Integrative BioSystems Institute and Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.
PLoS Comput Biol. 2013;9(5):e1003078. doi: 10.1371/journal.pcbi.1003078. Epub 2013 May 30.
The regulatory roles of sphingolipids in diverse cell functions have been characterized extensively. However, the dynamics and interactions among the different sphingolipid species are difficult to assess, because de novo biosynthesis, metabolic inter-conversions, and the retrieval of sphingolipids from membranes form a complex, highly regulated pathway system. Here we analyze the heat stress response of this system in the yeast Saccharomyces cerevisiae and demonstrate how the cell dynamically adjusts its enzyme profile so that it is appropriate for operation under stress conditions before changes in gene expression become effective. The analysis uses metabolic time series data, a complex mathematical model, and a custom-tailored optimization strategy. The results demonstrate that all enzyme activities rapidly increase in an immediate response to the elevated temperature. After just a few minutes, different functional clusters of enzymes follow distinct activity patterns. Interestingly, starting after about six minutes, both de novo biosynthesis and all exit routes from central sphingolipid metabolism become blocked, and the remaining metabolic activity consists entirely of an internal redistribution among different sphingoid base and ceramide pools. After about 30 minutes, heat stress is still in effect and the enzyme activity profile is still significantly changed. Importantly, however, the metabolites have regained concentrations that are essentially the same as those under optimal conditions.
鞘脂在多种细胞功能中的调节作用已经得到了广泛的研究。然而，不同鞘脂种类之间的动态和相互作用是难以评估的，因为从头生物合成、代谢转化以及从膜中回收鞘脂形成了一个复杂的、高度调控的途径系统。在这里，我们分析了酵母酿酒酵母中该系统对热应激的反应，并展示了细胞如何在基因表达发生变化之前动态调整其酶谱，以适应应激条件下的操作。该分析使用代谢时间序列数据、复杂的数学模型和定制的优化策略。结果表明，所有酶活性在温度升高时都会迅速增加。仅仅几分钟后，不同功能的酶簇就会呈现出不同的活性模式。有趣的是，大约六分钟后，从头生物合成和所有从中枢鞘脂代谢的出口途径都被阻断，剩下的代谢活性完全由不同鞘氨醇碱基和神经酰胺池之间的内部再分配组成。大约 30 分钟后，热应激仍然存在，酶活性谱仍然有明显的变化。然而，重要的是，代谢物的浓度已经恢复到与最佳条件下基本相同的水平。
