Determining the underlying principles behind biological regulation is important for understanding the principles of life, treating complex diseases and creating de novo synthetic biology. Buffering—the use of reservoirs of molecules to maintain molecular concentrations—is a widespread and important mechanism for biological regulation. However, a lack of theory has limited our understanding of its roles and quantified effects. Here, we study buffering in energy metabolism using control theory and novel buffer analysis. We find that buffering can enable the simultaneous, independent control of multiple coupled outputs. In metabolism, adenylate kinase and AMP deaminase enable simultaneous control of ATP and adenylate energy ratios, while feedback on metabolic pathways is fundamentally limited to controlling one of these outputs. We also quantify the regulatory effects of the phosphagen system—the above buffers and creatine kinase—revealing which mechanisms regulate which outputs. The results are supported by human muscle and mouse adipocyte data. Together, these results illustrate the synergy of feedback and buffering in molecular biology to simultaneously control multiple outputs.

确定生物调控背后的基本原理对于理解生命原理、治疗复杂疾病和创建从头合成生物学非常重要。缓冲——利用分子库来维持分子浓度——是一种广泛且重要的生物调节机制。然而，缺乏理论限制了我们对其作用和量化效果的理解。在这里，我们利用控制理论和新颖的缓冲分析来研究能量代谢中的缓冲。我们发现缓冲可以实现多个耦合输出的同时、独立控制。在代谢中，腺苷酸激酶和 AMP 脱氨酶能够同时控制 ATP 和腺苷酸能量比率，而代谢途径的反馈从根本上仅限于控制这些输出之一。我们还量化了磷酸原系统（上述缓冲液和肌酸激酶）的调节作用，揭示了哪些机制调节哪些输出。该结果得到人类肌肉和小鼠脂肪细胞数据的支持。总之，这些结果说明了分子生物学中反馈和缓冲的协同作用，以同时控制多个输出。