Bacterial Corrinoid Metabolism Across Scales: From Molecular Specificity to Community Dynamics

细菌跨尺度的类咕啉代谢：从分子特异性到群落动态

• 批准号: 10684534
• 负责人: Michiko E. Taga
• 金额: $ 8.35万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684534
• 关键词: Address; Amino Acids; Automobile Driving; Bacteria; Biochemical Pathway; Biochemistry; Bioinformatics; Cobalt; Coenzymes; Communities; Complex; Corrinoids; Development; Environment; Enzymes; Family; Foundations; Funding; Genes; Genetic; Genome; Goals; Health; Human; Human body; Metabolic; Metabolism; Methods; Microbiology; Modeling; Molecular; National Institute of General Medical Sciences; Outcome; Planet Earth; Reaction; Research; Sampling; Specificity; Structure; System; Testing; Vitamin B 12; Work; bioinformatics pipeline; cofactor; design; genetic approach; human model; microbial community; microorganism interaction; nucleobase; predictive signature; preference; programs

Project Summary/Abstract -- No Change Microbial communities inhabit nearly all environments on earth, including the human body, where they can influence health in myriad ways. These communities are often composed of hundreds or more species that form networks of metabolic interactions. Because metabolic interactions are complex and difficult to study at a molecular level, my research program focuses on interactions involving one family of metabolites – corrinoid cofactors – as a model to understand metabolic interactions among bacteria. Corrinoids are the vitamin B12 family of cobalt-containing metabolites that are used as enzyme cofactors for a variety of reactions. Corrinoids, like many amino acids, nucleobases, and other cofactors, are synthesized by only a fraction of bacteria that use them, and therefore are considered to be shared metabolites. Corrinoids are unique in their structural diversity, with over a dozen different forms discovered and up to eight of these forms found in microbial community samples, including the human gut. This structural diversity is a significant factor in microbial interactions because most bacteria are selective in the corrinoids they can use. The hypothesis driving this work is that structurally distinct corrinoids can be used as handles to manipulate microbial communities. Our previous NIGMS-funded research has laid the groundwork for the proposed research by establishing experimental methods; discovering and characterizing new genes; investigating corrinoid selectivity in enzymes, riboswitches, and bacteria; and creating a bioinformatic pipeline to predict corrinoid metabolism in bacteria. Our long-term vision is to build on this foundation to generate a newly detailed understanding of microbial community interactions through the study of corrinoids across scales, from molecular mechanisms to whole community perturbations. We will achieve this goal by (1) identifying genome sequence signatures predictive of bacterial corrinoid preferences in corrinoid-dependent enzymes and riboswitches, with an emphasis on evolutionary approaches and (2) investigating the molecular basis of corrinoid-dependent community dynamics by applying sequencing, culture-dependent, and genetic approaches to a model human gut-derived enrichment culture. As a test of our ability to understand and predict corrinoid-based metabolism and community dynamics, we will design and build bacterial strains with corrinoid-dependent metabolic networks, as well as consortia of bacteria with predictable dynamics. This research will be accomplished by using a combination of genetics, biochemistry, microbiology, and bioinformatics, building upon the past research of my group. Our work on corrinoids will not only serve as a model for microbial community interactions across systems, but may also lead to the development of new methods to alter microbial communities for beneficial outcomes.

项目摘要/摘要--未更改 微生物群落居住在地球上几乎所有的环境中，包括人体，在它们可能的地方 以各种方式影响健康。这些群落通常由数百种或更多物种组成，这些物种 形成代谢相互作用的网络。因为代谢相互作用是复杂的，很难研究 在分子水平上，我的研究项目专注于涉及一种代谢物家族的相互作用- 皮质醇辅因子--作为了解细菌间代谢相互作用的模型。类科里诺是维他命 B12家族的含钴代谢物，用作各种反应的酶辅助因子。 与许多氨基酸、碱基和其他辅因子一样，类胡萝卜素只由一小部分 使用它们的细菌，因此被认为是共同的代谢物。科里诺斯是独一无二的 结构多样性，发现了十几种不同的形式，其中多达八种形式在 微生物群落样本，包括人类肠道。这种结构多样性是一个重要的因素 微生物的相互作用，因为大多数细菌对它们可以使用的Corrinoid是有选择性的。假说 推动这项工作的是结构上不同的Corrinoid可以用作操控微生物的手柄 社区。我们之前由NIGMS资助的研究已经为拟议的研究奠定了基础， 建立实验方法；发现和鉴定新基因；研究皮质醇 酶、核糖开关和细菌的选择性；以及建立预测皮质激素的生物信息学管道 细菌的新陈代谢。我们的长期愿景是在这个基础上产生一个新的详细的 从分子水平跨尺度研究Corrinoid对微生物群落相互作用的理解 整个社区扰乱的机制。我们将通过(1)鉴定基因组序列来实现这一目标 预测皮质醇依赖酶和核糖开关中细菌皮质醇偏好的特征， 强调进化途径和(2)研究皮质激素依赖的分子基础 通过将测序、依赖于文化和遗传的方法应用于模型人类的群落动力学 肠源性浓缩培养。作为对我们理解和预测皮质醇代谢能力的测试 和群落动力学，我们将设计和构建依赖皮质醇代谢的细菌菌株 网络，以及具有可预测动态的细菌联合体。这项研究将是 通过结合遗传学、生物化学、微生物学和生物信息学来完成， 以我的团队过去的研究为基础。我们在Corrinoid上的工作不仅将作为 微生物群落之间的相互作用，但也可能导致新方法的开发 为了有益的结果而改变微生物群落。