In silico experimentation with a model of hepatic mitochondrial folate metabolism
In silico experimentation with a model of hepatic mitochondrial folate metabolism
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DOI：
10.1186/1742-4682-3-40
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发表时间：
2006-01-01
影响因子：
--
通讯作者：
Ulrich, Cornelia M.
中科院分区：
文献类型：
--
作者：
Nijhout, H. Frederik;Reed, Michael C.;Ulrich, Cornelia M.
背景：在真核生物中，叶酸代谢是分开的，并且发生在细胞质和线粒体中。这种区室化的功能以及在胚胎发育和快速生长的癌细胞中线粒体区室发生的巨大变化正在逐渐被人们所了解，尽管许多方面仍然令人困惑和有争议。 方法：我们通过实验肝脏一碳代谢的数学模型来探索细胞质和线粒体叶酸代谢的特性。该模型基于线粒体和胞质酶的已知生化特性。我们使用该模型来研究实验文献中提出的有关细胞质和线粒体叶酸循环的相对作用的问题。我们研究了：线粒体和胞浆丝氨酸羟甲基转移酶 (SHMT) 反应方向的控制、线粒体双功能酶的作用、甘氨酸裂解系统的作用、丝氨酸和甘氨酸输入变化的影响以及蛋氨酸和蛋白质负载的影响。结论：该模型再现了许多实验结果，并对线粒体叶酸代谢的基本特性给出了新的见解。特别有趣的是，面对丝氨酸和甘氨酸输入的巨大变化，线粒体中甲酸盐的产生具有显着的稳定性。该模型表明，在双功能酶存在的情况下（如在胚胎组织和癌细胞中），线粒体主要通过甲酸的输出支持胞质嘌呤和嘧啶的合成，而在成人组织中，线粒体产生用于糖异生的丝氨酸。
Background: In eukaryotes, folate metabolism is compartmentalized and occurs in both the cytosol and the mitochondria. The function of this compartmentalization and the great changes that occur in the mitochondrial compartment during embryonic development and in rapidly growing cancer cells are gradually becoming understood, though many aspects remain puzzling and controversial.Approach: We explore the properties of cytosolic and mitochondrial folate metabolism by experimenting with a mathematical model of hepatic one-carbon metabolism. The model is based on known biochemical properties of mitochondrial and cytosolic enzymes. We use the model to study questions about the relative roles of the cytosolic and mitochondrial folate cycles posed in the experimental literature. We investigate: the control of the direction of the mitochondrial and cytosolic serine hydroxymethyltransferase (SHMT) reactions, the role of the mitochondrial bifunctional enzyme, the role of the glycine cleavage system, the effects of variations in serine and glycine inputs, and the effects of methionine and protein loading.Conclusion: The model reproduces many experimental findings and gives new insights into the underlying properties of mitochondrial folate metabolism. Particularly interesting is the remarkable stability of formate production in the mitochondria in the face of large changes in serine and glycine input. The model shows that in the presence of the bifunctional enzyme (as in embryonic tissues and cancer cells), the mitochondria primarily support cytosolic purine and pyrimidine synthesis via the export of formate, while in adult tissues the mitochondria produce serine for gluconeogenesis.