Modular design of central metabolism in methylotrophs

描述(由申请人提供)：这项建议解决了中央代谢途径如何适应环境和细胞内条件的变化这一开放的问题。越来越多的研究表明，新陈代谢被组织成功能单位，或根据细胞的新陈代谢需求选择性地激活和抑制的模块。拟议的研究通过评估某些营养物质的可获得性的变化如何改变甲基营养细菌模块内和模块之间的代谢通量，直接解决了这一假说。具体地说，这项提议的目的是(1)(用数学模型)预测甲基营养细菌的中心代谢通量如何适应影响乙酰辅酶A生产和消费的环境变化，以及(2)将这些预测与通量的经验测量进行比较。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模块视图(以通量平衡和能量平衡分析为基础)在多大程度上能够解释观察到的通量变化(用13C标记示踪法测量)。对于这项工作，兼性甲基细菌是一个有吸引力的模型系统，因为(1)所有必要的工具都在手中；(2)可用来改变代谢结果的方案；(3)当充分了解甲基细菌代谢途径时，可能被利用来生产具有商业重要性的化学品，并将危险废物降至最低。

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.