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.

这一研究方案的主要关注点是小说的发现和阐释 复杂和简单生物合成和代谢的生化途径 人体肠道微生物群中的碳水化合物。中包含的基因总数 居住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。这些细菌体内的代谢多样性有助于 对维护人类健康和生理有重大意义。不幸的是，一个重要的 细菌物种中包含的酶和代谢途径的一部分 在人类的肠道中有一个不确定的、未知的或不正确的功能注释。这 不确定性表明，在体内发现的新陈代谢潜力的很大一部分 人类肠道微生物群的特征还有待进一步研究。一种实验方法，用于 复合体代谢新生化途径的发现和阐明 碳水化合物将利用计算生物学的协同和协同利用， 生物信息学、蛋白质三维结构测定、代谢组学和物理学 重点化合物文库的筛选。这项调查将进一步针对 对各种囊膜的组装和生物合成有完整的了解 人类致病主要病原体空肠弯曲菌中的多糖 全球范围的胃肠炎。被膜多糖在侵袭过程中起重要作用。 寄主生物体和组成CPS的单糖在不同种类中的定植 空肠弯曲菌的菌株是不寻常的，也是复杂的。这一努力将集中在阐明 非同寻常的单糖构建块生物合成的分子途径 以及用于定向组装独特的多糖序列的相关分子逻辑 由一系列糖转移酶组成。底物和反应的测定 这些新发现的酶催化反应中包含的多样性将提供 对小说进化和发展的分子机制的独特见解 酶活性，将为治疗干预提供潜在的靶点。