Discovery, biosynthesis and bioactivity of phosphonic acid natural products

项目摘要 由稳定的碳-磷(C-P)键的存在定义的磷酸是一种未被开发的 一组具有巨大生物医学前景的化合物，这源于(1)在临床和 商业应用，(2)细胞靶标和作用模式的巨大多样性(3)提供 一套研究工具，可以方便地发现和描述特征，(4)经过验证的新奇、未知的- 类的特征成员，以及(5)其特征增强的不寻常的生物合成途径 并扩大了我们的基础生物化学知识。这项研究项目利用了这些特点-- 产业，重点是具有有用生物活性和有趣的化学特征的磷酸盐天然产物，如 以及新型磷酸盐的发现。该项目的长期目标包括阐明基因， 选择的磷酸盐的生物合成途径、抗性机制和生物活性，以及它们的特性。 与其合成有关的新的酶活性的特化。拟议资金的具体目标 时期为：(1)硫代磷脂及其相关分子的生物合成和生物活性的表征， (2)宿主相关肠杆菌产生的磷酸盐的生物合成和生物活性的表征- Teria，以及(3)发现磷酸盐的改进的基因组挖掘工具的开发。 相关性 这项研究有可能发现具有有用生物活性和趣味性的磷酸盐天然产物。 化学特征。此外，对基因、酶和生物合成途径的表征 这些化合物的生产可能会揭示新的生物化学，大大扩展我们对 由微生物催化的化学转化，同时为创造过度生产的菌株铺平道路 有用的分子及其衍生品。

Project Summary Phosphonic acids, defined by the presence of stable carbon-phosphorus (C-P) bonds, are an underexploited group of compounds with great biomedical promise, which stems from (1) a proven track record in clinical and commercial applications, (2) an immense diversity of cellular targets and modes of action (3) availability of a suite of research tools that allow facile discovery and characterization, (4) a proven reservoir of novel, unchar- acterized members of the class, and (5) unusual biosynthetic pathways whose characterization has enhanced and expanded our knowledge of fundamental biochemistry. This research project takes advantage of these fea- tures, focusing on phosphonate natural products with useful bioactivities and interesting chemical features, as well as the discovery of novel phosphonates. The long-term goals of the project include elucidation of the genes, biosynthetic pathways, resistance mechanisms and bioactivities of selected phosphonates, as well as charac- terization of novel enzymatic activities involved in their synthesis. The specific aims for the proposed funding period are: (1) characterization of the biosynthesis and bioactivity of phosphonothrixin and related molecules, (2) characterization of the biosynthesis and bioactivity of phosphonates produced by host-associated enterobac- teria, and (3) development of improved genome-mining tools for phosphonate discovery. Relevance This research has the potential to discover phosphonate natural products with useful bioactivities and interesting chemical features. Moreover, characterization of the genes, enzymes and biosynthetic pathways needed for production of these compounds is likely to reveal novel biochemistry that significantly expands our understanding of the chemical transformations catalyzed by microbes, while paving the way for creation of strains that overpro- duce useful molecules and their derivatives.