Structural Biology of Biosynthetic Enzymes

该计划项目的目标是发现和表征新型膦酸盐，并从这些天然产物生物合成中涉及的酶的生化和结构生物学表征中受益匪浅。此外，对这些酶及其同源底物/抑制剂复合物的三维结构的详细了解有助于这些催化剂的工程设计，以产生具有改进的生物和/或药代动力学性质的衍生化合物。在下一个周期中，我们将把我们的研究目标扩展到生化方面

The Program Project goals towards the discovery and characterization of novel phosphonates have benefited significantly from biochemical and structural biological characterization oif the enzymes involved in the biosynthesis of these natural products. Additionally, detailed knowledge of the three dimensional structures of such enzymes in complex with their cognate substrates/inhibitors can aid in the engineering of these catalysts to yield derivative compounds with improved biological and/or pharmacokinetic properties. In this next cycle, we expand our research aims towards the biochemical characterization of gene clusters involved in the biosynthesis of the antibacterial plumbemycin and the antifungal rhizoctlcin. The enzymes from these clusters direct the production of two natural products consisting of a common warhead (the threonine synthase inhibitor (Z)-L-2-amino-5-phosphono-3-pentenoic acid (APPA)) but with different peptide-based delivery vehicles. We will carry out in vitro reconstitution of individual enzymes from each of these clusters and utilize this knowledge for the producfion of addifional pepfidic and non-peptidic derivatives of APPA that can target a range of additional pathogenic organisms. Concurrently, we also aim to continue our structure-function studies of several of the biosynthetic enzymes that have been characterized during the initial cycle. Lastly, we will also characterize the mechanisms of resistance that are utilized by the producing organisms and may limit the biological utility of several phosphonates.