CAREER: Accessing Chemical Diversity through the Characterization and Redesign of Natural Product Synthases

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Louise Charkoudian from Haverford College to engage undergraduates in the discovery of new routes to chemical diversity by learning and applying lessons from nature. Nature has evolved remarkably simple routes to make very complicated molecules, many of which are too complex to be readily synthesized in the laboratory. The funded research focuses on characterizing the chemistry of the most ancient and unique biosynthetic pathways, which have yet to be explored by scientists. The experimental procedures lead to the identification of new compounds and enzymes encoded by nature, as well as new tools to enable the engineering of natural pathways to build molecules of novel structure and function. This project also integrates a professional development series to expose undergraduate students to post-graduation career opportunities in the chemical sciences, as well as BioArt outreach activities that employ pigmented bacteria to illustrate fundamental concepts of chemistry and biology.The research engagees undergraduates in the discovery of new biosynthetic routes to chemical diversity through the characterization of unexplored polyketide synthase (PKS) gene clusters and enzymes. Orphaned type II (polyaromatic) polyketide gene clusters from diverse phyla are characterized to elucidate the chemical diversity encoded by ancient non-actinomycete species. These bacterial species are evaluated as a source of PKS enzymes that can be expressed in tractable heterologous hosts to enable in vitro characterization of poorly understood type II PKSs. Finally, acyl carrier proteins (ACPs) representing diverse stages of PKS evolution are characterized using a combination of traditional and innovative biochemical and biophysical methods. Results will lead to the identification of new chemical diversity encoded by nature, as well as new tools to enable the biosynthetic engineering of hybrid PKSs. The work also includes the student-led annotation of uncharacterized biosynthetic gene clusters, a professional development series to expose students to post-graduation career opportunities in the sciences, and BioArt outreach activities that leverage the pigmented nature of polyketide-producing bacteria. The outreach activities introduce concepts of chemistry and biology to young students from diverse cultural and socioeconomic backgrounds, as well as to adults with intellectual and developmental disabilities.