Mining the Aspergillus nidulans Secondary Metabolome

描述（由申请人提供）：本项目的主要目标是利用基因组学、分子遗传学和天然产物化学的协同组合来鉴定和纯化丝状真菌细粒曲霉的潜在有用的次级代谢物。最近公布的三种曲霉的基因组测序显示，这些物种具有惊人的大量次级代谢途径，是新的和有用的天然产物的潜在来源。目前尚不清楚毛竹次级代谢途径的产物，三个研究小组将共同努力，确定和纯化毛竹中每个次级代谢基因簇的产物。项目1由俄亥俄州立大学（Ohio State University）的伯尔·奥克利（Berl Oakley）博士领导，他是项目的总负责人，他将开发系统启动子交换和通过靶向基因替换系统破坏基因的工具。将建立一个完整的带关键非核糖体肽合成酶或聚酮合成酶基因缺失菌株文库。项目2由威斯康星大学的Nancy Keller博士领导，她将专注于染色质突变，以提高最低表达簇的产生，并激活“沉默”簇。项目#3由南加州大学的Clay Wang博士领导，他将专注于从Oakley和Keller实验室分离和鉴定A. nidulans菌株产生的次级代谢物。总之，这一多学科合作将从细粒曲霉中发现新的次生代谢物，并开发可用于挖掘其他真菌物种的次生代谢物的方法，以获得有价值的天然产物。

DESCRIPTION (provided by applicant): The primary goal of this Program Project is to use a synergistic combination of genomics, molecular genetics and natural products chemistry to identify and purify potentially useful secondary metabolites of the filamentous fungus Aspergillus nidulans. The recently published sequencing of genomes of three species of Aspergillus has revealed that these species have a surprisingly large number of secondary metabolism pathways that are potential sources of new and useful natural products. The products of most of the A. nidulans secondary metabolism pathways are currently unknown and the three research groups will work together towards the goal of identifying and purifying the product(s) of each of the secondary metabolism gene clusters in A. nidulans. Project #1 is headed by Dr. Berl Oakley at Ohio State University, the overall P.I., who will develop tools for systematic promoter exchanges and for the systematic disruption of genes through targeted gene replacements. A complete library of A. nidulans strains carrying deletions of key nonribosomal peptide synthetase or polyketide synthase genes will be created. Project #2 is headed by Dr. Nancy Keller at the University of Wisconsin, who will focus on chromatin mutants to enhance the production of minimally expressed clusters and to activate "silent" clusters. Project #3 is headed by Dr. Clay Wang at the University of Southern California, who will focus on isolation and characterization of secondary metabolites produced by A. nidulans strains from the Oakley and Keller laboratories. In summary, this multidisciplinary collaboration will discover new secondary metabolites from Aspergillus nidulans and develop methods that can be used to mine the secondary metabolomes of other species of fungi for valuable natural products. Relevance to public health: The three investigators will use a multi-disciplinary synergistic approach directed towards elucidating the products of previously unexplored secondary metabolite biosynthesis pathways of the organism Aspergillus nidulans. We expect the project to generate a large number of exciting new natural products for testing and development as a new generation of chemotherapeutics, antimicrobials and other medically valuable classes of compounds.