Genomics of Coenzyme Metabolism in Bacterial Pathogens

描述（由申请人提供）：在过去十年中，200多种细菌（包括100多种病原体）的基因组已经可用，这带来了巨大的机会。比较和功能基因组学强烈影响我们探索代谢与毒力、宿主-病原体相互作用以及传染病其他重要方面之间联系的能力。同时，序列数据的雪崩给标注带来了新的挑战。尽管最近取得了进展，但大多数可用基因组中的大部分基因仍然存在不正确或不精确的注释。提出的跨学科研究项目的动机之一是建立一种综合方法来生成可靠和一致的基因组注释，准确地投影在测序基因组的集合上。我们的方法将优化的实验验证策略与生物信息学技术、代谢子系统重建和基因组上下文分析相结合。在本研究中，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)各种细菌病原体和共生体中的FMN和FAD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、基本途径及其组合（功能变体）。我们研究中选择的辅酶参与了数百种生化反应和调节过程，并且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，一些关键的酶参与了它们的生物合成，作为潜在的抗感染药物靶点。对各自子系统的精确全局映射将为我们提供这些靶点的功能背景，并将有助于对病原体核心代谢的基本理解。

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.