Centre for Ecological and Evolutionary Synthesis (CEES), Department of Biosciences, University of Oslo, Oslo, Norway.
Systems Bioinformatics Section, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Vrije Universiteit, Amsterdam, The Netherlands.
PLoS Comput Biol. 2018 Feb 16;14(2):e1006010. doi: 10.1371/journal.pcbi.1006010. eCollection 2018 Feb.
Microbes may maximize the number of daughter cells per time or per amount of nutrients consumed. These two strategies correspond, respectively, to the use of enzyme-efficient or substrate-efficient metabolic pathways. In reality, fast growth is often associated with wasteful, yield-inefficient metabolism, and a general thermodynamic trade-off between growth rate and biomass yield has been proposed to explain this. We studied growth rate/yield trade-offs by using a novel modeling framework, Enzyme-Flux Cost Minimization (EFCM) and by assuming that the growth rate depends directly on the enzyme investment per rate of biomass production. In a comprehensive mathematical model of core metabolism in E. coli, we screened all elementary flux modes leading to cell synthesis, characterized them by the growth rates and yields they provide, and studied the shape of the resulting rate/yield Pareto front. By varying the model parameters, we found that the rate/yield trade-off is not universal, but depends on metabolic kinetics and environmental conditions. A prominent trade-off emerges under oxygen-limited growth, where yield-inefficient pathways support a 2-to-3 times higher growth rate than yield-efficient pathways. EFCM can be widely used to predict optimal metabolic states and growth rates under varying nutrient levels, perturbations of enzyme parameters, and single or multiple gene knockouts.
微生物可能会最大化每个时间或每个消耗营养物质的量的子细胞数量。这两种策略分别对应于使用酶高效或基质高效代谢途径。实际上，快速生长通常与浪费、产率低效的代谢有关，并且已经提出了一种普遍的热力学权衡关系来解释这一点，即生长速率和生物量产率之间的权衡关系。我们使用一种新的建模框架——酶通量成本最小化（EFCM）来研究生长速率/产率权衡关系，并假设生长速率直接取决于每单位生物质生产速率的酶投资。在大肠杆菌核心代谢的综合数学模型中，我们筛选了所有导致细胞合成的基本通量模式，根据它们提供的生长速率和产率对其进行了特征描述，并研究了由此产生的速率/产率 Pareto 前沿的形状。通过改变模型参数，我们发现生长速率/产率权衡不是普遍的，而是取决于代谢动力学和环境条件。在限氧生长下，出现了一个明显的权衡，其中低效产率途径的生长速率比高效产率途径高 2 到 3 倍。EFCM 可以广泛用于预测在不同营养水平、酶参数扰动、单个或多个基因敲除下的最佳代谢状态和生长速率。
