Biosynthesis of marine terpenoid natural products

项目摘要/摘要 来自海洋生物的天然产品继续激发新药的灵感，自2009年以来，已有9种药物获准临床使用 2010年。开发海洋生物衍生生物活性化学品的历史挑战之一是 供应有限。通常，天然药物铅是从稀有或环境敏感的海洋无脊椎动物中分离出来的。 以及藻类，当需求超过自然需求时，这对有前途的候选人的临床前评估提出了挑战 补给。一些陆地植物衍生的药物现在可以在基因工程微生物细胞中生产 工厂，一种对海洋衍生分子有吸引力的方法。然而，生物合成的 负责在海洋动物和藻类中生物合成生物活性天然产物的机械在很大程度上 未知。直到现在。我们已经发现并验证了珊瑚和珊瑚生物合成途径的第一步 藻类中含有6000多种萜类化合物，包括抗炎的伪蝶形物和抗癌物质 光环。我们提出了一个多学科的项目来研究萜类化合物多样化的分子基础。 含有具有良好生物学特性的萜类化合物的海洋真核生物。这将带来重大的后果 研究项目将包括海洋真核生物中萜类生物合成逻辑的新范例，以及 将这一基本知识应用于海洋动物和藻类分子的微生物生产。我们 提出了三个具体目标，即：1)开发海洋真核藻类基因组挖掘平台； 珊瑚；2)对海洋真核生物萜类合成酶进行功能鉴定，以获得高产萜类； 以及3)发现和表征与以下有关的萜类剪裁酶(卤化/氧合) 生物活性珊瑚和藻类天然产物。

Project Summary / Abstract Natural product leads from marine life continue to inspire new drugs, with nine approved for clinical use since 2010. A historical challenge with developing marine organism-derived bioactive chemicals has been one of limited supply. Often, natural drug leads are isolated from rare or environmentally sensitive marine invertebrates and algae, which challenges the pre-clinical evaluation of promising candidates when demands outweigh natural supplies. Some terrestrial plant-derived drugs can now be produced in genetically engineered microbial cell factories, an approach that would be attractive for marine-derived molecules. However, the biosynthetic machinery responsible for the biosynthesis of bioactive natural products in marine animals and algae is largely unknown. Until now. We have discovered and validated the first steps of biosynthetic pathways in corals and algae that lead to over 6,000 terpenoids, including the anti-inflammatory pseudopterosin and anticancer halomon. We propose a multidisciplinary project to investigate the molecular basis of terpenoid diversification in marine eukaryotes that harbor terpenoids with promising biological properties. Significant outcomes of this research project will include a new paradigm for terpenoid biosynthetic logic in marine eukaryotes, and the application of this basic knowledge toward the microbial production of marine animal and algal molecules. We propose three specific aims, namely: 1) To develop a marine eukaryotic genome mining platform for algae and corals; 2) To functionally characterize marine eukaryotic terpene synthases for high yield terpene production; and 3) To discover and characterize terpene tailoring enzymes (halogenation/oxygenation) associated with bioactive coral and algal natural products.