Department of Chemical and Biological Engineering, Princeton University, Princeton, USA.
Curr Biol. 2013 Nov 4;23(21):R972-9. doi: 10.1016/j.cub.2013.09.033.
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), which controls a myriad functions in cells, 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 Michaelis' and Menten's seminal 1913 paper.
1913 年，莱昂诺尔·迈克尔利斯和梅德·门腾发表了他们关于蔗糖水解的研究成果，这标志着酶催化的化学图像研究迈出了关键的一步。基于新颖的实验设计和数学模型，他们的工作在酶的蛋白质性质被确定之前，以及可以检测到与底物的复合物之前，就提供了生化动力学的定量观点。米氏动力学为体外酶动力学提供了一个坚实的框架，但在细胞内动力学中呢？在细胞内，酶可以受到高度调控，并参与多种相互作用。我们使用细胞中控制多种功能的细胞外信号调节激酶（ERK）作为模型来讨论这个问题，ERK 是一种重要的酶，我们已经有了其晶体结构、定量的体外测定以及大量的结合伙伴。尽管已经取得了很大的进展，但我们仍然无法定量预测 ERK 依赖性反应的速率如何对遗传和药理学扰动做出响应。从基础和实际的角度来看，实现这一目标是很重要的，这需要在其天然环境中测量酶反应的速率，并使用简单但现实的数学模型来解释这些测量结果——这两个元素是迈克尔利斯和门腾 1913 年开创性论文的基石。
