Metabolic and Biosynthetic Engineering of Statin-Producing Filamentous Fungus

描述（由申请人提供）： 天然产物是农业和制药应用中生物活性化合物的极其重要的来源。许多最畅销的药物是天然产品或天然产品的半合成衍生物。丝状真菌构成了人类已知的一些最重要药物的多产者，包括来自Penicillium notatum的青霉素和来自曲霉属物种的他汀类药物。因此，从科学和生物技术的角度来看，工业上重要的丝状真菌的代谢工程是一个有吸引力的研究目标。在这项工作中，我们将代谢和生物合成工程生产的重磅炸弹药物辛伐他汀（佐克）从曲霉土。辛伐他汀在降低胆固醇水平方面非常有效，是世界上最畅销的药物之一，年销售额超过50亿美元。辛伐他汀是一种半合成药物，来源于天然产物洛伐他汀（Mevacor），目前采用低效且费力的多步化学合成法生产。因此，研究新的合成方法，提高辛伐他汀的合成效率，降低生产成本将具有重要意义。本项目将对洛伐他汀产生菌A进行代谢工程改造。terreus直接生物合成辛伐他汀。根据广泛的初步结果，将追求三个具体目标： 目的1：A.用于前体导向生物合成的terreus。 目的2：辛伐他汀前体生物合成的优化。 目的3：A. terreus 这项研究是创新性的，因为代谢工程对生物合成的重磅炸弹药物，如辛伐他汀尚未完成。这项工作将代表一个重要的里程碑，在应用代谢工程和生物合成工程对合成的化合物作为商业上重要的辛伐他汀。该项目的成功结果将导致一个全新的方法生产辛伐他汀，比目前的工艺更有效。除了应用驱动的目标，从这个项目的结果将有助于我们对A的基本理解。土的代谢，蛋白质的结构和功能，以及真菌的生物合成途径。

DESCRIPTION (provided by applicant): Natural products are extremely important sources of bioactive compounds for agricultural and pharmaceutical applications. Many of the top selling drugs are natural products or semisynthetic derivatives of natural product leads. Filamentous fungi constitutes a prolific producer of some of the most important drugs known to human kind, including penicillin from Penicillium notatum and the statins from Aspergillus species. Metabolic engineering of industrially important filamentous fungi is therefore an attractive research goal from both scientific and biotechnological perspectives. In this work, we will metabolically and biosynthetically engineer the production of the blockbuster drug simvastatin (Zocor) from Aspergillus terreus. Simvastatin is highly effective in lowering cholesterol levels and is one of the best selling drugs in the world with annual sales exceeding $5 billion. Simvastatin is a semisynthetic drug derived from the natural product lovastatin (Mevacor) and is currently produced using an inefficient and laborious multistep chemical synthesis. Therefore, new methods that can increase the efficiency of simvastatin synthesis, and decrease the cost of production will be of significant impact. In this project, we will perform metabolic engineering of the lovastatin producer A. terreus towards direct biosynthesis of simvastatin. Based on extensive preliminary results, three specific aims will be pursued: Aim 1: Metabolic Engineering of A. terreus for Precursor-Directed Biosynthesis. Aim 2: Optimization of the Precursor-Directed Biosynthesis of Simvastatin. Aim 3: Biosynthetic Pathway Engineering of A. terreus. The proposed research is innovative because metabolic engineering towards the biosynthesis of a blockbuster drug such as simvastatin has not been accomplished. This work will represent an important milestone in applying metabolic engineering and biosynthetic engineering towards the synthesis of a compound as commercially important as simvastatin. Successful outcome of this project will lead to a completely new method of producing simvastatin that is more efficient than the current processes. In addition to the application-driven goal, results from this project will contribute to our fundamental understanding of A. terreus metabolism, protein structure and function, as well as fungal biosynthetic pathways.