Accessing the hidden biosynthetic capabilities of fungi

获取真菌隐藏的生物合成能力

• 批准号: 10728368
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728368
• 关键词: Address; Agriculture; Algorithmic Software; Algorithms; Alkaloids; Alleles; Amino Acids; Architecture; Area; Aspergillus fumigatus; Bacteria; Biochemistry; Bioinformatics; Biological; Biology; Birth; Carbon; Chemicals; Chemistry; Computer software; Coupled; Couples; Cytostatics; Development; Dioxygenases; Enzymes; Exhibits; Family; Foundations; 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; Pathway interactions; Peptides; Pharmaceutical Preparations; Plants; Process; Production; Property; Proteins; Public Health; Research; Signal Induction; Signal Transduction; Signaling Molecule; Structure; Technology; Terpenes; Testing; Work; antimicrobial; comparative; design; fungal genetics; fungus; genome sequencing; grasp; hybrid protein; innovation; insight; isocyanide; metabolomics; novel; promoter; secondary metabolite; tool; transcriptome sequencing; transcriptomics

ABSTRACT 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.

抽象的 丝状真菌通过生物活动产生广阔的次级代谢产物（SM） 对于医学和农业进步而言，这至关重要。例如，真菌短信 表现出细胞抑制，免疫抑制剂，脂质降低或抗菌特性。快速进步 在测序丝状真菌的基因组中，发现了大量推定 没有已知代谢物的生物合成途径，这表明发现了巨大的潜力 新的化合物和活动。但是，对真菌的充分表征的重大障碍 存在BGC多样性：（a）许多SMS由“非传统”生物合成基因簇合成 （BGC）未经生物信息学算法识别，（b）许多BGC并未在标准中表达 实验室条件（例如“隐秘” BGC）和（c）某些生物合成途径的基因不是 所有聚集并涉及一个以上的基因座。此外，（d）对 功能BGC的起源。我们最近的结果清楚地表明，非经典BGC揭示了 真正新颖的结构或异常的生物化学，特定的真菌分化信号 诱导全球BGC表达，重组的“热点”会产生BGC多样性。在 这笔赠款，我们将（i）表征异氰酸酯合酶（ICS）BGC，最近发现的 我们目前的软件算法识别的非规范真菌BGC家族我们 有初步的结果证明了新的和令人兴奋的生物化学，（ii）使用真菌 分化信号，用于对潜水员的“无形” BGC的转录组识别 真菌分类群和（iii）解决了重组基因组“热点”和 水平转移生了新的BGC。基于非规范基因的前提 簇特别可能生产具有高度结构性和的化学实体 功能性新颖性，加上两个能够识别活跃BGC的进步以及BGC的方式 形成的，我们的比较转录组学的工具集，高级内源性和异源 表达平台和最近开发的比较代谢组学平台将 通过提供大量的新结构，生物合成途径和生物学活动 真菌BGC的生物学，遗传学和化学的扩展。而且，洞察BGC 全球BGC感应信号的起源和识别呈现出真正的新过程 进一步，真菌BGC发现和功能注释的范围。