Investigating Microbial Natural Product Biosynthesis

微生物占据了地球上的每一个栖息地，并具有惊人的代谢多样性。这种代谢能力在自然界中被用来驱动生物地球化学循环，并被人类用于绿色化学、生物修复和生产抗生素等化学品。虽然微生物在环境和人类健康中的关键作用日益明显，但由于我们无法培养它们，长期以来对其特征的描述和充分利用一直受到限制。事实上，只有不到1%的微生物可以在实验室培养中生长，这表明微生物代谢多样性的巨大储存库尚未开发。从环境样本中分离总DNA，并在可培养的细菌宿主中表达这些基因（宏基因组学），可以捕获这个储存库，并提供以前未知的微生物酶和小分子的途径，这些酶和小分子有可能解决人类健康、能源、农业和环境方面的社会挑战。在这些挑战中，发现新的生物活性有机磷化合物是一个重要的目标，可以通过了解磷酸盐生物合成的微生物策略来实现。提出的研究计划的长期目标是发现新的小分子和由未培养的微生物编码的生物合成酶。提出的研究的直接目标是发现含有C-P键的小分子（膦酸盐/膦酸盐）并表征参与其生物合成的酶。膦酸盐是用作除草剂和抗生素的小分子天然产物，但已知的天然膦酸盐相对较少。提出的研究旨在确定具有潜在应用于农业和医学的新型膦酸盐，并发现能够用于生物催化和绿色化学应用的新酶。

Microorganisms occupy every habitat on earth and possess an astounding array of metabolic diversity. This metabolic power is used in Nature to drive biogeochemical cycles, and has been harnessed by humans for green chemistry, bioremediation, and the production of chemicals such as antibiotics. Although the crucial role of microbes in the environment and human health is increasingly apparent, characterizing and exploiting their full potential has long been limited by our inability to culture them. Indeed, less than 1% of microorganisms may be grown in laboratory culture, indicating that a vast reservoir of microbial metabolic diversity remains untapped. Isolating total DNA from an environmental sample and expressing these genes in a cultivable bacterial host (metagenomics) can capture this reservoir and provide access to previously unknown microbial enzymes and small molecules with potential to address societal challenges in human health, energy, agriculture, and the environment. Among such challenges, discovering new bioactive organophosphorus compounds is an important goal that can be realized by understanding microbial strategies of phosphonate biosynthesis. The long-term objective of the proposed research program is to discover novel small molecules and biosynthetic enzymes encoded by uncultivated microorganisms. The immediate goals of the proposed research are to discover C-P bond-containing small molecules (phosphonates/phosphinates) and characterize the enzymes involved in their biosynthesis. Phosphonates are small molecule natural products used as herbicides and antibiotics, but relatively few natural phosphonates are known. The proposed research aims to identify novel phosphonates with potential applications in agriculture and medicine, and uncover new enzymes capable of being exploited for biocatalysis and green chemistry applications.