A Gene Cluster from a Marine Streptomyces Encoding the Biosynthesis of the Aromatic Spiroketal Polyketide Griseorhodin A

The telomerase inhibitor griseorhodin A is probably the most heavily oxidized bacterial polyketide known and features a unique epoxyspiroketal moiety crucial for its activity. To gain insight into which tailoring enzymes generate this pharmacophore, we have cloned and fully sequenced the griseorhodin biosynthesis gene cluster. Among other unusual features, this aromatic polyketide synthase (PKS) system encodes an unprecedented number of functionally diverse oxidoreductases, which are involved in the oxidative modification of a polyaromatic tridecaketide precursor by cleavage of three carbon-carbon bonds. The cluster was highly unstable on a variety of shuttle plasmids but could finally be functionally expressed in its entirety in Streptomyces lividans using a novel integrative cosmid vector. The availability of the tailoring system now opens up the possibility of engineering nonnatural biosynthetic pathways yielding novel pharmacologically active analogs with a similar pharmacophore.