Novel Biochemical Pathways for the Metabolism of Carbohydrates in the Human gut Micriobiome

人类肠道微生物组中碳水化合物代谢的新生化途径

基本信息

批准号：
10063528
负责人：
Frank M. Raushel
金额：
$ 30.97万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063528
关键词：
3-Dimensional Amino Acid Sequence Bacteria Bacterial Genome Benchmarking Biochemical Biochemical Pathway Bioinformatics Campylobacter jejuni Candidate Disease Gene Carbohydrate Metabolism Pathway Carbohydrates Cells Complex Computational Biology DNA Library DNA sequencing Development Enzymatic Biochemistry Enzymes Escherichia coli Evolution Gene Cluster Genes Genome Health Homologous Gene Human Human body In Vitro Intestines Investigation Libraries Maintenance Metabolic Metabolic Pathway Metabolism Methods Molecular Pathway interactions Physiology Property Proteins Protocols documentation Reaction Research Research Project Grants Research Proposals Resolution Salmonella enterica Structure Substrate Specificity Therapeutic Intervention Uncertainty base carbohydrate biosynthesis carbohydrate metabolism commensal bacteria gut microbiome human reference genome in vivo insight knockout gene metabolomics novel novel strategies pathogenic bacteria protein structure screening structural biology targeted treatment

项目摘要

The primary focus of this research proposal will be the identification, discovery, and elucidation of novel biochemical pathways for the metabolism of complex carbohydrates in the human gut microbiome. Currently, more than one thousand different bacterial species have been identified in the human intestinal tract and the total number of genes contained within these bacteria exceeds the number of human genes by more than two orders of magnitude. Moreover, it has been demonstrated that the composition of the human gut microbiome and the associated metabolic diversity contained within these bacteria contribute significantly to the maintenance of human health and physiology. Unfortunately, a significant fraction of the enzymes and corresponding metabolic pathways contained within the bacteria found in the human gut have an uncertain, unknown, or incorrect functional annotation. This uncertainty suggests that a substantial fraction of the metabolic potential contained within the human gut microbiome remains to be properly characterized. Our proposed experimental approach for the discovery and elucidation of novel metabolic pathways for the metabolism of complex carbohydrates will involve the concerted and synergistic utilization of bioinformatics, computational biology, three-dimensional protein structure determination, metabolomics and physical screening of focused compound libraries. The determination of the substrate and reaction diversity contained within the newly discovered enzyme-catalyzed reactions will provide unique insights into the molecular mechanisms for the evolution and development of novel enzymatic activities and will provide potential targets for therapeutic intervention.

该研究建议的主要重点是识别，发现和阐明人类复杂碳水化合物代谢的新型生化途径肠道微生物组。目前，已经确定了超过一千种不同的细菌物种人类肠道和这些细菌中包含的基因总数超过人类基因数量的数量超过两个数量级。而且，它已被证明人类肠道微生物组的组成和相关的代谢多样性包含在这些细菌中，对人类健康和生理学的维持产生了重大贡献。不幸的是，大量的酶和相应的代谢途径包含在人肠中发现的细菌中具有不确定，未知或不正确的功能注解。这种不确定性表明，代谢潜力的很大一部分在人类肠道微生物组中，仍有待正确表征。我们提出的实验发现和阐明新型代谢途径的新陈代谢的方法复杂的碳水化合物将涉及生物信息学的一致和协同利用，计算生物学，三维蛋白质结构确定，代谢组学和聚焦化合物库的物理筛选。底物和反应的确定新发现的酶催化反应中包含的多样性将提供独特的对新型酶促的进化和发展的分子机制的见解活动并将为治疗干预提供潜在的目标。