Institutes of Evolutionary Biology and Environmental Studies, University of Zurich, CH-8057 Zurich, Switzerland.
Proc Natl Acad Sci U S A. 2012 May 1;109(18):E1121-30. doi: 10.1073/pnas.1113065109. Epub 2012 Apr 16.
The metabolic genotype of an organism can change through loss and acquisition of enzyme-coding genes, while preserving its ability to survive and synthesize biomass in specific environments. This evolutionary plasticity allows pathogens to evolve resistance to antimetabolic drugs by acquiring new metabolic pathways that bypass an enzyme blocked by a drug. We here study quantitatively the extent to which individual metabolic reactions and enzymes can be bypassed. To this end, we use a recently developed computational approach to create large metabolic network ensembles that can synthesize all biomass components in a given environment but contain an otherwise random set of known biochemical reactions. Using this approach, we identify a small connected core of 124 reactions that are absolutely superessential (that is, required in all metabolic networks). Many of these reactions have been experimentally confirmed as essential in different organisms. We also report a superessentiality index for thousands of reactions. This index indicates how easily a reaction can be bypassed. We find that it correlates with the number of sequenced genomes that encode an enzyme for the reaction. Superessentiality can help choose an enzyme as a potential drug target, especially because the index is not highly sensitive to the chemical environment that a pathogen requires. Our work also shows how analyses of large network ensembles can help understand the evolution of complex and robust metabolic networks.
生物体的代谢基因型可以通过失去和获得编码酶的基因而改变，同时保持其在特定环境中生存和合成生物量的能力。这种进化的可塑性使病原体能够通过获得绕过药物阻断的酶的新代谢途径来对抗代谢药物产生抗药性。在这里，我们定量研究了个体代谢反应和酶可以被绕过的程度。为此，我们使用了一种最近开发的计算方法来创建大型代谢网络集合，这些集合可以在给定的环境中合成所有生物量成分，但包含一组已知的随机生化反应。使用这种方法，我们确定了 124 个反应的小连通核心，这些反应是绝对必需的（即在所有代谢网络中都需要）。其中许多反应已经在不同的生物体中被实验证实是必需的。我们还报告了数千个反应的超必需性指数。该指数表示反应被绕过的难易程度。我们发现它与编码该反应酶的测序基因组数量相关。超必需性有助于选择酶作为潜在的药物靶点，特别是因为该指数对病原体所需的化学环境不太敏感。我们的工作还表明，对大型网络集合的分析如何帮助理解复杂和稳健的代谢网络的进化。
