ERK as a model for systems biology of enzyme kinetics in cells.
ERK as a model for systems biology of enzyme kinetics in cells.
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DOI：
10.1016/j.cub.2013.09.033
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发表时间：
2013-11-04
期刊：
影响因子：
9.2
通讯作者：
Shvartsman, Stanislav Y.
中科院分区：
文献类型：
--
作者：
Futran, Alan S.;Link, A. James;Seger, Rony;Shvartsman, Stanislav Y.
1913年，莱奥诺尔·米切里斯和莫德·门滕发表了他们关于蔗糖被转化酶水解的研究，这是酶催化化学图景的关键一步。基于一种新的实验设计和数学模型，他们的工作提供了一个定量的生化动力学的观点之前，酶的蛋白质性质的建立和复合物与底物可以检测。Michaelis-Menten动力学为体外酶动力学提供了一个坚实的框架，但细胞中的动力学又如何呢？在细胞中，酶可以被高度调节并参与多种相互作用。我们讨论这个问题，使用细胞外信号调节激酶（ERK）作为一个重要的酶，我们有晶体结构，定量体外测定，和大量的结合伙伴的模型。尽管取得了很大的进展，我们仍然不能定量预测ERK依赖性反应的速率如何响应遗传和药理学扰动。实现这一目标，这是重要的从根本和实际的角度来看，需要测量酶反应的速率在其原生环境中，并解释这些测量使用简单但现实的数学模型，这两个要素作为基石的开创性1913年的文件。
A key step towards a chemical picture of enzyme catalysis was taken in 1913, when Leonor Michaelis and Maud Menten published their studies of sucrose hydrolysis by invertase. Based on a novel experimental design and a mathematical model, their work offered a quantitative view of biochemical kinetics well before the protein nature of enzymes was established and complexes with substrates could be detected. Michaelis-Menten kinetics provides a solid framework for enzyme kinetics in vitro, but what about kinetics in cells, where enzymes can be highly regulated and participate in a multitude of interactions? We discuss this question using the Extracellular Signal Regulated Kinase (ERK) as a model of an important enzyme for which we have crystal structures, quantitative in vitro assays, and a vast list of binding partners. Despite great progress, we still cannot quantitatively predict how the rates of ERK-dependent reactions respond to genetic and pharmacological perturbations. Achieving this goal, which is important from both fundamental and practical standpoints, requires measuring the rates of enzyme reactions in their native environment and interpreting these measurements using simple but realistic mathematical models, the two elements which served as the cornerstones for the seminal 1913 paper.
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