Transhydrogenase promotes the robustness and evolvability of E. coli deficient in NADPH production.
Transhydrogenase promotes the robustness and evolvability of E. coli deficient in NADPH production.
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DOI：
10.1371/journal.pgen.1005007
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发表时间：
2015
期刊：
影响因子：
4.5
通讯作者：
Sauer U
中科院分区：
文献类型：
--
作者：
Chou HH;Marx CJ;Sauer U
代谢网络围绕着少数能被不同的酶识别并参与无数反应的代谢物。虽然中枢代谢物被认为是促进生化途径进化扩展的垫脚石，但它们的生产或消费的变化往往通过它们系统范围的联系来损害细胞生理。新陈代谢如何承受途径修饰带来的干扰，并在长期内恢复中枢内环境平衡？为了解决这个问题，我们研究了途径工程大肠杆菌的实验室进化，这种大肠杆菌在葡萄糖上不能产生氧化还原辅因子NADPH。文献表明有多种恢复NADPH动态平衡的可能性。令人惊讶的是，对我们12个进化群体的分离株的遗传解剖只揭示了两种解决方案：(1)在每个群体中调节膜结合转氢酶(MTH)的表达；(2)在两个亚群中同时消耗葡萄糖和醋酸盐，醋酸盐是一种在葡萄糖分解代谢过程中通常会排出的不良副产物。值得注意的是，MTH显示了广泛的系统发育分布，并在缺乏NADPH产生的甲烷杆菌的实验室进化中发挥了主导作用。两个在系统发育和代谢上不同的物种的趋同进化表明，MTH是一种保守的缓冲机制，促进了新陈代谢的稳健性和进化性。此外，通过进化的双底物消耗实现的适应性多样化突出了生理系统利用生态机会的灵活性。生物网络的结构，如交通系统或互联网，其特点是由许多组件连接的枢纽很少。虽然枢纽的保护和高连通性是促进网络扩张的关键节点，但枢纽周围连接的增加或移除可能会通过其全球联系来干扰整个系统。生物网络如何在进化过程中缓解中枢扰动？以新陈代谢为例，我们研究了在大肠杆菌中产生中枢代谢物NADPH的遗传扰动的生理和进化后果。我们发现，mth是一种在系统发育上保守的酶，它的表达立即上调，并且对于抵消Hub的扰动是必不可少的。此外，该途径修饰的大肠杆菌在葡萄糖生长介质中的长期进化反复选择用于上调突变，以恢复所有12个重复群体中的NADPH平衡，而不管文献中建议的几种替代解决方案。我们的研究得到了高度分化的物种M.extorquens的实验室进化的类似发现的证实，我们的研究表明，致力于缓解中枢扰动的机制既促进了生物网络的稳健性，也促进了生物网络的进化性。
Metabolic networks revolve around few metabolites recognized by diverse enzymes and involved in myriad reactions. Though hub metabolites are considered as stepping stones to facilitate the evolutionary expansion of biochemical pathways, changes in their production or consumption often impair cellular physiology through their system-wide connections. How does metabolism endure perturbations brought immediately by pathway modification and restore hub homeostasis in the long run? To address this question we studied laboratory evolution of pathway-engineered Escherichia coli that underproduces the redox cofactor NADPH on glucose. Literature suggests multiple possibilities to restore NADPH homeostasis. Surprisingly, genetic dissection of isolates from our twelve evolved populations revealed merely two solutions: (1) modulating the expression of membrane-bound transhydrogenase (mTH) in every population; (2) simultaneously consuming glucose with acetate, an unfavored byproduct normally excreted during glucose catabolism, in two subpopulations. Notably, mTH displays broad phylogenetic distribution and has also played a predominant role in laboratory evolution of Methylobacterium extorquens deficient in NADPH production. Convergent evolution of two phylogenetically and metabolically distinct species suggests mTH as a conserved buffering mechanism that promotes the robustness and evolvability of metabolism. Moreover, adaptive diversification via evolving dual substrate consumption highlights the flexibility of physiological systems to exploit ecological opportunities. The structure of biological networks, like traffic systems or the Internet, features few hubs connected by numerous components. Though the conservation and high connectivity of hubs serve as key junctions to promote network expansion, addition or removal of connections surrounding hubs may disturb the whole system through their global linkage. How do biological networks mitigate hub perturbations during evolution? Using metabolism as an example, we studied the physiological and evolutionary consequences of genetically perturbed production of a hub metabolite NADPH in E. coli. We found that the expression of mTH, a phylogenetically conserved enzyme, was immediately upregulated and essential to counteract the hub perturbation. Moreover, long-term evolution of this pathway-modified E. coli in glucose growth media recurrently selected for mTH-upregulating mutations to restore the NADPH balance in all twelve replicate populations, regardless of several alternative solutions suggested in the literature. Corroborated by similar findings from laboratory evolution of a highly diverged species M. extorquens, our study suggests that mechanisms dedicated to mitigating hub perturbations promote both the robustness and evolvability of biological networks.
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