扩散内流和载体外流对大肠杆菌乳糖操纵子的双稳态有很强的影响
The diffusive influx and carrier efflux have a strong effect on the bistability of the lac operon in Escherichia coli
摘要：
大肠杆菌的乳糖操纵子在有无诱导物存在时表现出双稳态。文献中的大多数模型假设诱导剂通过载体（通透酶）进入细胞，并通过扩散样过程退出。忽略扩散流入和载流子流出。然而，数据分析表明，在非诱导细胞中，扩散流入与载体流入相当，而在诱导细胞中，载体流出是扩散流出的7倍。由于双稳态需要共存的稳态对应于非诱导和诱导细胞，这些通量都不能忽略。在这里，我们制定了一个模型占两个通量。我们发现：（a）双稳态的阈值都深刻地影响这两个通量。扩散流入通过增强诱导物在非诱导细胞中的积累来降低开启阈值。载体外排通过减少诱导细胞中诱导物的积累来增加关闭阈值。(b)用实验测得的参数值对模型进行的模拟与IPTG的数据吻合良好。然而，TMG的数据存在差异。它们最有可能是由于模型中缺少两个特征，即诱导物排除效应和特定生长速率随乳糖酶水平的变化。(c)在两种通量存在下得到的稳态和阈值很好地近似由简单的解析表达式，这可能是有用的，在合成生物学的乳糖基因开关的初步设计。
英文摘要：
In the presence of gratuitous inducers, the lac operon of Escherichia coli exhibits bistability. Most models in the literature assume that the inducer enters the cell via the carrier (permease), and exits by a diffusion-like process. The diffusive influx and carrier efflux are neglected. However, analysis of the data shows that in non-induced cells, the diffusive influx is comparable to the carrier influx, and in induced cells, the carrier efflux is 7 times the diffusive efflux. Since bistability entails the coexistence of steady states corresponding to both non-induced and induced cells, neither one of these fluxes can be ignored. Here, we formulate a model accounting for both fluxes. We show that: (a) The thresholds of bistability are profoundly affected by both fluxes. The diffusive influx reduces the on threshold by enhancing inducer accumulation in non-induced cells. The carrier efflux increases the off threshold by decreasing inducer accumulation in induced cells. (b) Simulations of the model with experimentally measured parameter values are in good agreement with the data for IPTG. However, there are discrepancies with respect to the data for TMG. They are most likely due to two features missing from the model, namely, the variation of the inducer exclusion effect and the specific growth rate with the lactose enzyme levels. (c) The steady states and thresholds obtained in the presence of both fluxes are well approximated by simple analytical expressions, which may be useful for the preliminary design of the lac genetic switch in synthetic biology.
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