Genomics-Accelerated Discovery and Biosynthesis of Phosphonic Acid Natural Products

项目总结（未变更） 微生物膦酸是一类研究较少的天然产物，具有重要的药用价值。的 许多有用的膦酸的抗微生物、抗病毒和抗疟疾活性来源于有效的 通过化学模拟其天然底物来特异性抑制代谢酶。这些属性， 沿着在微生物基因组数据集中编码的新型生物合成基因簇的宝库， 它们是潜在的膦酸类天然产物新的抗菌剂。在这个项目中，我们的努力集中在 通过建立基本的遗传和生物化学机制， 定义其生物合成和生物活性景观的原则。填补这些知识空白将提供一个 对天然产物生物合成的系统级理解是改进发现和工程所必需的 新的膦酸。具体来说，我们研究了三个最近发现的膦酸肽， 发现不寻常的羟基化，还原，胺化和氨基酸连接酶，和分子 基于其抗菌活性。我们扩展和完善了膦酸天然产物的框架 通过从隐藏基因簇中分离新化合物，发现新途径， 酶的C-P键形成，并制定了一个分类方案，以提高预测 膦酸基因簇及其化学产物。

PROJECT SUMMARY (UNCHANGED) Microbial phosphonic acids are a class of understudied natural products with significant utility in medicine. The antimicrobial, antiviral, and antimalarial activity of many useful phosphonic acids derives from potent and specific inhibition of metabolic enzymes through chemical mimicry of their natural substrates. These properties, along with the trove of novel biosynthetic gene clusters encoded within microbial genomic datasets, highlight their potential of phosphonic acid natural products new antimicrobials. In this project we focus our efforts on realizing their genomic potential of these compounds by establishing fundamental genetic and biochemical principles that define their biosynthetic and bioactivity landscape. Filling these gaps in knowledge will provide a systems-level understanding of natural product biosynthesis necessary to improve discovery and engineering of new phosphonic acids. Specifically, we investigate three recently discovered phosphonic acid peptides to uncover unusual hydroxylation, reduction, amination, and amino acid ligation enzymes, and the molecular basis of their antimicrobial activity. We expand and refine the framework for phosphonic acid natural product genomics through the isolation of new compounds from cryptic gene clusters, discovery of new pathways and enzymes for C-P bond formation, and the development of a classification scheme to improve prediction of phosphonic acid gene clusters and their chemical products.