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Resorcylic acid lactones represent a unique class of fungal polyketides and display a wide range of biological activities, such as nanomolar inhibitors of Hsp90 and MAP kinase. The biosynthesis of these compounds is proposed to involve two fungal polyketide synthases (PKS) that function collaboratively to yield a 14-membered macrolactone with a resorcylate core. We report here the reconstitution of Gibberella zeae PKS13, which is the nonreducing PKS associated with zearalenone biosynthesis. Using a small molecule mimic of the natural hexaketide starter unit, we reconstituted the entire repertoire of PKS13 activities in vitro, including starter-unit selection, iterative condensation, regioselective C2-C7 cyclization, and macrolactone formation. PKS13 synthesized both natural 14-membered and previously uncharacterized 16-membered resorcylic acid lactones, indicating relaxed control in both iterative elongation and macrocyclization. PKS13 exhibited broad starter-unit specificities toward fatty acyl-CoAs ranging in sizes between C6 and C16 and displayed the highest activity toward decanoyl-CoA. PKS13 was shown to be active in Escherichia coli and synthesized numerous alkyl pyrones and alkyl resorcylic esters without exogenously supplied precursors. We demonstrated that PKS13 can interact with E. coli fatty acid biosynthetic machinery and can be primed with fatty-acyl ACPp at low-micromolar concentrations. PKS13 synthesized new polyketides in E. coli when the culture was supplemented with synthetic precursors, showcasing its utility in precursor-directed biosynthesis. PKS13 is therefore a highly versatile polyketide macrolactone synthase that is useful in the engineered biosynthesis of polyketides, including resorcylic acid lactones that are not found in nature.

A polyketide macrolactone synthase from the filamentous fungus Gibberella zeae