Sequential metabolic phases as a means to optimize cellular output in a constant environment.
Sequential metabolic phases as a means to optimize cellular output in a constant environment.
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DOI：
10.1371/journal.pone.0118347
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Holzhütter HG
中科院分区：
文献类型：
--
作者：
Palinkas A;Bulik S;Bockmayr A;Holzhütter HG
基因表达的时间变化是所有细胞众所周知的调控特征，这通常被视为一种使蛋白质组适应不同外部条件的策略。然而，在几乎恒定的外部条件下也能观察到基因表达的时间（节律性和非节律性）变化。在此我们假设，这种变化是一种使代谢产物合成比在基因活性恒定的条件下更高效的手段。为了证实这一假设，我们使用了一个细胞代谢的通量平衡模型。生产一组给定目标代谢物所花费的总时间跨度被划分为一系列较短的时间间隔（代谢阶段），在这些阶段中只有选定的几组代谢基因是活跃的。在基因要么活跃要么不活跃的约束条件下计算相关的通量分布，其中与活跃基因相关的蛋白质数量仅由活跃基因的数量控制：活跃基因数量越少，可分配给具有非零通量的酶的蛋白质就越多。这种基因表达效率主要受蛋白质限制的概念明显不同于其他基于以下假设的概念，即存在一种能够为所有酶和转运蛋白分配恰好足以防止速率限制的蛋白质比例的最佳基因调控。将这一概念应用于以葡萄糖或乳酸作为替代底物的中心碳代谢的简化代谢网络，我们证明，在包含不同组活跃基因的最佳选择的稳态通量模式之间切换，能够比在固定基因活性下的单一最佳通量模式在显著更短的时间内生产所需数量的目标代谢物。我们基于模型的研究结果表明，即使在外部底物供应恒定的条件下，代谢基因的时间表达也可能是有利的。
Temporal changes of gene expression are a well-known regulatory feature of all cells, which is commonly perceived as a strategy to adapt the proteome to varying external conditions. However, temporal (rhythmic and non-rhythmic) changes of gene expression are also observed under virtually constant external conditions. Here we hypothesize that such changes are a means to render the synthesis of the metabolic output more efficient than under conditions of constant gene activities. In order to substantiate this hypothesis, we used a flux-balance model of the cellular metabolism. The total time span spent on the production of a given set of target metabolites was split into a series of shorter time intervals (metabolic phases) during which only selected groups of metabolic genes are active. The related flux distributions were calculated under the constraint that genes can be either active or inactive whereby the amount of protein related to an active gene is only controlled by the number of active genes: the lower the number of active genes the more protein can be allocated to the enzymes carrying non-zero fluxes. This concept of a predominantly protein-limited efficiency of gene expression clearly differs from other concepts resting on the assumption of an optimal gene regulation capable of allocating to all enzymes and transporters just that fraction of protein necessary to prevent rate limitation. Applying this concept to a simplified metabolic network of the central carbon metabolism with glucose or lactate as alternative substrates, we demonstrate that switching between optimally chosen stationary flux modes comprising different sets of active genes allows producing a demanded amount of target metabolites in a significantly shorter time than by a single optimal flux mode at fixed gene activities. Our model-based findings suggest that temporal expression of metabolic genes can be advantageous even under conditions of constant external substrate supply.
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DOI：
10.1073/pnas.1118726109
发表时间：
2012-04-03
影响因子：
11.1
作者：
Eckel-Mahan, Kristin L.;Patel, Vishal R.;Sassone-Corsi, Paolo
通讯作者：
Sassone-Corsi, Paolo
影响因子：
9.9
作者：
Chubukov, Victor;Uhr, Markus;Le Chat, Ludovic;Kleijn, Roelco J.;Jules, Matthieu;Link, Hannes;Aymerich, Stephane;Stelling, Joerg;Sauer, Uwe
通讯作者：
Sauer, Uwe
DOI：
10.1073/pnas.1114235109
发表时间：
2012-03-27
影响因子：
11.1
作者：
Chubukov, Victor;Zuleta, Ignacio A.;Li, Hao
通讯作者：
Li, Hao
DOI：
10.1046/j.1432-1033.2002.03223.x
发表时间：
2002-11-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Klipp, E;Heinrich, R;Holzhütter, HG
通讯作者：
Holzhütter, HG
影响因子：
3.5
作者：
Oyarzun, Diego A.;Ingalls, Brian P.;Kalamatianos, Dimitrios
通讯作者：
Kalamatianos, Dimitrios