Rediscovering Natural Chemical Diversity

描述 摘要： 利用具有精致和多样催化能力的酶， 复杂的天然产物（NP）是在不同的界中合成的。绝 化学多样性，特别是来自植物和微生物的NP，有助于广泛的 纳米颗粒显示的一系列有用的生物活性。NP和NP衍生药物 对不同疾病的治疗和预防都是必不可少的 保持健康的生活方式。 由于疾病对现有药物的耐药性不断增加， 我们对化学多样性的需求变得越来越重要。最好的 开采化学多样性的来源仍然是纳米颗粒。虽然传统的基于表型的 从世界上神秘地区发现的生物体中筛选NP仍然是 新的化学实体，很明显，使用大量基因组的新方法 信息，以及强大的工具，在化学生物学可以应用于 重新发现天然化学多样性，从丰富的NP生物合成开始 到目前为止积累的信息。基本上，我们认为许多微生物 已经被鉴定和培养的生物合成潜力远远超过 到目前为止，已知的生物合成酶的操纵将导致更多的 多样性，比目前的。 在这个建议中，我们将使用两种方法来重新发现自然界的化学多样性。 首先，我们将使用基因组学驱动的方法来发现大多数编码的NP， 在正常培养条件下微生物不能合成。合成生物学 将开发在天然和异源宿主中的策略，以充分实现 已知生物体的生物合成潜力。第二，我们将发展蛋白质工程 进化已知的生物合成酶以产生新的化学多样性的策略。一 将构建三组分代谢物敏感电路， 代谢物结构多样性与细胞表型的关系。我们在此提议的工作将 充分收获和扩大大自然中惊人的化学多样性。

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 metabolite-sensitive circuitry will be constructed to allow coupling of metabolite structure diversity to cellular phenotype. Together, our proposed work here will fully harvest and expand the amazing chemical diversity present in Mother Nature.