Chemoenzymatic analysis of bryostatin biosynthesis

苔藓抑素生物合成的化学酶分析

• 批准号: 7076825
• 负责人: NICOLE Beth LOPANIK
• 金额: $ 5.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076825
• 关键词: Invertebrata; animal extract; bacteria; bacterial genetics; bryostatin; host organism interaction; microorganism culture; microorganism metabolism; polyketide synthase; postdoctoral investigator; symbiosis

DESCRIPTION (provided by applicant): Bryostatins are polyketide secondary metabolites isolated from the marine bryozoan Bugula neritina. Bryostatin 1 is a very promising anti-cancer drug, and is currently undergoing Phase II clinical trials. Unfortunately, bryostatin concentrations in B. neritina are very low and, to date, there are no chemical synthetic alternatives, requiring the harvest of large amounts of the animal to obtain sufficient quantities of bryostatin for biotesting. Recent research has revealed that the bryostatins are produced by the bacterial endosymbiont, Endobugula sertula, but attempts to culture the microbe have not been successful. Consequently, the latest research effort has resulted in the identification of a polyketide synthase (PKS) gene cluster from symbiont-enriched DMA that may be responsible for bryostatin biosynthesis. However, as the organism cannot be cultured, mutation and complementation experiments that can verify whether this cluster produces bryostatin cannot be conducted. In this project, I propose to use in vitro studies with purified putative bryostatin PKS modules to determine whether this gene cluster is in fact responsible for the production of bryostatin. This research may lead to production of bryostatin by a heterologous host.

描述（由申请人提供）：苔藓抑素是从海洋苔藓动物 Bugula neritina 中分离出来的聚酮化合物次生代谢物。 Bryostatin 1是一种非常有前途的抗癌药物，目前正在进行II期临床试验。不幸的是，B. neritina 中的苔藓抑素浓度非常低，并且迄今为止还没有化学合成替代品，需要收获大量动物以获得足够量的苔藓抑素用于生物测试。最近的研究表明，苔藓抑素是由细菌内共生体 Endobugula sertula 产生的，但培养这种微生物的尝试尚未成功。因此，最新的研究成果从富含共生体的 DMA 中鉴定出聚酮合酶 (PKS) 基因簇，该基因簇可能负责苔藓抑素的生物合成。然而，由于该生物体无法培养，因此无法进行突变和互补实验来验证该簇是否产生苔藓抑素。在这个项目中，我建议使用纯化的假定苔藓抑素 PKS 模块进行体外研究，以确定该基因簇是否实际上负责苔藓抑素的产生。这项研究可能导致异源宿主产生苔藓抑素。