Almaas Eivind, Oltvai Zoltán N, Barabási Albert-László
Microbial Systems Division, Biosciences Directorate, Lawrence Livermore National Laboratory, Livermore, California, USA.
PLoS Comput Biol. 2005 Dec;1(7):e68. doi: 10.1371/journal.pcbi.0010068. Epub 2005 Dec 16.
Understanding the system-level adaptive changes taking place in an organism in response to variations in the environment is a key issue of contemporary biology. Current modeling approaches, such as constraint-based flux-balance analysis, have proved highly successful in analyzing the capabilities of cellular metabolism, including its capacity to predict deletion phenotypes, the ability to calculate the relative flux values of metabolic reactions, and the capability to identify properties of optimal growth states. Here, we use flux-balance analysis to thoroughly assess the activity of Escherichia coli, Helicobacter pylori, and Saccharomyces cerevisiae metabolism in 30,000 diverse simulated environments. We identify a set of metabolic reactions forming a connected metabolic core that carry non-zero fluxes under all growth conditions, and whose flux variations are highly correlated. Furthermore, we find that the enzymes catalyzing the core reactions display a considerably higher fraction of phenotypic essentiality and evolutionary conservation than those catalyzing noncore reactions. Cellular metabolism is characterized by a large number of species-specific conditionally active reactions organized around an evolutionary conserved, but always active, metabolic core. Finally, we find that most current antibiotics interfering with bacterial metabolism target the core enzymes, indicating that our findings may have important implications for antimicrobial drug-target discovery.
理解生物体为响应环境变化而发生的系统层面适应性变化是当代生物学的一个关键问题。当前的建模方法，如基于约束的通量平衡分析，已被证明在分析细胞代谢能力方面非常成功，包括预测基因敲除表型的能力、计算代谢反应相对通量值的能力以及识别最优生长状态特性的能力。在此，我们使用通量平衡分析来全面评估大肠杆菌、幽门螺杆菌和酿酒酵母在30000种不同模拟环境中的代谢活性。我们识别出一组形成连通代谢核心的代谢反应，这些反应在所有生长条件下都具有非零通量，并且其通量变化高度相关。此外，我们发现催化核心反应的酶比催化非核心反应的酶表现出更高比例的表型必需性和进化保守性。细胞代谢的特征是围绕一个进化保守但始终活跃的代谢核心组织了大量物种特异性的条件性活跃反应。最后，我们发现大多数干扰细菌代谢的现有抗生素靶向核心酶，这表明我们的发现可能对抗菌药物靶点发现具有重要意义。
