Genomics-Accelerated Discovery and Biosynthesis of Phosphonic Acid Natural Products

基因组学-膦酸天然产物的加速发现和生物合成

基本信息

批准号：
10260569
负责人：
Kou-San Ju
金额：
$ 30.6万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10260569
关键词：
Actinobacteria class Acute Agriculture Amination Amino Acids Anabolism Antibiotics Antimalarials Antimicrobial Resistance Antiviral Agents Arginine Biochemical Biochemistry Biological Biotechnology Carbon Chemicals Classification Classification Scheme Communicable Diseases DNA Sequence Development Dwarfism Engineering Enzymatic Biochemistry Enzymes Esters Family Future Gene Cluster Genetic Genetic Variation Genome Genomics Goals Health Heme Human Hydroxylation Infection Knowledge Ligase Ligation Medicine Metabolic Mining Modification Molecular Molecular Target Natural Products Nature Outcome Oxidoreductase Pathway interactions Peptides Phosphonic Acids Phosphorus Property Research Route Source Stream Structure Substrate Specificity System Transfer RNA antimicrobial chemical genetics drug development effective therapy genomic data grasp human mortality improved innovation insight interest microbial microbial genome microbial genomics mimicry multi-drug resistant pathogen novel pharmacophore phosphonate public repository response

项目摘要

PROJECT SUMMARY 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.

项目概要微生物膦酸是一类尚未得到充分研究的天然产物，在医学上具有重要用途。这许多有用的膦酸的抗菌、抗病毒和抗疟活性源自有效且通过化学模拟代谢酶的天然底物来特异性抑制代谢酶。这些属性，连同微生物基因组数据集中编码的大量新型生物合成基因簇，突出显示他们的膦酸天然产物具有新型抗菌剂的潜力。在这个项目中，我们的重点是通过建立基本的遗传和生化基础来实现这些化合物的基因组潜力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对天然产物生物合成的系统级理解对于改进发现和工程是必要的新型膦酸。具体来说，我们研究了三种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，以及分子其抗菌活性的基础。我们扩展和完善了膦酸天然产物的框架基因组学通过从神秘基因簇中分离新化合物、发现新途径和用于 C-P 键形成的酶，以及开发分类方案以改进预测膦酸基因簇及其化学产品。