Biosynthesis of the Prenylated Salicylaldehyde Flavoglaucin Requires Temporary Reduction to Salicyl Alcohol for Decoration before Reoxidation to the Final Product.

The biosynthetic pathway of the prenylated salicylaldehyde flavoglaucin and congeners in Aspergillus ruber was elucidated by genome mining, heterologous expression, precursor feeding, and biochemical characterization. The polyketide skeleton was released as alkylated salicyl alcohols, which is a prerequisite for consecutive hydroxylation and prenylation, before reoxidation to the final aldehyde products. Our results provide an excellent example for a highly programmed machinery in natural product biosynthesis.