Dynamics of co-substrate pools can constrain and regulate metabolic fluxes.
Dynamics of co-substrate pools can constrain and regulate metabolic fluxes.
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共覆盖池的动力学可以约束和调节代谢通量。
DOI：
10.7554/elife.84379
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发表时间：
2023-02-17
期刊：
影响因子：
7.7
通讯作者：
Soyer OS
中科院分区：
文献类型：
--
作者：
West R;Delattre H;Noor E;Feliu E;Soyer OS
共底物的循环，即代谢物通过不同的反应在交替形式之间转化，在代谢中普遍存在。几种循环共底物是众所周知的能量和电子载体（例如ATP和NAD（P）H），但也有其他代谢物在中枢代谢的不同部分中充当循环共底物。在这里，我们开发了一个数学框架来分析共基质循环对代谢通量的影响。在一个单一的反应和线性途径的情况下，我们发现，共底物循环施加额外的通量限制的反应，不同的限制所施加的动力学的主要酶催化该反应。使用分析方法，我们表明，这个额外的限制是一个功能的总池大小和周转率的循环共基板。扩展从这个洞察力，并使用模拟，我们表明，这两个参数的调节可以允许调节流量动态分支和耦合途径。为了支持这些理论见解，我们分析了现有的通量测量和酶水平从中央碳代谢，并确定了几个反应，可能会受到限制的动力学的共底物循环。我们讨论了如何限制共底物循环提供实验验证的假设特定的代谢表型。我们的结论是，测量和控制共底物动力学的理解和工程细胞中的代谢通量是至关重要的。新陈代谢为单个细胞并最终为身体提供动力。它包括细胞用来分解物质和产生能量的一系列化学反应。这些反应由酶催化，酶是加速反应速率的蛋白质。许多反应还涉及共底物，它们本身通过单独的反应转化，但最终在一系列步骤中转化回其原始形式。这个过程被称为共基质循环。长期以来，科学家们一直有兴趣了解是什么控制着代谢反应和代谢途径将物质转化为最终产物的速率。这是一个很难研究的课题，因为代谢途径的复杂性，具有分支，线性或耦合结构。在过去，研究人员已经研究了酶对代谢途径速率的影响，但对共底物循环的影响知之甚少。为了了解更多，West，Delattre等人开发了一系列数学模型来描述不同类型的代谢途径，包括进入和离开它的代谢物的数量，包括共底物的影响。他们发现，当参与代谢反应时，共底物循环限制了反应发生的速度。这与酶对反应速度的限制不同。它取决于细胞中共底物的总量：改变细胞中共底物的数量会影响代谢反应发生的速度。这项研究增加了我们对代谢途径如何工作的理解，以及是什么控制了反应发生的速度。它开辟了一种新的潜在方法，用于解释细胞如何控制代谢反应速率，以及代谢底物如何通过不同的途径被引导。这项研究可能会激发未来研究不同细胞类型和条件下共底物的影响。
Cycling of co-substrates, whereby a metabolite is converted among alternate forms via different reactions, is ubiquitous in metabolism. Several cycled co-substrates are well known as energy and electron carriers (e.g. ATP and NAD(P)H), but there are also other metabolites that act as cycled co-substrates in different parts of central metabolism. Here, we develop a mathematical framework to analyse the effect of co-substrate cycling on metabolic flux. In the cases of a single reaction and linear pathways, we find that co-substrate cycling imposes an additional flux limit on a reaction, distinct to the limit imposed by the kinetics of the primary enzyme catalysing that reaction. Using analytical methods, we show that this additional limit is a function of the total pool size and turnover rate of the cycled co-substrate. Expanding from this insight and using simulations, we show that regulation of these two parameters can allow regulation of flux dynamics in branched and coupled pathways. To support these theoretical insights, we analysed existing flux measurements and enzyme levels from the central carbon metabolism and identified several reactions that could be limited by the dynamics of co-substrate cycling. We discuss how the limitations imposed by co-substrate cycling provide experimentally testable hypotheses on specific metabolic phenotypes. We conclude that measuring and controlling co-substrate dynamics is crucial for understanding and engineering metabolic fluxes in cells. Metabolism powers individual cells and ultimately the body. It comprises a sequence of chemical reactions that cells use to break down substances and generate energy. These reactions are catalyzed by enzymes, which are proteins that speed up the rate of the reaction. Many reactions also involve co-substrates, which are themselves transformed by individual reactions but are eventually converted back into their original form in a series of steps. This process is known as co-substrate cycling. Scientists have long been interested in understanding what controls the rate at which metabolic reactions and metabolic pathways convert a substance into a final product. This is a difficult subject to study because of the complexity of the metabolic pathways, with their branched, linear or coupled structures. In the past, researchers have looked at the influence of enzymes on the rate of a metabolic pathway, but less has been known about the effect of co-substrate cycling. To find out more, West, Delattre et al. developed a series of mathematical models to describe different types of metabolic pathways in terms of the number of metabolites that enter and leave it, including the influence of co-substrates. They found that co-substrate cycling, when involved in a metabolic reaction, limits the speed with which the reaction happens. This is distinct from the limit that enzymes impose on the speed of the reaction. It depends on the total amount of co-substrates in the cell: changing the number of co-substrates in the cell influences the speed at which the metabolic reaction takes place. This study has increased our understanding of how metabolic pathways work, and what controls the speed at which reactions take place. It opens up a new potential method for explaining how cells control metabolic reaction rates and how metabolic substrates can be directed across different pathways. This research is likely to inspire future research into the influence of co-substrates in different cell types and conditions.
影响因子：
4.3
作者：
Hatakeyama TS;Furusawa C
通讯作者：
Furusawa C