Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Biomedical Engineering, Boston University, Boston, MA, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland; Systems Biology Graduate School, Zurich 8057, Switzerland.
Cell Rep. 2017 Sep 12;20(11):2666-2677. doi: 10.1016/j.celrep.2017.08.066.
Metabolic flux is in part regulated by endogenous small molecules that modulate the catalytic activity of an enzyme, e.g., allosteric inhibition. In contrast to transcriptional regulation of enzymes, technical limitations have hindered the production of a genome-scale atlas of small molecule-enzyme regulatory interactions. Here, we develop a framework leveraging the vast, but fragmented, biochemical literature to reconstruct and analyze the small molecule regulatory network (SMRN) of the model organism Escherichia coli, including the primary metabolite regulators and enzyme targets. Using metabolic control analysis, we prove a fundamental trade-off between regulation and enzymatic activity, and we combine it with metabolomic measurements and the SMRN to make inferences on the sensitivity of enzymes to their regulators. Generalizing the analysis to other organisms, we identify highly conserved regulatory interactions across evolutionarily divergent species, further emphasizing a critical role for small molecule interactions in the maintenance of metabolic homeostasis.
代谢通量部分受到内源性小分子的调节，这些小分子可以调节酶的催化活性，例如别构抑制。与酶的转录调控相比，技术限制阻碍了全基因组范围内小分子-酶调控相互作用图谱的生成。在这里，我们开发了一种利用广泛但碎片化的生化文献来重建和分析模型生物大肠杆菌小分子调控网络（SMRN）的框架，包括主要代谢物调节剂和酶靶标。使用代谢控制分析，我们证明了调节和酶活性之间的基本权衡，并且我们将其与代谢组学测量和 SMRN 相结合，对酶对其调节剂的敏感性进行推断。将分析推广到其他生物体，我们在进化上差异很大的物种中发现了高度保守的调控相互作用，进一步强调了小分子相互作用在维持代谢稳态中的关键作用。
