Genomics of Coenzyme Metabolism in Bacterial Pathogens

细菌病原体辅酶代谢的基因组学

• 批准号: 7414783
• 负责人: ANDREI L OSTERMAN
• 金额: $ 40.52万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414783
• 关键词: Anabolism; Animal Model; Anti-Infective Agents; Bacteria; Biochemical Genetics; Biochemical Reaction; Bioinformatics; Biological Assay; Candidate Disease Gene; Categories; Classification; Coenzyme A; Coenzymes; Collaborations; Collection; Communicable Diseases; Data; Drug Delivery Systems; Enzymes; Flavin Mononucleotide; Gene Family; Generations; Genes; Genetic; Genetic Techniques; Genome; Genomic Library; Genomics; Glutaminase; Goals; In Vitro; Knowledge; Life; Maps; Metabolic; Metabolic Pathway; Metabolism; Microbial Physiology; Modeling; Motivation; NAD synthase; NADP; National Institute of Allergy and Infectious Disease; Nicotinamide adenine dinucleotide; Numbers; Organism; Pathway interactions; Phosphoric Monoester Hydrolases; Process; Protein Family; Protein Overexpression; Proteins; Protocols documentation; Pyrimidine; Pyrimidines; Recycling; Research Project Grants; Riboflavin; Role; Screening procedure; Techniques; Testing; Time; Validation; Variant; Virulence; comparative; functional genomics; gene cloning; genome sequencing; in vivo; insight; microbial; nicotinamidenucleotide amidase; novel; pathogen; pathogenic bacteria; reconstruction; research study; tool

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.

描述（由申请人提供）：在过去的十年中，已获得200多种细菌（包括100多种病原体）的基因组，开辟了巨大的机会。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的其他重要方面之间联系的能力。同时，序列数据的雪崩带来了新的注释挑战。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存在错误或不恰当的注释。提出的跨学科研究项目的动机之一是建立一种综合方法，以产生可靠和一致的基因组注释，准确地投影了测序基因组的收集。我们的方法将优化的实验验证策略与生物信息学技术，代谢子系统的重建以及基因组上下文分析相结合。在拟议的研究中，我们将采用这种方法来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）在多种细菌病原体和儿童中的FMN和FAD代谢。我们将通过多种生化和遗传技术来验证选定的基因分配，基本途径及其组合（功能变体）。为我们的研究选择的辅酶参与数百种生化反应和调节过程，并且在各种形式的细胞生活中都是必不可少的。我们以前的研究涉及几种与其生物合成有关的关键酶作为潜在的抗感染药物靶标。相应子系统的准确全球映射将为我们提供此类目标的功能环境，并有助于对病原体中核心代谢的基本理解。