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

项目摘要/摘要 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，形成 代谢相互作用的网络。因为代谢相互作用是复杂的，很难在 在分子水平上，我的研究项目专注于涉及一种代谢物家族-皮质醇的相互作用 辅因子--作为了解细菌间代谢相互作用的模型。类胡萝卜素是维生素B12家族 含有钴的代谢物，用作各种反应的酶辅助因子。科里诺斯，就像 许多氨基酸、碱基和其他辅因子只由一小部分使用 因此被认为是共有的代谢物。科里诺类在结构多样性上是独一无二的， 在微生物群落中发现了十几种不同的形式和多达八种不同的形式 样本，包括人类的内脏。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Corrinoid具有选择性。推动这项工作的假设是，在结构上 不同的Corrinoid可以用作操控微生物群落的把手。我们之前由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 鉴定新基因；研究酶、核糖开关和细菌中皮质醇的选择性；以及 创建一条生物信息学管道来预测细菌中的皮质醇代谢。我们的长期愿景是在 这一基础通过研究产生了对微生物群落相互作用的新的详细了解 从分子机制到整个群落的扰动。我们将实现这一目标 目标通过(1)识别预测皮质类菌偏爱的基因组序列特征- 依赖的酶和核糖开关，重点是进化方法和(2)研究 应用测序、培养依赖和 人类肠源性浓缩培养模型的遗传学方法。作为对我们理解和理解能力的测试 预测基于皮质激素的新陈代谢和群落动态，我们将设计和构建细菌菌株 依赖皮质激素的代谢网络，以及具有可预测动态的细菌联合体。这 研究将通过结合遗传学、生物化学、微生物学和 生物信息学，建立在我的团队过去的研究基础上。我们在Corrinoid方面的工作不仅将作为 微生物群落跨系统相互作用的模型，但也可能导致新的 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.