Department of Systems Biology, Institute of Cytology and Genetics SB RAS, 630090 Novosibirsk, Russia.
Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia.
Int J Mol Sci. 2023 Mar 2;24(5):4806. doi: 10.3390/ijms24054806.
Earlier studies aimed at investigating the metabolism of endogenous nucleoside triphosphates in synchronous cultures of cells revealed an auto-oscillatory mode of functioning of the pyrimidine and purine nucleotide biosynthesis system, which the authors associated with the dynamics of cell division. Theoretically, this system has an intrinsic oscillatory potential, since the dynamics of its functioning are controlled through feedback mechanisms. The question of whether the nucleotide biosynthesis system has its own oscillatory circuit is still open. To address this issue, an integral mathematical model of pyrimidine biosynthesis was developed, taking into account all experimentally verified negative feedback in the regulation of enzymatic reactions, the data of which were obtained under in vitro conditions. Analysis of the dynamic modes of the model functioning has shown that in the pyrimidine biosynthesis system, both the steady-state and oscillatory functioning modes can be realized under certain sets of kinetic parameters that fit in the physiological boundaries of the investigated metabolic system. It has been demonstrated that the occurrence of the oscillatory nature of metabolite synthesis depended on the ratio of two parameters: the Hill coefficient, -the nonlinearity of the UMP effect on the activity of carbamoyl-phosphate synthetase, and the parameter characterizing the contribution of the noncompetitive mechanism of UTP inhibition to the regulation of the enzymatic reaction of UMP phosphorylation. Thus, it has been theoretically shown that the pyrimidine biosynthesis system possesses its own oscillatory circuit whose oscillatory potential depends to a significant degree on the mechanism of regulation of UMP kinase activity.
早期的研究旨在研究细胞同步培养物中内源性核苷三磷酸的代谢，揭示嘧啶和嘌呤核苷酸生物合成系统的自动振荡工作模式，作者将其与细胞分裂动力学联系起来。从理论上讲，由于其功能的动态受反馈机制控制，该系统具有内在的振荡潜力。核苷酸生物合成系统是否具有自己的振荡电路的问题仍然没有答案。为了解决这个问题，开发了嘧啶生物合成的整体数学模型，该模型考虑了在酶促反应调节中所有经过实验验证的负反馈，这些数据是在体外条件下获得的。对模型功能的动态模式的分析表明，在嘧啶生物合成系统中，在符合所研究代谢系统生理边界的某些动力学参数集下，可以实现稳态和振荡工作模式。已经证明，代谢物合成的振荡性质的发生取决于两个参数的比值：Hill 系数-UMP 对氨甲酰磷酸合成酶活性的非线性作用，以及参数表征 UTP 抑制的非竞争性机制对 UMP 磷酸化酶促反应的调节的贡献。因此，从理论上表明嘧啶生物合成系统具有自己的振荡电路，其振荡势在很大程度上取决于 UMP 激酶活性调节的机制。
