Genomics of Coenzyme Metabolism in Bacterial Pathogens

描述(申请人提供)：在过去的十年里，已经有200多种细菌(包括100多种病原体)的基因组可用，这带来了巨大的机会。比较基因组学和功能基因组学强烈影响我们探索新陈代谢和毒力之间的联系、宿主-病原体相互作用以及传染病的其他重要方面的能力。与此同时，序列数据的雪崩也带来了新的注解挑战。尽管最近取得了进展，但大多数可用基因组中的很大一部分基因仍然被错误或不精确地注释。拟议的跨学科研究项目的动机之一是建立一种综合方法，以生成可靠和一致的基因组注释，准确地投影到已测序的基因组集合中。我们的方法将优化的实验验证策略与生物信息学技术、代谢子系统的重建和基因组上下文分析结合在一起。在拟议的研究中，我们将应用这种方法对三个子系统进行全面的基因组分析：(1)辅酶A，(2)NAD和NADP，以及(3)FMN和FAD在各种细菌病原体和共生体中的代谢。我们将通过各种生化和遗传技术验证选定的基因分配、基本途径和它们的组合(功能变体)。为我们的研究选择的辅酶参与了数百种生化反应和调节过程，在所有形式的细胞生命中都是必不可少的。我们之前的研究表明，参与其生物合成的几种关键酶是潜在的抗感染药物靶点。各个子系统的准确全球图谱将为我们提供这些靶点的功能背景，并将有助于从根本上理解病原体的核心代谢。

DESCRIPTION (provided by applicant): In the last decade, genomes of more than 200 bacteria (including more than 100 pathogens) have become available, opening tremendous opportunities. Comparative and functional genomics strongly impact our ability to explore connections between metabolism and virulence, host-pathogen interactions, and other important aspects of infectious diseases. At the same time, the avalanche of sequence data has created a new annotation challenge. In spite of recent progress, a large fraction of genes in most of the available genomes remains incorrectly or imprecisely annotated. One of the motivations of the proposed cross-disciplinary research project is to establish an integrated approach to generate reliable and consistent genomic annotations accurately projected over the collection of sequenced genomes. Our approach combines an optimized experimental validation strategy with bioinformatics techniques, reconstruction of metabolic subsystems, and genome context analysis. In the proposed study, we will apply this approach to develop a comprehensive genomic analysis of three subsystems: (1) Coenzyme A, (2) NAD and NADP, and (3) FMN and FAD metabolism in a variety of bacterial pathogens and commensals. We will validate selected gene assignments, elementary pathways, and their combinations (functional variants) by a variety of biochemical and genetic techniques. The coenzymes chosen for our study are involved in hundreds of biochemical reactions and regulatory processes, and are essential in all forms of cellular life. Our previous studies implicated several key enzymes involved in their biosynthesis as potential anti-infective drug targets. Accurate global mapping of the respective subsystems will provide us with a functional context for such targets and will contribute to the fundamental understanding of core metabolism in pathogens.