CASOP: A Computational Approach for Strain Optimization aiming at high Productivity
CASOP: A Computational Approach for Strain Optimization aiming at high Productivity
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DOI：
10.1016/j.jbiotec.2010.03.006
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发表时间：
2010-05-17
影响因子：
4.1
通讯作者：
Klamt, Steffen
中科院分区：
文献类型：
--
作者：
Haedicke, Oliver;Klamt, Steffen
确定合适的干预策略，提高微生物的生产力是代谢工程的核心问题。在这里，我们介绍了一个计算框架的应变优化的基础上反应的重要性措施来自加权基本模式。目的是将天然通量分布转移到以高生产率合成所需产物，从而保留宿主生物体生产生物质前体的能力。化学计量方法允许考虑监管/运营约束，并明确考虑产品产量和网络容量-（特定）生产率的两个主要决定因素。通过分析可用的转化路线（基本模式）的光谱，估计每个反应对产率和网络容量以及生产率的相对贡献。我们的程序的结果是一个反应排名表明敲除和过表达的候选人。此外，我们表明，该方法允许与产品合成的辅因子和共代谢产物的要求进行评估。我们说明所提出的方法，通过研究过量生产的琥珀酸和乳酸的大肠杆菌。二氧化硅中鉴定的代谢工程策略类似于为合成相应产物而设计的现有突变株。此外，一些非直观的干预策略被揭示。(C)2010 Elsevier B. V.保留所有权利。
The identification of suitable intervention strategies increasing the productivity of microorganisms is a central issue in metabolic engineering. Here, we introduce a computational framework for strain optimization based on reaction importance measures derived from weighted elementary modes. The objective is to shift the natural flux distribution to synthesis of the desired product with high production rates thereby retaining the ability of the host organism to produce biomass precursors. The stoichiometric approach allows consideration of regulatory/operational constraints and takes product yield and network capacity - the two major determinants of (specific) productivity - explicitly into account. The relative contribution of each reaction to yield and network capacity and thus productivity is estimated by analyzing the spectrum of available conversion routes (elementary modes). A result of our procedure is a reaction ranking suggesting knockout and overexpression candidates. Moreover, we show that the methodology allows for the evaluation of cofactor and co-metabolite requirements in conjunction with product synthesis. We illustrate the proposed method by studying the overproduction of succinate and lactate by Escherichia coli. The metabolic engineering strategies identified in silica resemble existing mutant strains designed for the synthesis of the respective products. Additionally, some non-intuitive intervention strategies are revealed. (C) 2010 Elsevier B.V. All rights reserved.