Verma Babita K, Mannan Ahmad A, Zhang Fuzhong, Oyarzún Diego A
School of Biological Sciences, The University of Edinburgh, Edinburgh EH9 3BF, U.K.
Warwick Integrative Synthetic Biology Centre, School of Engineering, University of Warwick, Coventry CV4 7AL, U.K.
ACS Synth Biol. 2022 Jan 21;11(1):228-240. doi: 10.1021/acssynbio.1c00391. Epub 2021 Dec 30.
Recent progress in synthetic biology allows the construction of dynamic control circuits for metabolic engineering. This technology promises to overcome many challenges encountered in traditional pathway engineering, thanks to its ability to self-regulate gene expression in response to bioreactor perturbations. The central components in these control circuits are metabolite biosensors that read out pathway signals and actuate enzyme expression. However, the construction of metabolite biosensors is a major bottleneck for strain design, and a key challenge is to understand the relation between biosensor dose-response curves and pathway performance. Here we employ multiobjective optimization to quantify performance trade-offs that arise in the design of metabolite biosensors. Our approach reveals strategies for tuning dose-response curves along an optimal trade-off between production flux and the cost of an increased expression burden on the host. We explore properties of control architectures built in the literature and identify their advantages and caveats in terms of performance and robustness to growth conditions and leaky promoters. We demonstrate the optimality of a control circuit for glucaric acid production in , which has been shown to increase the titer by 2.5-fold as compared to static designs. Our results lay the groundwork for the automated design of control circuits for pathway engineering, with applications in the food, energy, and pharmaceutical sectors.
合成生物学的最新进展使得构建用于代谢工程的动态控制电路成为可能。这项技术有望克服传统途径工程中遇到的许多挑战，这得益于其能够根据生物反应器的扰动自我调节基因表达。这些控制电路的核心组件是代谢物生物传感器，它能读取途径信号并驱动酶的表达。然而，代谢物生物传感器的构建是菌株设计的一个主要瓶颈，一个关键挑战是理解生物传感器剂量响应曲线与途径性能之间的关系。在此，我们采用多目标优化来量化代谢物生物传感器设计中出现的性能权衡。我们的方法揭示了沿着生产通量与宿主上增加的表达负担成本之间的最优权衡来调整剂量响应曲线的策略。我们探索了文献中构建的控制架构的特性，并确定了它们在性能以及对生长条件和渗漏启动子的稳健性方面的优点和注意事项。我们证明了用于生产葡萄糖二酸的控制电路的最优性，与静态设计相比，该控制电路已显示出将产量提高了2.5倍。我们的结果为途径工程控制电路的自动化设计奠定了基础，可应用于食品、能源和制药领域。
