Symbiosis and Chemical Diversity Generation

项目概要/摘要 该计划侧重于两个相关的科学领域：1）基于假设的方法来发现新的 来自海洋动物的生物合成途径和生物医学上重要的化合物； 2）理解 产生多样性的生物合成并将其应用于合成生物学。 1) 海洋中的动物种类比其他任何地方都多，包括数百万种不同的动物 种。许多海洋动物生活在高度竞争的环境中，因此它们或它们的共生 细菌合成小分子化学防御，已发现其作为 FDA 批准的治疗方法的价值 和铅化合物。它们含有仅在海洋中发现的化学支架，在地球上其他地方都没有。 尽管已经发现了许多重要的海洋动物天然产物，但实际上，生物和 海洋的化学多样性几乎没有受到影响。大多数海洋动物都太小、稀有或 为药物发现和开发提供足够的化合物供应。在研究中将 继续通过这个计划，我们正在消除发现新的潜在药物的障碍， 来自动物的酶和生化途径。我们将采用假设驱动的方法来确定 谁制造海洋天然产品（动物、共生体或其他）以及这些化合物是如何制造的 生物化学上。我们将发现并提供新型化学品和潜在的药物。 2) 动物物种不含有单一的生物活性天然产物，而是含有化合物家族， 个体动物将携带母体结构的变体。在这种化学多样性的基础上，我们有 研究表明，几种生物合成途径具有多样性，能够合成数百万种 衍生物。这种不寻常的可塑性已被用作合成生物学的工具。在其他应用中， 最令人兴奋的事情之一是能够设计化合物，然后在不同的生活环境中生产它们 细胞。例如，编码数百万种非天然天然产物的基因库已经被创建。 另一个用途是为基于细胞的疗法创建设计的细胞。通过更好地理解 产生多样性的生物合成的基础科学，我们正在帮助为这个未来奠定基础。在这里， 通过假设检验，我们将提出有关多样性生成途径的基本问题。在课程中 在这项工作中，我们将立即应用新的配体和化学库进行药物发现和开发。

Project Summary/Abstract This program focuses on two related scientific areas: 1) a hypothesis-based approach to discovering new biosynthetic pathways and biomedically important compounds from marine animals; and 2) understanding diversity-generating biosynthesis and applying it to synthetic biology. 1) There is a greater variety of animal life in the sea than anywhere else, including millions of diverse animal species. Many marine animals live in highly competitive environments, and therefore they or their symbiotic bacteria synthesize small molecule chemical defenses, which have found value as FDA-approved therapeutics and lead compounds. They contain chemical scaffolds found only in the oceans and nowhere else on Earth. Although many important marine animal natural products have been discovered, in reality, the biological and chemical diversity of the oceans has barely been touched. Most marine animals are simply too small, rare, or variable to provide a sufficient supply of compounds for drug discovery and development. In research that will continue through this program, we are eliminating the barriers to discovering new potential pharmaceuticals, enzymes, and biochemical pathways from animals. We will take a hypothesis-driven approach to determine who makes marine natural products (animal, symbiont, or other) and how the compounds are made biochemically. We will discover and provide novel chemicals and potential pharmaceuticals. 2) Instead of containing a single bioactive natural product, species of animals contain families of compounds, where individual animals will harbor variants of a parent structure. Underlying this chemical diversity, we have shown that several biosynthetic pathways are diversity generating, capable of synthesizing millions of derivatives. This unusual plasticity has been applied as a tool for synthetic biology. Among other applications, one of the most exciting is the ability to design compounds and then produce them in different kinds of living cells. For example, genetic libraries encoding millions of unnatural natural products have already been created. Another use would be in the creation of designed cells for cell-based therapies. By better understanding the basic science of diversity-generating biosynthesis, we are helping to set the groundwork for this future. Here, using hypothesis testing, we will ask fundamental questions about diversity-generating pathways. In the course of this work, we will immediately apply new ligands and chemical libraries for drug discovery and development.