Combination of Genome-Scale Models and Bioreactor Dynamics to Optimize the Production of Commodity Chemicals.
Combination of Genome-Scale Models and Bioreactor Dynamics to Optimize the Production of Commodity Chemicals.
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DOI：
10.3389/fmolb.2022.855735
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发表时间：
2022
影响因子：
5
通讯作者：
中科院分区：
文献类型：
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作者：
目前许多商品化学品的生产依赖于化石燃料的开采，因此对环境产生了不可逆转的影响。生物技术过程通过转基因微生物生产化学品提供了一种有吸引力的替代方案。然而，这种替代方法带来了一些重要的技术挑战，必须解决这些挑战才能使其具有竞争力。一方面，生物技术工艺的设计基于试错方法，这不仅在时间和金钱方面成本高昂，而且还会导致设计不理想。另一方面，通过生物过程制造化学品几乎完全通过分批或补料分批培养进行。鉴于分批培养成本高昂且不易规模化，必须开发技术手段使连续培养变得可行且高效。为了应对这些挑战，我们开发了一种数学模型，能够将合成感兴趣的化学物质的生物体的基因组规模代谢模型和培养生物体的生物反应器的动力学集成到单个模型中。这种模型基于灵活网络的使用，这是一种动态系统的建模形式。将微观（有机体）和宏观（生物反应器）模型集成在一个网络中提供了整个系统的整体视图，并为全局优化打开了大门。作为一个案例研究，对大肠杆菌消耗的底物的柠檬苹果酸生产进行了建模、模拟和优化，以找到稳态连续培养中的最大生产率。预测的计算结果与湿实验室实验一致。
The current production of a number of commodity chemicals relies on the exploitation of fossil fuels and hence has an irreversible impact on the environment. Biotechnological processes offer an attractive alternative by enabling the manufacturing of chemicals by genetically modified microorganisms. However, this alternative approach poses some important technical challenges that must be tackled to make it competitive. On the one hand, the design of biotechnological processes is based on trial-and-error approaches, which are not only costly in terms of time and money, but also result in suboptimal designs. On the other hand, the manufacturing of chemicals by biological processes is almost exclusively carried out by batch or fed-batch cultures. Given that batch cultures are expensive and not easy to scale, technical means must be developed to make continuous cultures feasible and efficient. In order to address these challenges, we have developed a mathematical model able to integrate in a single model both the genome-scale metabolic model for the organism synthesizing the chemical of interest and the dynamics of the bioreactor in which the organism is cultured. Such a model is based on the use of Flexible Nets, a modeling formalism for dynamical systems. The integration of a microscopic (organism) and a macroscopic (bioreactor) model in a single net provides an overall view of the whole system and opens the door to global optimizations. As a case study, the production of citramalate with respect to the substrate consumed by E. coli is modeled, simulated and optimized in order to find the maximum productivity in a steady-state continuous culture. The predicted computational results were consistent with the wet lab experiments.
影响因子：
4
作者：
Júlvez J;Dikicioglu D;Oliver SG
通讯作者：
Oliver SG