Department of Mathematics, Duke University, Durham, North Carolina, United States of America.
Department of Biology, Duke University, Durham, North Carolina, United States of America.
PLoS Comput Biol. 2021 Dec 16;17(12):e1009708. doi: 10.1371/journal.pcbi.1009708. eCollection 2021 Dec.
Many enzymes in one-carbon metabolism (OCM) are up- or down-regulated by the sex hormones which vary diurnally and throughout the menstrual cycle. During pregnancy, estradiol and progesterone levels increase tremendously to modulate physiological changes in the reproductive system. In this work, we extend and improve an existing mathematical model of hepatic OCM to understand the dynamic metabolic changes that happen during the menstrual cycle and pregnancy due to estradiol variation. In particular, we add the polyamine drain on S-adenosyl methionine and the direct effects of estradiol on the enzymes cystathionine β-synthase (CBS), thymidylate synthase (TS), and dihydrofolate reductase (DHFR). We show that the homocysteine concentration varies inversely with estradiol concentration, discuss the fluctuations in 14 other one-carbon metabolites and velocities throughout the menstrual cycle, and draw comparisons with the literature. We then use the model to study the effects of vitamin B12, vitamin B6, and folate deficiencies and explain why homocysteine is not a good biomarker for vitamin deficiencies. Additionally, we compute homocysteine throughout pregnancy, and compare the results with experimental data. Our mathematical model explains how numerous homeostatic mechanisms in OCM function and provides new insights into how homocysteine and its deleterious effects are influenced by estradiol. The mathematical model can be used by others for further in silico experiments on changes in one-carbon metabolism during the menstrual cycle and pregnancy.
许多一碳代谢（OCM）中的酶受到性激素的调节，性激素的水平会随昼夜和月经周期而变化。在怀孕期间，雌二醇和孕酮水平会大幅升高，以调节生殖系统的生理变化。在这项工作中，我们扩展并改进了现有的肝脏 OCM 数学模型，以了解由于雌二醇变化而在月经周期和怀孕期间发生的动态代谢变化。特别是，我们添加了聚胺对 S-腺苷甲硫氨酸的消耗以及雌二醇对胱硫醚β-合酶（CBS）、胸苷酸合成酶（TS）和二氢叶酸还原酶（DHFR）的直接作用。我们表明，同型半胱氨酸浓度与雌二醇浓度呈反比，讨论了月经周期中 14 种其他一碳代谢物和速度的波动，并与文献进行了比较。然后，我们使用该模型研究了维生素 B12、维生素 B6 和叶酸缺乏的影响，并解释了为什么同型半胱氨酸不是维生素缺乏的良好生物标志物。此外，我们还计算了整个怀孕期间的同型半胱氨酸，并将结果与实验数据进行了比较。我们的数学模型解释了 OCM 中的许多体内平衡机制是如何运作的，并提供了关于同型半胱氨酸及其有害影响如何受雌二醇影响的新见解。其他人可以使用该数学模型对月经周期和怀孕期间一碳代谢变化进行进一步的计算机模拟实验。
