Kinetic model optimization and its application to mitigating the Warburg effect through multiple enzyme alterations.
Kinetic model optimization and its application to mitigating the Warburg effect through multiple enzyme alterations.
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动力学模型优化及其通过多种酶改变减轻 Warburg 效应的应用。
DOI：
10.1016/j.ymben.2019.08.005
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发表时间：
2019
影响因子：
8.4
通讯作者：
Wei
中科院分区：
文献类型：
--
作者：
Conor M O'Brien;A. Allman;P. Daoutidis;Wei
通路工程在生物技术和临床应用中是一种强有力的工具。然而，许多现象不能用单一的酶改变来重新连接，在像能量代谢这样的复杂网络中，选择要工程化的目标组合是一项艰巨的任务。为了促进这一过程，我们已经开发了一个优化框架，并将其应用于能量代谢的机械动力学模型。然后，我们确定了酶改变的组合，这些酶改变导致消除了癌细胞和细胞系代谢中观察到的瓦尔堡效应，这是一种将快速增殖与乳酸产生相结合的现象。通常，优化方法使用整数变量来实现具有最小数量的改变基因的期望通量重新分布。该框架使用凸罚项来代替这些整数变量，提高了计算的易处理性。确定了使用三种或更多种酶基本上减少或消除乳酸盐产生同时维持细胞增殖的要求的最佳解决方案。
Pathway engineering is a powerful tool in biotechnological and clinical applications. However, many phenomena cannot be rewired with a single enzyme change, and in a complex network like energy metabolism, the selection of combinations of targets to engineer is a daunting task. To facilitate this process, we have developed an optimization framework and applied it to a mechanistic kinetic model of energy metabolism. We then identified combinations of enzyme alternations that led to the elimination of the Warburg effect seen in the metabolism of cancer cells and cell lines, a phenomenon coupling rapid proliferation to lactate production. Typically, optimization approaches use integer variables to achieve the desired flux redistribution with a minimum number of altered genes. This framework uses convex penalty terms to replace these integer variables and improve computational tractability. Optimal solutions are identified which substantially reduce or eliminate lactate production while maintaining the requirements for cellular proliferation using three or more enzymes.
影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
影响因子：
29
作者：
DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
4.1
作者：
SNELL, K;NATSUMEDA, Y;WEBER, G
通讯作者：
WEBER, G