Impact of limited solvent capacity on metabolic rate, enzyme activities, and metabolite concentrations of S. cerevisiae glycolysis.
Impact of limited solvent capacity on metabolic rate, enzyme activities, and metabolite concentrations of S. cerevisiae glycolysis.
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DOI：
10.1371/journal.pcbi.1000195
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发表时间：
2008-10
影响因子：
4.3
通讯作者：
Oltvai ZN
中科院分区：
文献类型：
--
作者：
Vazquez A;de Menezes MA;Barabási AL;Oltvai ZN
细胞的细胞质挤满了各种分子成分，导致分配新蛋白质的溶剂能力有限，从而限制了新陈代谢等各种细胞过程。在这里，我们使用酿酒酵母糖酵解的计算模型作为案例研究，研究有限溶剂容量约束对代谢率、酶活性和代谢物浓度的影响。我们表明，考虑到有限的溶剂容量限制，实现最大糖酵解速率所需的最佳酶活性和代谢物浓度与其实验测量值一致。此外，由溶剂容量限制确定的预测最大糖酵解速率接近于体内测量的值。这些结果表明，有限溶剂容量是在生理生长条件下作用于酿酒酵母的相关约束，并且完整动力学模型与有限溶剂容量约束一起可用于预测体内代谢物浓度和酶活性。酶和代谢物的浓度不断调整，以达到特定的代谢需求。很可能在进化过程中，全局代谢调节已经进化到通过细胞内资源的最佳利用来实现给定的代谢需求。然而，酶和中间代谢物的大小却截然不同。酶是大分子，在细胞拥挤的细胞质中占据相对较大的空间，而代谢物则小得多。这意味着可能会调整代谢物浓度以最小化总体“酶成本”（就空间成本而言）。在这项工作中，我们以酿酒酵母糖酵解作为案例研究来探索这一假设。我们的结果表明，代谢物浓度达到最佳值，最大限度地减少代谢酶占据的细胞内空间。并且，在这些最佳浓度下，考虑到糖酵解酶占据的细胞内体积分数，糖酵解达到最大速率。结合之前对大肠杆菌的研究，我们的结果表明大分子拥挤是细胞代谢的普遍限制。
The cell's cytoplasm is crowded by its various molecular components, resulting in a limited solvent capacity for the allocation of new proteins, thus constraining various cellular processes such as metabolism. Here we study the impact of the limited solvent capacity constraint on the metabolic rate, enzyme activities, and metabolite concentrations using a computational model of Saccharomyces cerevisiae glycolysis as a case study. We show that given the limited solvent capacity constraint, the optimal enzyme activities and the metabolite concentrations necessary to achieve a maximum rate of glycolysis are in agreement with their experimentally measured values. Furthermore, the predicted maximum glycolytic rate determined by the solvent capacity constraint is close to that measured in vivo. These results indicate that the limited solvent capacity is a relevant constraint acting on S. cerevisiae at physiological growth conditions, and that a full kinetic model together with the limited solvent capacity constraint can be used to predict both metabolite concentrations and enzyme activities in vivo. The concentration of enzymes and metabolites is continuously adjusted in order to achieve specific metabolic demands. It is highly likely that during evolution global metabolic regulation has evolved such as to achieve a given metabolic demand with an optimal use of intracellular resources. However, the size of enzymes and intermediate metabolites is dramatically different. Enzymes are macromolecules that occupy a relatively large amount of space within a cell's crowded cytoplasm, while metabolites are much smaller. This implies that metabolite concentrations are likely to be adjusted to minimize the overall “enzymatic cost” (in terms of space cost). In this work, we explore this hypothesis using Saccharomyces cerevisiae glycolysis as a case study. Our results indicate that metabolite concentrations attain optimal values, minimizing the intracellular space occupied by metabolic enzymes. And, at these optimal concentrations, glycolysis achieves the maximum rate given the intracellular volume fraction occupied by glycolysis enzymes. Taken together with previous studies for Escherichia coli, our results indicate that macromolecular crowding is a general constraint on cell metabolism.
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影响因子：
7
作者：
Kolkman, A;Olsthoorn, MMA;Slijper, M
通讯作者：
Slijper, M
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：
4
作者：
Minton, Allen P.
通讯作者：
Minton, Allen P.
影响因子：
5.6
作者：
ZIMMERMAN, SB;TRACH, SO
通讯作者：
TRACH, SO
影响因子：
4.4
作者：
Alcázar, EB;Rocha-Leao, MHM;Dweck, J
通讯作者：
Dweck, J