Mathematical Institute, University of Oxford, Oxford, OX2 6GG, UK.
Synthetic Biology Research Centre, University of Nottingham, Nottingham, NG7 2RD, UK.
Bull Math Biol. 2020 Mar 6;82(3):36. doi: 10.1007/s11538-020-00714-1.
There has been recent interest in creating an efficient microbial production route for 3-hydroxypropionic acid, an important platform chemical. We develop and solve a mathematical model for the time-dependent metabolite concentrations in the malonyl-CoA pathway for 3-hydroxypropionic acid production in microbes, using a combination of numerical and asymptotic methods. This allows us to identify the most important targets for enzyme regulation therein under conditions of plentiful and sparse pyruvate, and to quantify their relative importance. In our model, we account for sinks of acetyl-CoA and malonyl-CoA to, for example, the citric acid cycle and fatty acid biosynthesis, respectively. Notably, in the plentiful pyruvate case we determine that there is a bifurcation in the asymptotic structure of the system, the crossing of which corresponds to a significant increase in 3-hydroxypropionic acid production. Moreover, we deduce that the most significant increases to 3-hydroxypropionic acid production can be obtained by up-regulating two specific enzymes in tandem, as the inherent nonlinearity of the system means that a solo up-regulation of either does not result in large increases in production. The types of issue arising here are prevalent in synthetic biology applications, and it is hoped that the system considered provides an instructive exemplar for broader applications.
最近人们对创造一种高效的微生物生产 3-羟基丙酸的方法产生了兴趣，3-羟基丙酸是一种重要的平台化学品。我们采用数值和渐近方法相结合的方式，针对微生物中 3-羟基丙酸生产的丙二酰辅酶 A 途径的时变代谢物浓度，开发并解决了一个数学模型。这使我们能够确定在丙酮酸丰富和稀缺条件下，其中酶调节的最重要目标，并量化它们的相对重要性。在我们的模型中，我们考虑了乙酰辅酶 A 和丙二酰辅酶 A 的汇，例如柠檬酸循环和脂肪酸生物合成。值得注意的是，在丙酮酸丰富的情况下，我们确定系统的渐近结构存在分岔，其交点对应 3-羟基丙酸产量的显著增加。此外，我们推断通过串联上调两个特定的酶可以获得 3-羟基丙酸产量的最大增加，因为系统的固有非线性意味着单独上调任何一个都不会导致产量的大幅增加。这里出现的问题类型在合成生物学应用中很常见，希望所考虑的系统为更广泛的应用提供一个有益的范例。
