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

项目概要/摘要 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 代谢相互作用网络。因为代谢相互作用非常复杂且难以在实验室进行研究 分子水平上，我的研究项目侧重于涉及一个代谢物家族——类咕啉的相互作用 辅助因子——作为了解细菌之间代谢相互作用的模型。类咕啉属于维生素 B12 家族 用作各种反应的酶辅因子的含钴代谢物。类咕啉，如 许多氨基酸、核碱基和其他辅助因子仅由一小部分细菌合成，这些细菌使用 它们，因此被认为是共享代谢物。类咕啉的结构多样性是独一无二的， 发现了十多种不同的形式，其中在微生物群落中发现了多达八种形式 样本，包括人类肠道。这种结构多样性是微生物相互作用的一个重要因素，因为 大多数细菌对它们可以使用的类咕啉具有选择性。推动这项工作的假设是结构上 不同的类咕啉可用作操纵微生物群落的手柄。我们之前的 NIGMS 资助的 研究通过建立实验方法为拟议的研究奠定了基础；发现 并表征新基因；研究类咕啉在酶、核糖开关和细菌中的选择性；和 创建生物信息管道来预测细菌中的类咕啉代谢。我们的长期愿景是建立在 该基础旨在通过研究对微生物群落相互作用产生新的详细了解 从分子机制到整个群落扰动，跨尺度的类咕啉。我们将实现这一目标 通过（1）识别预测细菌类咕啉偏好的基因组序列特征来实现目标- 依赖酶和核糖开关，重点是进化方法和（2）研究 通过应用测序、培养依赖和 人类肠道来源的富集培养模型的遗传方法。作为对我们理解和理解能力的考验 预测基于类咕啉的代谢和群落动态，我们将设计和构建细菌菌株 类咕啉依赖性代谢网络，以及具有可预测动态的细菌群落。这个 研究将通过结合遗传学、生物化学、微生物学和 生物信息学，建立在我的小组过去的研究基础上。我们在类咕啉方面的工作不仅可以作为 跨系统微生物群落相互作用的模型，但也可能导致新的开发 改变微生物群落以获得有益结果的方法。

Project Summary/Abstract 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.