Genomics-Accelerated Discovery and Biosynthesis of Phosphonic Acid Natural Products

项目摘要(未更改) 微生物膦酸是一类尚未被研究的天然产物，在医学上具有重要的用途。这个 许多有用的膦酸的抗微生物、抗病毒和抗疟疾活性来自于有效的和 通过对天然底物的化学模拟，对代谢酶进行特定的抑制。这些属性， 与微生物基因组数据集中编码的新型生物合成基因簇一起，重点是 其潜在的膦酸天然产物为新型抗菌剂。在这个项目中，我们集中精力 通过建立基础遗传和生化来实现这些化合物的基因组潜力 定义了它们的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 对天然产物生物合成的系统水平的理解对于改进发现和工程是必要的 一种新型的膦酸。具体地说，我们研究了最近发现的三个膦酸肽 发现异常的羟化、还原、胺化和氨基酸连接酶，以及分子 它们的抗菌活性的基础。我们扩展和提炼了磷酸天然产物的框架。 基因组学通过从隐蔽的基因簇中分离新化合物，发现新的途径和 C-P键形成的酶，以及改进预测的分类方案的开发 磷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.