Role of Bacteria in production of ET-743 in E. turbinata

细菌在 E. turbinata 生产 ET-743 中的作用

• 批准号: 7154441
• 负责人: Margo Genevieve Haygood
• 金额: $ 19.35万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154441
• 关键词: Tunicata; antineoplastics; aquatic organism; biological products; biosynthesis; drug design /synthesis /production; gene expression; marine biology; method development; microorganism culture; microorganism genetics; molecular cloning; symbiosis; water microbiology

DESCRIPTION (provided by applicant): Our long-term objectives are: 1) to investigate the role of microbial symbionts in the biosynthesis of marine natural products, 2) to develop methods to exploit symbionts and their biosynthetic genes for economical and environmentally sound production of drugs derived from marine natural products, and 3) to investigate and exploit biosynthetic pathways of marine microorganisms to produce known and novel structures. Marine invertebrates are rich sources of bioactive metabolites, many of which are excellent candidates for drug development. Lack of supply is one of the most serious barriers to development of many of these compounds. In some cases, bacterial symbionts are hypothesized to be the true biosynthetic source of the compound. ET-743 is an anti-cancer drug from a marine ascidian, Ecteinascidia turbinata, that is suspected to be of symbiotic origin, and which is in Phase II clinical trials. One obstacle to exploring the full potential of ET-743 is lack of supply. Both aquaculture and semi-synthesis have been used to obtain the compound but neither are cost effective. We have developed a biosynthetic scheme for ET-743, based on the nonribosomal peptide synthetase genes for the closely related bacterial compound saframycin MX1 from Myxococcus xanthus. Furthermore, we have identified a bacterial symbiont, the possible source of ET-743, in E. turbinata. Our project aims to solve the supply problem by cultivating the ET-743 producing symbiont and/ or cloning the genes for the biosynthetic pathway to fulfill the long-term goal of expression in a heterologous host. The specific aims are to: 1. Identify, characterize and cultivate the ET-743 producing bacterial symbiont of E. turbinata 2. Identify and clone ET-743 biosynthetic pathway genes.

描述（由申请人提供）：我们的长期目标是：1）研究微生物共生体在海洋天然产物的生物合成中的作用，2）开发方法，开发方法来利用共生体及其生物合成基因，以使其经济和环境合理的药物产生来自海洋天然产品的经济和环境声音，并调查海洋天然生物，以及3）启发性生物剂，以及3）：3）新颖的结构。海洋无脊椎动物是生物活性代谢物的丰富来源，其中许多是药物开发的出色候选者。缺乏供应是许多这些化合物开发的最严重障碍之一。在某些情况下，细菌共生体被认为是该化合物的真正生物合成来源。 ET-743是一种来自海洋海藻ecteinascidia turbinata的抗癌药物，被怀疑是共生的起源，并且正在II期临床试验中。探索ET-743的全部潜力的一个障碍是缺乏供应。水产养殖和半合成都已用于获得该化合物，但都不是具有成本效益的。我们基于来自xanthus粘液中密切相关的细菌化合物Saframycin MX1的非核糖体肽合成酶基因开发了ET-743的生物合成方案。此外，我们已经确定了一个细菌共生体，这是ET-743的可能来源，在E. turbinata中。我们的项目旨在通过培养ET-743产生共生体和/或克隆生物合成途径的基因来解决供应问题，以实现在异源宿主中表达的长期目标。 具体目的是： 1。识别，表征和培养ET-743产生大肠杆菌的细菌共生体 2。识别和克隆ET-743生物合成途径基因。