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The 5-formyltetrahydrofolate futile cycle reduces pathway stochasticity in an extended hybrid-stochastic model of folate-mediated one-carbon metabolism
Scientific Reports ( IF 3.8 ) Pub Date : 2019-03-13 , DOI: 10.1038/s41598-019-40230-4
Karla Misselbeck , Luca Marchetti , Corrado Priami , Patrick J. Stover , Martha S. Field

In folate-mediated one-carbon metabolism (FOCM), 5-formyltetrahydrofolate (5fTHF), a one-carbon substituted tetrahydrofolate (THF) vitamer, acts as an intracellular storage form of folate and as an inhibitor of the folate-dependent enzymes phosphoribosylaminoimidazolecarboxamide formyltransferase (AICARFT) and serine hydroxymethyltransferase (SHMT). Cellular levels of 5fTHF are regulated by a futile cycle comprising the enzymes SHMT and 5,10-methenyltetrahydrofolate synthetase (MTHFS). MTHFS is an essential gene in mice; however, the roles of both 5fTHF and MTHFS in mammalian FOCM remain to be fully elucidated. We present an extension of our previously published hybrid-stochastic model of FOCM by including the 5fTHF futile-cycle to explore its effect on the FOCM network. Model simulations indicate that MTHFS plays an essential role in preventing 5fTHF accumulation, which consequently averts inhibition of all other reactions in the metabolic network. Moreover, in silico experiments show that 10-formylTHF inhibition of MTHFS is critical for regulating purine synthesis. Model simulations also provide evidence that 5-methylTHF (and not 5fTHF) is the predominant physiological binder/inhibitor of SHMT. Finally, the model simulations indicate that the 5fTHF futile cycle dampens the stochastic noise in FOCM that results from both folate deficiency and a common variant in the methylenetetrahydrofolate reductase (MTHFR) gene.



中文翻译:

5-甲酰基四氢叶酸的无用循环在叶酸介导的一碳代谢的扩展混合-随机模型中降低了路径的随机性

在叶酸介导的一碳代谢(FOCM)中,一碳取代的四氢叶酸(THF)维生素5-甲酰基四氢叶酸(5fTHF)充当叶酸的细胞内储存形式,并作为叶酸依赖性酶的磷酸核糖基氨基咪唑羧酰胺甲酰转移酶的抑制剂(AICARFT)和丝氨酸羟甲基转移酶(SHMT)。细胞的5fTHF水平受无效循环的调节,该循环包括酶SHMT和5,10-亚甲基四氢叶酸合成酶(MTHFS)。MTHFS是小鼠的必需基因。然而,5fTHF和MTHFS在哺乳动物FOCM中的作用仍有待充分阐明。我们通过包括5fTHF无效循环来探讨我们对FOCM网络的影响,从而扩展了我们先前发布的FOCM混合随机模型。模型仿真表明,MTHFS在防止5fTHF积累中起着至关重要的作用,从而避免了对代谢网络中所有其他反应的抑制。而且,硅计算机实验表明,抑制10-甲酰基THF对MTHFS的作用对于调节嘌呤的合成至关重要。模型模拟还提供了证据,表明5-甲基THF(而不是5fTHF)是SHMT的主要生理结合剂/抑制剂。最后,模型仿真表明,5fTHF无效循环抑制了叶酸缺乏和亚甲基四氢叶酸还原酶(MTHFR)基因的常见变异造成的FOCM中的随机噪声。

更新日期:2019-03-13
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