Harnessing Unusual Precursors in Polyketide Biosynthesis

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Polyketides biosynthesized by type I polyketide synthases (PKSs) are a large class of natural products that have a wide range of important biological and pharmacological properties. The diversity of activities of these natural products is due to the structural variations afforded by type I PKSs. These enzymes recognize thioesterified carboxylic acid precursors and condense these precursors to generate the polyketide backbone. While PKSs incorporate predominantly malonyl‐CoA and (2S)‐methylmalonyl‐CoA precursors, additional precursors are being identified. We identified two unusual PKS precursors with unique chemical attributes while studying zwittermicin A biosynthesis by Bacillus cereus. These precursors, (2S)‐aminomalonyl‐acyl carrier protein (ACP) and (2R)‐hydroxymalonyl‐ACP, introduce an amino or hydroxyl group, respectively, into the polyketide. Understanding how these precursors are recognized and incorporated into a polyketide backbone will provide a means for reprogramming other PKSs to incorporate these unusual precursors. This will extend the possibilities of polyketide structural variation. Our structure‐function analyses of precursor recognition by PKSs will be discussed