Metabolic regulation is sufficient for global and robust coordination of glucose uptake, catabolism, energy production and growth in Escherichia coli.
Metabolic regulation is sufficient for global and robust coordination of glucose uptake, catabolism, energy production and growth in Escherichia coli.
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代谢调节足以对大肠杆菌中的葡萄糖摄取、分解代谢、能量产生和生长进行全面且强有力的协调。
DOI：
10.1371/journal.pcbi.1005396
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发表时间：
2017-02
影响因子：
4.3
通讯作者：
Mendes P
中科院分区：
文献类型：
--
作者：
Millard P;Smallbone K;Mendes P
微生物的代谢通过两种主要机制进行调节：基因表达调节导致酶能力的变化（“层次控制”）和代谢-酶相互作用导致酶活性的变化。越来越多的证据表明，等级控制不足以解释代谢行为，但代谢调节的全系统影响在很大程度上仍未被描述。为了阐明其作用，我们开发并验证了大肠杆菌中心代谢的详细动力学模型，该模型将生长与环境联系起来。代谢控制分析证实，这种控制在整个网络中广泛分布，并突出了所有途径之间的强相互联系。对模型解空间的探索揭示了代谢调节中出现的一些强大特性，从分子水平（例如总代谢物池的稳态）到整体细胞生理学（例如碳吸收、分解代谢、能量和氧化还原产生以及生长的协调），同时在大多数单个代谢步骤中允许很大程度的灵活性。这些特性对大肠杆菌具有重要的生理意义，并显著增强了其代谢的自我调节能力。新陈代谢是一种基本的生化过程，通过将营养物质转化为“构建模块”和能量，使细胞能够运作和生长。新陈代谢是通过酶的作用进行的，而酶是由基因编码的。因此，基因及其调控通常被认为是控制新陈代谢的，在某种程度上处于分层控制系统的顶端。然而，越来越多的证据表明，代谢通过代谢-酶相互作用的密集网络在控制其自身运作中起着积极的作用。代谢调节的全系统作用很难剖析，到目前为止，它在很大程度上仍未被描述。为了更好地理解它的作用，我们构建了大肠杆菌的碳和能量代谢的详细动力学模型，大肠杆菌是系统与合成生物学中的模式生物。模型模拟表明，仅考虑代谢的动力学因素就可以解释数百个实验的数据，而无需调用基因表达的调节。特别是，代谢调节足以协调碳利用、氧化还原和能量产生以及生长，同时在单个代谢步骤中保持局部灵活性。这些发现表明，大肠杆菌代谢的自我调节能力远比之前预期的重要，并提高了我们对细胞如何工作的理解。
The metabolism of microorganisms is regulated through two main mechanisms: changes of enzyme capacities as a consequence of gene expression modulation (“hierarchical control”) and changes of enzyme activities through metabolite-enzyme interactions. An increasing body of evidence indicates that hierarchical control is insufficient to explain metabolic behaviors, but the system-wide impact of metabolic regulation remains largely uncharacterized. To clarify its role, we developed and validated a detailed kinetic model of Escherichia coli central metabolism that links growth to environment. Metabolic control analyses confirm that the control is widely distributed across the network and highlight strong interconnections between all the pathways. Exploration of the model solution space reveals that several robust properties emerge from metabolic regulation, from the molecular level (e.g. homeostasis of total metabolite pool) to the overall cellular physiology (e.g. coordination of carbon uptake, catabolism, energy and redox production, and growth), while allowing a large degree of flexibility at most individual metabolic steps. These properties have important physiological implications for E. coli and significantly expand the self-regulating capacities of its metabolism. Metabolism is a fundamental biochemical process that enables cells to operate and grow by converting nutrients into ‘building blocks’ and energy. Metabolism happens through the work of enzymes, which are encoded by genes. Thus, genes and their regulation are often thought of controlling metabolism, somewhat at the top of a hierarchical control system. However, an increasing body of evidence indicates that metabolism plays an active role in the control of its own operation via a dense network of metabolite-enzyme interactions. The system-wide role of metabolic regulation is hard to dissect and so far remains largely uncharacterized. To better understand its role, we constructed a detailed kinetic model of the carbon and energy metabolism of the bacterium Escherichia coli, a model organism in Systems and Synthetic biology. Model simulations indicate that kinetic considerations of metabolism alone can explain data from hundreds of experiments, without needing to invoke regulation of gene expression. In particular, metabolic regulation is sufficient to coordinate carbon utilization, redox and energy production, and growth, while maintaining local flexibility at individual metabolic steps. These findings indicate that the self-regulating capacities of E. coli metabolism are far more significant than previously expected, and improve our understanding on how cells work.