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Biosynthesis of marine terpenoid natural products

海洋萜类天然产物的生物合成

基本信息

批准号：
10737210
负责人：
GEOFFREY A CHANG
金额：
$ 50.4万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737210
关键词：
Acceleration Address Algae Anabolism Animals Anti-Inflammatory Agents Antineoplastic Agents Bacteria Biochemical Reaction Biochemistry Biological Biomedical Engineering Biotechnology Calculi Cells Chemicals Chemistry Clinical Collection Communicable Diseases Complex Crystallography Cytochrome P450 Development Diphosphates Environment Enzymatic Biochemistry Enzymes Escherichia coli Eukaryota Evaluation Family Fermentation Gene Cluster Genes Genetic Engineering Genome Genomics Goals Isoprene Knowledge Laboratories Life Link Logic Malignant Neoplasms Marine Invertebrates Medicine Methods Microbe Microbial Genetics Mining Modernization Molecular Natural Product Drug Natural Products Outcomes Research Pain Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Plants Production Property Protein Biochemistry Protein Overexpression Proteins Recombinant Proteins Red Algae Research Research Project Grants Resources Role Science Scientist Structure Terpenes Terpenoid Biosynthesis Pathway Vanadium Vertebral column Work X-Ray Crystallography Yeasts anti-cancer bioactive natural products coral deep ocean drug development drug discovery enzyme biosynthesis fascinate frontier halogenation manufacture marine marine natural product marine organism metabolomics microbial multidisciplinary novel therapeutics preclinical evaluation programs pseudopterosins public health relevance scaffold synthetic biology terpene synthase tool transcriptomics

项目摘要

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.

项目总结/摘要来自海洋生物的天然产物继续激发新药，自2009年以来，已有9种药物被批准用于临床。 2010.开发海洋生物衍生的生物活性化学品的历史挑战之一是供应有限。通常，天然药物先导物是从稀有或环境敏感的海洋无脊椎动物中分离出来的和藻类，当需求超过天然时，这对有希望的候选物的临床前评估提出了挑战用品.一些陆生植物源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，生物合成在海洋动物和藻类中负责生物活性天然产物生物合成的机制主要是未知到现在我们已经发现并验证了珊瑚生物合成途径的第一步，藻类，导致超过6,000萜类化合物，包括抗炎假蝶呤和抗癌哈洛蒙。我们提出了一个多学科的项目，调查萜类多样化的分子基础，含有具有生物学特性的萜类化合物的海洋真核生物。这一重大成果研究项目将包括一个新的范例萜类生物合成逻辑在海洋真核生物，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）开发海洋藻类真核基因组挖掘平台， 2）研究海洋真核生物萜烯脱氢酶的功能特性，以获得高产萜烯; 和3）发现和表征与以下相关的萜烯剪裁酶（卤化/氧化）：生物活性珊瑚和藻类天然产品。