biosynthetic intermediates.