San Román Magdalena, Cancela Héctor, Acerenza Luis
Systems Biology Laboratory, Faculty of Sciences, Universidad de la República, Iguá 4225, Montevideo 11400, Uruguay.
BMC Syst Biol. 2014 Jun 14;8:67. doi: 10.1186/1752-0509-8-67.
Metabolic responses are essential for the adaptation of microorganisms to changing environmental conditions. The repertoire of flux responses that the metabolic network can display in different external conditions may be quantified applying flux variability analysis to genome-scale metabolic reconstructions.
A procedure is developed to classify and quantify the sources of flux variability. We apply the procedure to the latest Escherichia coli metabolic reconstruction, in glucose minimal medium, with an additional constraint to account for the mechanism coordinating carbon and nitrogen utilization mediated by α-ketoglutarate. Flux variability can be decomposed into three components: internal, external and growth variability. Unexpectedly, growth variability is the only significant component of flux variability in the physiological ranges of glucose, oxygen and ammonia uptake rates. To obtain substantial increases in metabolic flexibility, E. coli must decrease growth rate to suboptimal values. This growth-flexibility trade-off gives a straightforward interpretation to recent work showing that most overall cell-to-cell flux variability in a population of E. coli can be attained sampling a small number of enzymes most likely to constrain cell growth. Importantly, it provides an explanation for the global reorganization occurring in metabolic networks during adaptations to environmental challenges. The calculations were repeated with a pathogenic strain and an old reconstruction of the commensal strain, having less than 50% of the reactions of the latest reconstruction, obtaining the same general conclusions.
In E. coli growing on glucose, growth variability is the only significant component of flux variability for all physiological conditions explored. Increasing flux variability requires reducing growth to suboptimal values. The growth-flexibility trade-off operates in physiological and evolutionary adaptations, and provides an explanation for the global reorganization occurring during adaptations to environmental challenges. The results obtained do not rely on the knowledge of kinetic and regulatory details of the system and are highly robust to incomplete or incorrect knowledge of the reaction network.
代谢反应对于微生物适应不断变化的环境条件至关重要。通过对基因组规模的代谢重建应用通量变异性分析，可以量化代谢网络在不同外部条件下所能呈现的通量反应库。
开发了一种程序来分类和量化通量变异性的来源。我们将该程序应用于最新的大肠杆菌代谢重建，在葡萄糖基本培养基中，并添加了一个额外的约束条件以考虑由α-酮戊二酸介导的协调碳和氮利用的机制。通量变异性可分解为三个组成部分：内部、外部和生长变异性。出乎意料的是，在葡萄糖、氧气和氨摄取率的生理范围内，生长变异性是通量变异性的唯一重要组成部分。为了大幅提高代谢灵活性，大肠杆菌必须将生长速率降低至次优值。这种生长-灵活性权衡为最近的研究工作提供了直接的解释，该研究表明，在大肠杆菌群体中，大多数细胞间的总体通量变异性可以通过对少数最有可能限制细胞生长的酶进行采样来实现。重要的是，它为适应环境挑战期间代谢网络中发生的全局重组提供了解释。使用一种致病菌株和共生菌株的旧重建版本重复了这些计算，该旧重建版本的反应数量不到最新重建版本的50%，得出了相同的总体结论。
在以葡萄糖为生长底物的大肠杆菌中，对于所探索的所有生理条件，生长变异性是通量变异性的唯一重要组成部分。增加通量变异性需要将生长降低至次优值。生长-灵活性权衡在生理和进化适应中起作用，并为适应环境挑战期间发生的全局重组提供了解释。所获得的结果不依赖于系统动力学和调控细节的知识，并且对反应网络的不完整或错误知识具有高度鲁棒性。
