Tareen Samar Hk, Kutmon Martina, Arts Ilja Cw, de Kok Theo M, Evelo Chris T, Adriaens Michiel E
1Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands.
2Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.
Genes Nutr. 2019 Sep 9;14:27. doi: 10.1186/s12263-019-0647-5. eCollection 2019.
Metabolic flexibility is the ability of an organism to switch between substrates for energy metabolism, in response to the changing nutritional state and needs of the organism. On the cellular level, metabolic flexibility revolves around the tricarboxylic acid cycle by switching acetyl coenzyme A production from glucose to fatty acids and vice versa. In this study, we modelled cellular metabolic flexibility by constructing a logical model connecting glycolysis, fatty acid oxidation, fatty acid synthesis and the tricarboxylic acid cycle, and then using network analysis to study the behaviours of the model.
We observed that the substrate switching usually occurs through the inhibition of pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinases (PDK), which moves the metabolism from glycolysis to fatty acid oxidation. Furthermore, we were able to verify four different regulatory models of PDK to contain known biological observations, leading to the biological plausibility of all four models across different cells and conditions.
These results suggest that the cellular metabolic flexibility depends upon the PDC-PDK regulatory interaction as a key regulatory switch for changing metabolic substrates.
代谢灵活性是生物体根据自身营养状态和需求的变化在能量代谢底物之间进行切换的能力。在细胞水平上，代谢灵活性围绕三羧酸循环展开，通过将乙酰辅酶A的产生从葡萄糖切换到脂肪酸，反之亦然。在本研究中，我们通过构建一个连接糖酵解、脂肪酸氧化、脂肪酸合成和三羧酸循环的逻辑模型来模拟细胞代谢灵活性，然后使用网络分析来研究该模型的行为。
我们观察到，底物切换通常通过丙酮酸脱氢酶激酶（PDK）对丙酮酸脱氢酶复合体（PDC）的抑制来实现，这使得代谢从糖酵解转向脂肪酸氧化。此外，我们能够验证PDK的四种不同调节模型包含已知的生物学观察结果，从而使所有四种模型在不同细胞和条件下都具有生物学合理性。
这些结果表明，细胞代谢灵活性依赖于PDC-PDK调节相互作用，这是改变代谢底物的关键调节开关。
