Accessing the hidden biosynthetic capabilities of fungi

获取真菌隐藏的生物合成能力

基本信息

批准号：
10539824
负责人：
NANCY P KELLER
金额：
$ 7.51万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10539824
关键词：
Address Agriculture Algorithmic Software Algorithms Alkaloids Alleles Amino Acids Architecture Area Aspergillus fumigatus Award Bacteria Biochemistry Bioinformatics Biological Biology Birth Carbon Chemicals Chemistry Computer software Coupled Couples Cytostatics Development Dioxygenases Enzymes Exhibits Family Foundations Funding Gene Cluster Gene Expression Gene Family Genes Genetic Genetic Recombination Genetic Transcription Genome Genomics Glycols Grant Horizontal Gene Transfer Hot Spot Immunosuppressive Agents Laboratories Lipids Medicine Methodology Methods Mining Molds Natural Products Nature Parents Pathway interactions Peptides Pharmaceutical Preparations Plants Process Production Property Proteins Research Signal Induction Signal Transduction Signaling Molecule Structure Technology Terpenes Testing Work antimicrobial base comparative design fungal genetics fungus genome sequencing grasp hybrid protein innovation insight isocyanide metabolomics novel parent grant promoter tool transcriptome sequencing transcriptomics

项目摘要

Abstract from Parent Grant R01GM112739 Filamentous fungi produce a vast universe of secondary metabolites (SM) with biological activities that are of central importance for progress in medicine and agriculture. For example, fungal SMs exhibit cytostatic, immunosuppressant, lipid lowering, or antimicrobial properties. Rapid progress in sequencing the genomes of filamentous fungi has revealed a very large number of putative biosynthetic pathways with no known metabolites, suggesting a vast potential for the discovery of new compounds and activities. However, significant impediments to full characterization of fungal BGC diversity exist: (a) many SMs are synthesized by ‘non-canonical’ biosynthetic gene clusters (BGCs) not recognized by bioinformatic algorithms, (b) many BGCs are not expressed in standard laboratory conditions (e.g. ‘cryptic’ BGCs), and (c) genes for some biosynthetic pathways are not all clustered and involve more than one locus. Further, there is (d) little understanding of the genesis of functional BGCs. Our recent results clearly indicate that non-canonical BGCs reveal genuinely novel structures or unusual biochemistry, that specific fungal differentiation signals induce global BGC expression and that “hot spots” of recombination generate BGC diversity. In this grant, we will (i) characterize isocyanide synthase (ICS) BGCs, a recently discovered family of noncanonical fungal BGCs not recognized by current software algorithms for which we have preliminary results demonstrating new and exciting biochemistry, (ii) use a fungal differentiation signal for transcriptomic identification of ‘invisible' BGCs across diverse fungal taxa and (iii) address the hypothesis that genomic “hot spots” of recombination and horizontal transfer give birth to new BGCs. Based on the premise that non-canonical gene clusters are particularly likely to produce chemical entities with a high degree of structural and functional novelty coupled with two advances able to identify active BGCs and how BGC are formed, our tool set of comparative transcriptomics, advanced endogenous and heterologous expression platforms and a recently developed platform for comparative metabolomics will provide a wealth of new structures, biosynthetic pathways, and biological activities through expansion of the biology, genetics and chemistry of fungal BGCs. Moreover, insight into BGC genesis and identification of global BGC induction signals present genuinely new processes to further the scope of fungal BGC discovery and functional annotation.

家长资助摘要 R01GM112739 丝状真菌产生大量具有生物活性的次生代谢物（SM）这对于医学和农业的进步至关重要，例如真菌 SM。表现出细胞抑制、免疫抑制剂、降脂或抗菌特性快速进展。在对丝状真菌的基因组进行测序的过程中，我们发现了大量假定的没有已知代谢物的生物合成途径，表明发现的巨大潜力然而，新的化合物和活性对真菌的全面表征存在重大障碍。 BGC 存在多样性：(a) 许多 SM 是由“非规范”生物合成基因簇合成的 (BGC) 未被生物信息学算法识别，(b) 许多 BGC 没有以标准形式表达实验室条件（例如“神秘的”BGC），以及（c）某些生物合成途径的基因不所有这些都聚集在一起并且涉及多个基因座此外，对（d）知之甚少。我们最近的结果清楚地表明，非规范 BGC 揭示了功能性 BGC 的起源。真正新颖的结构或不寻常的生物化学，特定的真菌分化信号诱导全局 BGC 表达，并且重组的“热点”产生 BGC 多样性。这笔资助，我们将 (i) 表征异氰化物合酶 (ICS) BGC，这是最近发现的一种当前软件算法无法识别的非规范真菌 BGC 家族初步结果表明新的和令人兴奋的生物化学，（ii）使用真菌用于转录组识别不同类型“隐形”BGC 的分化信号真菌类群和（iii）解决重组和基因组“热点”的假设水平转移产生新的BGCs的前提是非规范基因。集群特别有可能产生具有高度结构和结构的化学实体功能新颖性加上两个能够识别活跃 BGC 以及 BGC 的方式形成了我们的比较转录组学、高级内源性和异源性工具集表达平台和最近开发的比较代谢组学平台将通过提供丰富的新结构、生物合成途径和生物活性真菌 BGC 的生物学、遗传学和化学的扩展。全球 BGC 感应信号的发生和识别提出了真正的新过程进一步扩大了真菌 BGC 发现和功能注释的范围。