Modular design of central metabolism in methylotrophs

甲基营养菌中枢代谢的模块化设计

• 批准号: 6738204
• 负责人: GREGORY John CROWTHER
• 金额: $ 4.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-12 至 2007-03-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6738204
• 关键词: Methanobacteriaceae; acetyl coA; environmental adaptation; mathematical model; microorganism metabolism; postdoctoral investigator

DESCRIPTION (provided by applicant): This proposal addresses the open question of how central metabolic pathways adapt to changes in environmental and intracellular conditions. A growing body of work suggests that metabolism is organized into functional units, or modules that are selectively activated and suppressed according to the metabolic needs of the cell. The proposed research directly addresses this hypothesis by assessing how changes in the availability of certain nutrients alter the metabolic fluxes within and between modules in a methylotrophic bacterium. Specifically, the aims of this proposal are to (1) predict (with mathematical models) how the central metabolic fluxes of methylotrophic bacteria adjust to environmental changes affecting the production and consumption of acetyl CoA and (2) compare these predictions to empirical measurements of the fluxes. Acetyl CoA is a key metabolic intermediate that links three distinct modules of methylotrophic metabolism; therefore this work should reveal the extent to which a modular view of metabolism (grounded in flux-balance and energy-balance analysis) can explain the observed changes in flux (measured with 13C label tracing). The facultative methylotroph Methylobacterium extorquens AM1 is an attractive model system for this work because (i) the necessary tools are all in hand; (ii) protocols are available to alter metabolic outcomes; and (iii) methylotroph metabolic pathways, when fully understood, could potentially be harnessed to produce commercially important chemicals with a minimum of hazardous waste.

描述（由申请人提供）：该提案解决了中心代谢途径如何适应环境和细胞内条件变化的开放性问题。越来越多的研究表明，代谢被组织成功能单位或模块，这些功能单位或模块根据细胞的代谢需要被选择性地激活和抑制。拟议的研究通过评估某些营养素可用性的变化如何改变甲基营养细菌模块内部和模块之间的代谢通量，直接解决了这一假设。具体来说，本提案的目的是：(1)预测（用数学模型）甲基营养细菌的中心代谢通量如何适应影响乙酰辅酶a生产和消耗的环境变化，(2)将这些预测与通量的经验测量结果进行比较。乙酰辅酶a是连接甲基营养代谢三个不同模块的关键代谢中间体；因此，这项工作应该揭示代谢的模块化观点（以通量平衡和能量平衡分析为基础）在多大程度上可以解释观察到的通量变化（用13C标签追踪测量）。兼性甲基化菌Methylobacterium extorquens AM1是这项工作的一个有吸引力的模型系统，因为(i)必要的工具都在手中；（ii）可用于改变代谢结果的方案；（iii）一旦充分了解甲基化代谢途径，就有可能利用这些途径以最少的危险废物生产具有重要商业意义的化学品。