The Discovery of Novel Metabolic Pathways for the Biosynthesis and Degradation of Complex Carbohydrates within the Human Gut Microbiome

人类肠道微生物组内复杂碳水化合物生物合成和降解的新代谢途径的发现

• 批准号: 10323657
• 负责人: Frank M. Raushel
• 金额: $ 60.6万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10323657
• 关键词: 3-Dimensional; Anabolism; Bacteria; Biochemical Pathway; Bioinformatics; Campylobacter jejuni; Carbohydrates; Complex; Computational Biology; Development; Enzymes; Evolution; Gastroenteritis; Genes; Health; Human; Investigation; Libraries; Logic; Maintenance; Metabolic; Metabolic Pathway; Metabolism; Molecular; Monosaccharides; Organism; Pathway interactions; Physiology; Polysaccharides; Reaction; Research Proposals; Series; Therapeutic Intervention; Transferase; Uncertainty; enzyme pathway; gut microbiome; host colonization; human pathogen; insight; metabolomics; novel; protein structure; screening; sugar; targeted treatment

The primary focus of this research proposal is the discovery and elucidation of novel biochemical pathways for the biosynthesis and metabolism of complex and simple carbohydrates in the human gut microbiome. The total number of genes contained within the distinct bacterial species that inhabit the human gut exceeds the number of human genes by more than two orders of magnitude. The metabolic diversity within these bacteria contributes significantly to the maintenance of human health and physiology. Unfortunately, a significant fraction of the enzymes and metabolic pathways contained within the bacterial species localized in the human gut have an uncertain, unknown, or incorrect functional annotation. This uncertainty demonstrates that a substantial fraction of the metabolic potential found within the human gut microbiome remains to be properly characterized. The experimental approach for the discovery and elucidation of novel biochemical pathways for the metabolism of complex carbohydrates will employ the concerted and synergistic utilization of computational biology, bioinformatics, three-dimensional protein structure determination, metabolomics, and physical screening of focused compound libraries. This investigation will further be directed towards a complete understanding of the assembly and biosynthesis of the diverse capsular polysaccharides in the human pathogen Campylobacter jejuni, the leading cause of human gastroenteritis world-wide. The capsular polysaccharides are important for the invasion and colonization of the host organism and the monosaccharides that comprise the CPS in various strains of C. jejuni are unusual and complex. This endeavor will focus on the elucidation of the molecular pathways for the biosynthesis of the unusual array of monosaccharide building blocks and the associated molecular logic for the directed assembly of unique polysaccharide sequences by a series of sugar transferase enzymes. The determination of the substrate and reaction diversity contained within these 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.

这项研究计划的主要重点是发现和阐明新的 生物合成和代谢复杂和简单的生化途径 碳水化合物在人体肠道微生物组。基因组中包含的基因总数 栖息在人类肠道中的不同细菌种类超过了人类基因的数量， 超过两个数量级。这些细菌内的代谢多样性 对维持人体健康和生理机能有重要意义。不幸的是， 局部细菌种内所含的酶和代谢途径的比例 具有不确定的、未知的或不正确的功能注释。这 不确定性表明，代谢潜力的很大一部分， 人类肠道微生物组仍有待适当表征。实验方法为 发现和阐明复杂代谢的新生化途径 碳水化合物将采用计算生物学的协调和协同利用， 生物信息学、三维蛋白质结构测定、代谢组学和物理 筛选重点化合物文库。这项调查将进一步针对一个 完整了解不同荚膜的组装和生物合成 多糖在人类病原体空肠弯曲杆菌，人类的主要原因， 全球性的肠胃炎荚膜多糖对于侵袭和 宿主生物体的定殖和构成CPS的单糖在各种环境中的定殖， 梭菌菌株空肠是不寻常的和复杂的。这一奋进将集中在阐明 一系列不寻常的单糖结构单元生物合成的分子途径 以及用于独特多糖序列的定向组装的相关分子逻辑 一系列的糖转移酶。底物和反应的确定 这些新发现的酶催化反应中所包含的多样性将提供 独特的见解的分子机制的进化和发展的新的 酶活性，并将提供潜在的治疗干预的目标。