Achieving Optimal Growth through Product Feedback Inhibition in Metabolism
Achieving Optimal Growth through Product Feedback Inhibition in Metabolism
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DOI：
10.1371/journal.pcbi.1000802
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发表时间：
2010-06-01
影响因子：
4.3
通讯作者：
Wingreen, Ned S.
中科院分区：
文献类型：
--
作者：
Goyal, Sidhartha;Yuan, Jie;Wingreen, Ned S.
最近的证据表明，某些生物体（如大肠杆菌）的新陈代谢非常有效，每消耗一单位营养素，就能产生接近最大量的生物质。这一观察结果提出了一个问题，即什么样的监管机制能够实现这种效率。在这里，我们提出，简单的产品反馈抑制本身是能够导致这样的最优性。我们分析了几个有代表性的代谢模块，从线性途径开始，推进到双向途径和代谢循环，最后到两种不同营养输入的整合。在每一种情况下，我们的数学分析表明，产品反馈抑制不仅是稳态的，而且，与适当的反馈连接，可以最大限度地减少徒劳的循环和优化流量。然而，简单的产物反馈抑制的有效性是以高水平的某些代谢物池为代价的，这可能与毒性和渗透压失衡有关。如果反馈抑制是超敏感的，那么这些大的代谢物池的大小可以受到限制。事实上，通过控制酶的表达、酶的共价修饰和变构作用对代谢进行的多层调节预计将导致这种超灵敏的反馈。为了实验检验我们对反馈抑制分析的定性预测是否适用于线性途径以外的代谢模块，我们研究了E.大肠杆菌，这涉及营养整合和代谢循环。我们发现，我们的数学分析所建议的反馈调节方案与网络的实际调节密切相关，足以解释营养转换实验中相关代谢物池大小的动力学行为。
Recent evidence suggests that the metabolism of some organisms, such as Escherichia coli, is remarkably efficient, producing close to the maximum amount of biomass per unit of nutrient consumed. This observation raises the question of what regulatory mechanisms enable such efficiency. Here, we propose that simple product-feedback inhibition by itself is capable of leading to such optimality. We analyze several representative metabolic modules-starting from a linear pathway and advancing to a bidirectional pathway and metabolic cycle, and finally to integration of two different nutrient inputs. In each case, our mathematical analysis shows that product-feedback inhibition is not only homeostatic but also, with appropriate feedback connections, can minimize futile cycling and optimize fluxes. However, the effectiveness of simple product-feedback inhibition comes at the cost of high levels of some metabolite pools, potentially associated with toxicity and osmotic imbalance. These large metabolite pool sizes can be restricted if feedback inhibition is ultrasensitive. Indeed, the multi-layer regulation of metabolism by control of enzyme expression, enzyme covalent modification, and allostery is expected to result in such ultrasensitive feedbacks. To experimentally test whether the qualitative predictions from our analysis of feedback inhibition apply to metabolic modules beyond linear pathways, we examine the case of nitrogen assimilation in E. coli, which involves both nutrient integration and a metabolic cycle. We find that the feedback regulation scheme suggested by our mathematical analysis closely aligns with the actual regulation of the network and is sufficient to explain much of the dynamical behavior of relevant metabolite pool sizes in nutrient-switching experiments.