Martinov M V, Vitvitsky V M, Mosharov E V, Banerjee R, Ataullakhanov F I
National Research Center for Hematology, Moscow, 125167, Russia.
J Theor Biol. 2000 Jun 21;204(4):521-32. doi: 10.1006/jtbi.2000.2035.
We propose a simple mathematical model of liver S -adenosylmethionine (AdoMet) metabolism. Analysis of the model has shown that AdoMet metabolism can operate under two different modes. The first, with low metabolic rate and low AdoMet concentration, serves predominantly to supply the cell with AdoMet, the substrate for various cellular methylation reactions. The second, with high metabolic rate and high AdoMet concentration, provides an avenue for cleavage of excess methionine and can serve as a source of cysteine when its increased synthesis is necessary. The switch that triggers interconversion between the "low" and "high" modes is methionine concentration. Under a certain set of parameters both modes may coexist. This behavior results from the kinetic properties of (i) the two isoenzymes of AdoMet synthetase, MATI and MATIII, that catalyse AdoMet production; one is inhibited by AdoMet, whereas the other is activated by it, and (ii) glycine- N -methyltransferase that displays highly cooperative kinetics that is different from that of other AdoMet-dependent methyltransferases. Thus, the model provides an explanation for how different cellular needs are met by regulation of this pathway. The model also correctly identifies a critical role for glycine N -methyltransferase in depleting excess methionine in the high mode, thus avoiding the toxicity associated with elevated levels of this essential amino acid.
我们提出了一个简单的肝脏S-腺苷甲硫氨酸（AdoMet）代谢数学模型。对该模型的分析表明，AdoMet代谢可以在两种不同模式下运行。第一种模式下，代谢率低且AdoMet浓度低，主要为细胞提供AdoMet，它是各种细胞甲基化反应的底物。第二种模式下，代谢率高且AdoMet浓度高，为过量甲硫氨酸的裂解提供了一条途径，并且在需要增加半胱氨酸合成时可作为半胱氨酸的来源。触发“低”模式和“高”模式相互转换的开关是甲硫氨酸浓度。在一组特定参数下，两种模式可能共存。这种行为源于以下两种酶的动力学特性：（i）催化AdoMet生成的两种腺苷甲硫氨酸合成酶同工酶MATI和MATIII，其中一种被AdoMet抑制，而另一种被其激活；（ii）甘氨酸-N-甲基转移酶，其表现出与其他依赖AdoMet的甲基转移酶不同的高度协同动力学。因此，该模型解释了如何通过调节这条途径来满足不同的细胞需求。该模型还正确地确定了甘氨酸-N-甲基转移酶在高模式下消耗过量甲硫氨酸中的关键作用，从而避免了与这种必需氨基酸水平升高相关的毒性。
