Genomics of Coenzyme Metabolism in Bacterial Pathogens

在过去的十年中，超过200种细菌（包括100多种病原体）的基因组已经变得可用，这带来了巨大的机会。比较基因组学和功能基因组学极大地影响了我们探索代谢和毒力、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。与此同时，大量的序列数据也带来了新的注释挑战。尽管最近取得了进展，但在大多数可用的基因组中，大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个综合的方法来生成可靠和一致的基因组注释，准确地预测在收集的测序基因组。我们的方法结合了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背景分析。在拟议的研究中，我们将应用这种方法来开发三个子系统的综合基因组分析：（1）辅酶A，（2）NAD和NADP，（3）FMN和FAD代谢在各种细菌病原体和细菌。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必不可少。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。准确的全球映射的各个子系统将为我们提供一个功能的背景下，这些目标，并将有助于病原体的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.