Polyketide-derived natural products are an enormously valuable source of biologically active compounds assembled via dedicated protein assemblies known as polyketide synthases (PKSs). Type I, or modular PKSs, consist of large, multienzyme polypetides arranged in assembly line fashion. Discreet clusters of covalently-tethered, catalytic domains are responsible for two-carbon elongation of the polyketide backbone and subsequent tailoring of the resultant carbonyl functionality. Given the modularity and product diversity typical of PKS assemblies, much attention has been focused toward viable engineering strategies for natural product analog generation.
Although significant strides have been made toward rational reprogramming of these megasynthases, progress has often suffered from low turnover and inherently high specificity for natural recognition partners. Our lab is primarily interested in developing engineered systems which help us to better understand and potentially curtail these primary hurdles. Using a variety of chemical and biological techniques, we plan to exploit combinations of existing biosynthetic systems for use as miniature small-molecule factories. Ultimately, we hope to establish a reliable means of tailoring polyketide structure through simple genetic manipulation of biosynthetic components.
Additionally, our lab is interested in developing novel techniques to analyze small-molecule output in complex PKS assemblies. More specifically, we will utilize “silent” functionalities with known binding behavior as either permanent or cleavable chemical handles on full-length and intermediate polyketide structures. Success in this endeavor will provide facile means of simultaneously assaying chemical output and potential barriers to efficient turnover during product assembly.