Rediscovering Natural Chemical Diversity

描述 摘要： 利用具有精致和多样化催化能力的酶，在不同的王国合成了大量复杂的天然产物(NP)。巨大的化学多样性，特别是来自植物和微生物的NPs，有助于NPs显示出广泛的有用的生物活性。总的来说，NP和NP衍生药物对于治疗不同的疾病和预防性地维持健康的生活方式是不可或缺的。由于对现有药物的抗病能力不断增强，以及新药线索的渠道不断减少，我们产生化学多样性的需求变得越来越重要。挖掘化学多样性的最好来源仍然是NPs。虽然从世界上神秘地区发现的生物中传统的、基于表型的NP筛选仍然是新的化学实体的来源，但显然可以利用大量的基因组信息以及化学生物学中的强大工具，从迄今积累的丰富的NP生物合成信息开始，重新发现自然的化学多样性。从本质上说，我们认为，许多已经鉴定和培养的微生物含有比迄今开发的更多的生物合成潜力，而对已知的生物合成酶的操纵将带来比目前更多的多样性。在这项提案中，我们将使用两种方法重新发现大自然的化学多样性。首先，我们将使用基因组学驱动的方法来发现大多数在正常培养条件下由微生物编码但不能合成的NPs。将在本地和异源寄主中开发合成生物学策略，以充分实现 已知生物体的生物合成潜力。其次，我们将开发蛋白质工程策略，以进化已知的生物合成酶，以产生新的化学多样性。三个组成部分

DESCRIPTION Abstract: Using enzymes that possess exquisite and diverse catalytic power, an enormous array of complex natural products (NPs) is synthesized across the different kingdoms. The vast chemical diversity, especially of NPs from plants and microorganisms, contributes to the wide range of useful biological activities displayed by NPs. Collectively, NP and NP-derived drugs have been indispensible towards the treatment of different diseases and the prophylactic maintenance of healthy lifestyle. Due to increasing disease resistance to existing drugs and a dwindling pipeline of new drug leads, our need to generate chemical diversity is becoming ever more important. The best source to mine chemical diversity remains to be from NPs. While traditional, phenotype-based screening of NP from organisms found in esoteric parts of the world continues to be a source of new chemical entities, it has become clear that new approaches using the vast genomic information, as well as powerful tools in chemical biology can be applied towards the rediscovery of natural chemical diversity, starting from the wealth of NP biosynthetic information accumulated to date. Essentially, we believe that many of the microorganisms already identified and cultured contain far more biosynthetic potential than what has been tapped so far, and the manipulation of the known biosynthetic enzymes will lead to even more diversity than currently accessible. In this proposal, we will use two approaches to rediscover the chemical diversity from Nature. First, we will use genomics driven methods to discover the majority of NPs that are encoded, but not synthesized by microorganisms during normal cultivating conditions. Synthetic biology strategies in both the native and heterologous hosts will be developed to fully realize the biosynthetic potential of known organisms. Second, we will develop protein engineering strategy to evolve known biosynthetic enzymes towards generation of new chemical diversity. A three component