Enzymatic Formation of Unnatural Novel Chalcone, Stilbene, and Benzophenone Scaffolds by Plant Type III Polyketide Synthase

A C<sub>19</sub> hexaketide stilbene and a C<sub>21</sub> heptaketide chalcone were synthesized by <i>Aloe arborescens</i> octaketide synthase (OKS), a plant-specific type III polyketide synthase (PKS). Remarkably, the C<sub>21</sub> chalcone-forming activity was dramatically increased in a structure-guided OKS N222G mutant that produces a C<sub>20</sub> decaketide SEK15 from 10 molecules of malonyl-CoA. The findings suggested further strategies for production of unnatural polyketides by combination of the precursor-directed biosynthesis and the structure-guided engineering of type III PKS.