Identification of Secondary Metabolites and Biosynthesis Pathways in A. nidulans

构巢曲霉次生代谢物和生物合成途径的鉴定

• 批准号: 7501711
• 负责人: CHIA C WANG
• 金额: $ 24.73万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7501711
• 关键词: Anabolism; Aspergillus; Aspergillus nidulans; Biological Factors; Biological Products; Biosynthesis of Secondary Metabolites Pathway; Chemical Structure; Chemicals; Condition; Data; Disease; Fatty-acid synthase; Gene Cluster; Gene Structure; Genes; Genetic; Genome; Genomics; Goals; Hand; Knock-out; Knowledge; Laboratories; Ligase; Lovastatin; Metabolism; Methods; Molds; Molecular Genetics; Mutate; Natural Products Chemistry; Nature; Numbers; Organism; Pathway interactions; Penicillins; Peptides; Process; Production; Range; Regulation; Screening procedure; Source; Sterigmatocystin; Structure; Subgroup; System; Techniques; Translating; analog; base; chemotherapeutic agent; design; drug discovery; experience; fungus; genome sequencing; interest; liquid chromatography mass spectroscopy; multidisciplinary; mutant; novel; novel strategies; novel therapeutics; peptide A; peptide synthase; polyketide synthase; prevent; programs; promoter; research study; synergism; tool; trichodiene synthase

The goal of this Project is to chemically identify each of the 40+ secondary metabolites and their corresponding biosynthetic gene clusters that the fungus Aspergillus nidulans is capable of producing. As the chemical component of this multidisciplinary program project, we will use chemical techniques to identify the compounds that have thus far eluded characterization in A. nidulans. The era of genomics presents a whole new exciting approach for identifying new therapeutic leads. Traditional natural product drug discovery programs in the past few decades have demonstrated that fungi species such as Aspergillus have been a rich source of chemotherapeutic agents against a variety of diseases. The genomes of several Aspergillus species have recently been sequenced and interestingly the genomes revealed a potential to produce surprising large range of natural products many of which are currently unknown. More importantly the species produce compounds that are drastically different from each other suggesting that there is a wealth of natural products yet to be discovered. This discovery will in turn depend on advancements in tools manipulating Aspergillus genetics (Project 1) and understanding of Aspergillus secondary metabolite regulations (Project 2). Our component will involve analyzing the Aspergillus mutants created by the two subgroups. In addition because of our experience in polyketide synthase and nonribosomal synthetase, we will interact with the two subgroups to design experiments to elucidate these currently unknown secondary metabolites. Experimentally we will analyze secondary metabolites produced by A. nidulans strains provided by the Oakley group and Keller group using our Thermofinnigan LCQ. Methods will be developed to isolate newly discovered secondary metabolites and their chemical structures solved using NMR.

该项目的目标是化学鉴定40多种次级代谢产物中的每一种及其 真菌构巢曲霉（Aspergillus nidulans）能够产生相应的生物合成基因簇。为 这个多学科计划项目的化学组成部分，我们将使用化学技术来确定 化合物，迄今为止，在A. nidulans。基因组学时代呈现出一个整体 新的令人兴奋的方法来确定新的治疗线索。传统天然产物药物发现 在过去的几十年里，一些研究项目已经证明，真菌物种，如曲霉菌，是一种丰富的 是治疗多种疾病的化学治疗剂的来源。几种曲霉的基因组 物种最近已经被测序，有趣的是，基因组显示出产生 令人惊讶的大量天然产物，其中许多是目前未知的。更重要的是， 产生的化合物彼此之间有很大的不同，这表明有丰富的天然 产品尚未发现。这一发现将反过来取决于工具的进步， 曲霉菌遗传学（项目1）和曲霉菌次级代谢产物调控的理解（项目 2）。我们的组成部分将涉及分析由两个亚组创建的曲霉突变体。此外 由于我们在聚酮合成酶和非核糖体合成酶方面的经验，我们将与两者相互作用 亚组设计实验，以阐明这些目前未知的次级代谢产物。 在实验上，我们将分析A.提供的nidulans菌株 奥克利组和凯勒组使用我们的Thermofinnigan LCQ。将开发新的分离方法 发现了次级代谢物，并使用NMR解析了它们的化学结构。