Liu Di, Zhang Fuzhong
Department of Energy, Environmental & Chemical Engineering, ‡Division of Biological & Biomedical Sciences, §Institute of Materials Science & Engineering, Washington University in St. Louis , St. Louis, Missouri 63130, United States.
ACS Synth Biol. 2018 Feb 16;7(2):347-356. doi: 10.1021/acssynbio.7b00342. Epub 2018 Jan 8.
Metabolism constitutes the basis of life, and the dynamics of metabolism dictate various cellular processes. However, exactly how metabolite dynamics are controlled remains poorly understood. By studying an engineered fatty acid-producing pathway as a model, we found that upon transcription activation a metabolic product from an unregulated pathway required seven cell cycles to reach to its steady state level, with the speed mostly limited by enzyme expression dynamics. To overcome this limit, we designed metabolic feedback circuits (MeFCs) with three different architectures, and experimentally measured and modeled their metabolite dynamics. Our engineered MeFCs could dramatically shorten the rise-time of metabolites, decreasing it by as much as 12-fold. The findings of this study provide a systematic understanding of metabolite dynamics in different architectures of MeFCs and have potentially immense applications in designing synthetic circuits to improve the productivities of engineered metabolic pathways.
新陈代谢构成生命的基础，而新陈代谢的动态变化决定了各种细胞过程。然而，代谢物动态变化究竟是如何被控制的，目前仍知之甚少。通过研究一条工程化的脂肪酸生成途径作为模型，我们发现，在转录激活后，一条未受调控途径产生的代谢产物需要七个细胞周期才能达到其稳态水平，其速度主要受酶表达动态变化的限制。为了克服这一限制，我们设计了具有三种不同架构的代谢反馈回路（MeFCs），并通过实验测量和模拟了它们的代谢物动态变化。我们构建的MeFCs能够显著缩短代谢物的上升时间，最多可减少12倍。这项研究的结果为不同架构的MeFCs中的代谢物动态变化提供了系统的理解，并在设计合成回路以提高工程化代谢途径的生产力方面具有潜在的巨大应用价值。
