Structure and Function of Animal Polyketide Synthases: Bridging Lipid and Polyketide Biology

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With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Dr. Eric Schmidt and collaborator Dr. Chris Hill from the University of Utah investigate molecular principles of how lipids are biosynthesized in animals and in humans. While the biochemical basis of fatty acid biosynthesis has long been studied, recently, new families of enzymes that create chemically diverse lipids have been uncovered in mammalian genomes. These enzymes address a biosynthetic challenge that bridges the gap between polyketides, structurally elaborate compounds that are used as pharmaceuticals, and the structurally simpler major fats found in humans and animals. The proposed experiments represent a new direction synthetic biology and are expected to provide a molecular-level understanding these interesting mammalian polyketide synthase and provide new tools for lipid and polyketide engineering and discovery. These studies will contribute to high level postdoctoral fellow training at the interface of chemistry and biology, with specialized training in the science of cryo-electron microscopy and advanced structural techniques. A summer training program will introduce high school students to structural biology.This research project seeks to understand the structure and function of novel polyketide synthases found in mammalian biology, including human biology. The enzymes will be characterized in vitro using biochemical methods, such as kinetic analysis with different substrates and cofactors and determination of the structures of the novel products of these enzymes. Cryo-electron microscopy studies will be applied to determine the enzyme structures, which will be followed up by hypothesis-guided mutational analyses. Taken together, these studies will determine the structural principles underlying mammalian polyketide synthase substrate and product selectivity. Further, the Schmidt and Hill team will compare the results obtained in the study of mammalian systems with those from human fatty acid synthase, using the results to build new lipid derivatives by designed engineering.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.