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——无变化 微生物群落几乎栖息在地球上的所有环境中，包括人体，在那里它们可以 以多种方式影响健康。这些群落通常由数百个或更多物种组成 形成代谢相互作用的网络。因为代谢相互作用很复杂且难以研究 在分子水平上，我的研究项目侧重于涉及一个代谢物家族的相互作用 - 类咕啉辅助因子——作为了解细菌之间代谢相互作用的模型。类咕啉是维生素 B12 家族含钴代谢物，用作多种反应的酶辅因子。 类咕啉与许多氨基酸、核碱基和其他辅助因子一样，仅由一小部分合成 使用它们的细菌，因此被认为是共享代谢物。 Corrinoids 的独特之处在于 结构多样性，发现了十多种不同的形式，并且在其中发现了多达八种形式 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因素 微生物相互作用，因为大多数细菌对它们可以使用的类咕啉具有选择性。假设 推动这项工作的原因是结构上不同的咕啉可以用作操纵微生物的手柄 社区。我们之前由 NIGMS 资助的研究为拟议的研究奠定了基础 建立实验方法；发现和表征新基因；研究类咕啉 酶、核糖开关和细菌的选择性；并创建生物信息学管道来预测类咕啉 细菌中的新陈代谢。我们的长期愿景是在此基础上生成一个新的详细的 通过跨尺度的类咕啉研究，从分子层面了解微生物群落的相互作用 整个社区扰动的机制。我们将通过（1）识别基因组序列来实现这一目标 预测细菌类咕啉依赖性酶和核糖开关中类咕啉偏好的特征， 重点是进化方法和（2）研究类咕啉依赖性的分子基础 通过对人类模型应用测序、文化依赖和遗传方法来实现群落动态 肠道来源的富集培养。作为对我们理解和预测类咕啉代谢能力的测试 和群落动态，我们将设计和构建具有类咕啉依赖性代谢的细菌菌株 网络以及具有可预测动态的细菌联盟。这项研究将 通过结合遗传学、生物化学、微生物学和生物信息学来完成， 以我的小组过去的研究为基础。我们对类咕啉的研究不仅可以作为模型 跨系统的微生物群落相互作用，但也可能导致新方法的开发 改变微生物群落以获得有益的结果。