Institute of Molecular Systems Biology, ETH Zürich, Zürich, 8093, Switzerland.
Nat Commun. 2019 Jul 26;10(1):3354. doi: 10.1038/s41467-019-11331-5.
How microbes dynamically coordinate uptake and simultaneous utilization of nutrients in complex nutritional ecosystems is still an open question. Here, we develop a constraint-based modeling approach that exploits non-targeted exo-metabolomics data to unravel adaptive decision-making processes in dynamic nutritional environments. We thereby investigate metabolic adaptation of Escherichia coli to continuously changing conditions during batch growth in complex medium. Unexpectedly, model-based analysis of time resolved exo-metabolome data revealed that fastest growth coincides with preferred catabolism of amino acids, which, in turn, reduces glucose uptake and increases acetate overflow. We show that high intracellular levels of the amino acid degradation metabolites pyruvate and oxaloacetate can directly inhibit the phosphotransferase system (PTS), and reveal their functional role in mediating regulatory decisions for uptake and catabolism of alternative carbon sources. Overall, the proposed methodology expands the spectrum of possible applications of flux balance analysis to decipher metabolic adaptation mechanisms in naturally occurring habitats and diverse organisms.
微生物如何在复杂的营养生态系统中动态协调养分的摄取和同时利用仍然是一个悬而未决的问题。在这里，我们开发了一种基于约束的建模方法，该方法利用非靶向外代谢组学数据来揭示动态营养环境中的适应性决策过程。我们从而研究了大肠杆菌在复杂培养基中分批培养过程中对不断变化的条件的代谢适应。出乎意料的是，基于模型的时间分辨外代谢组学数据分析显示，最快的生长与氨基酸的首选分解代谢相吻合，这反过来又减少了葡萄糖的摄取并增加了乙酸盐的溢出。我们表明，氨基酸降解代谢物丙酮酸和草酰乙酸的高细胞内水平可以直接抑制磷酸转移酶系统（PTS），并揭示它们在介导对替代碳源的摄取和分解代谢的调节决策中的功能作用。总的来说，所提出的方法扩展了通量平衡分析在破译自然发生的栖息地和不同生物体中的代谢适应机制的可能应用范围。
