ROLE OF BACTERIA IN THE PRODUCTION OF BRYOSTATINS

描述(逐字摘自申请者的摘要)：在许多情况下很自然 已知或怀疑来自海洋无脊椎动物的产品是生物合成的 细菌共生体。海洋苔藓虫Bugula neritina是 苔藓他汀类化合物是一类独特的具有抗癌活性的化合物。胡麻B. 海藻中含有一种特殊的细菌共生体“Candidatus Endobugula sertula”。 我们推测Bryostatins在B.neritina中的生物合成来源是 细菌共生菌“念珠菌内生锯齿假丝酵母” 我们的长期目标是：1)研究微生物共生体的作用 在海洋天然产物的生物合成方面，2)开发方法以 利用共生菌及其生物合成基因开发经济和 从海洋天然产品中提取的药物的无害环境生产， 3)研究和开发海洋生物合成途径。 微生物产生已知的和新的结构。 具体目的是：1)确定苔藓他汀类药物的生物合成来源 在B.neritina。2)克隆比他汀类药物的生物合成基因 在异源宿主中表达它们。3)培养任何细菌共生体 被鉴定为苔藓抑素的来源并诱导苔藓抑素的表达 文化中的生产。 苔藓他汀类化合物是一种复杂的多酮化合物，是一种含有许多 具有多种有效生物活性的化合物。苔藓他汀类药物有 治疗癌症和其他疾病的潜力；bryostatin 1处于开发阶段 癌症治疗的临床试验。发展的主要障碍是 苔藓他汀类药物供应不足。我们的项目旨在通过以下两种方式解决这个问题 1)克隆生物合成途径的基因，并在 异源宿主，或2)培养产生苔藓抑素的共生菌。 研究方法将是将Bryostatin的生物合成定位在 苔藓虫，克隆聚酮合成酶基因，并在链霉菌中表达 主持人。此外，我们将使用一种新的方法来优化种植 培养上清分离锯缘棘球绦虫的条件。

DESCRIPTION (verbatim from applicant's abstract): In many cases natural products from marine invertebrates are known or suspected to be biosynthesized by bacterial symbionts. The marine bryozoan Bugula neritina is the source of the bryostatins, a unique family of compounds with anticancer activity. B. neritina harbors a specific bacterial symbiont "Candidatus Endobugula sertula." We hypothesize that the biosynthetic source of bryostatins in B. neritina is the bacterial symbiont "Candidatus Endobugula sertula." 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. The specific aims are: 1) to determine the biosynthetic origin of bryostatins in B. neritina. 2) To clone the biosynthetic genes for byrostatins in and express them in a heterologous host. 3) To cultivate any bacterial symbionts identified as a source of bryostatins and induce expression of bryostatin production in culture. The bryostatins are complex polyketides, a chemical family that contains many compounds with diverse and potent biological activities. The bryostatins have potential for treatment of cancer and other diseases; bryostatin 1 is in Phase II clinical trials for cancer treatment. The chief obstacle to development of bryostatins is lack of supply. Our project aims to solve this problem by either 1) cloning the genes for the biosynthetic pathway and expressing them in a heterologous host, or 2) cultivating a bryostatin-producing symbiont. The research approach will be to localize bryostatin biosynthesis within the bryozoan, clone polyketide synthase genes, and express them in a Streptomyces host. In addition, we will use a novel approach to optimize cultivation conditions to isolate "E. sertula" in culture.