Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure.
Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure.
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DOI：
10.1016/j.celrep.2017.10.072
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发表时间：
2017-11-14
期刊：
影响因子：
8.8
通讯作者：
Greene NDE
中科院分区：
文献类型：
--
作者：
Leung KY;Pai YJ;Chen Q;Santos C;Calvani E;Sudiwala S;Savery D;Ralser M;Gross SS;Copp AJ;Greene NDE
异常叶酸单碳代谢（FOCM）与神经管缺陷（NTD），神经系统的严重畸形有关。MTHFR介导甲基从叶酸循环到甲硫氨酸循环的单向转移，因此，代表了FOCM功能输出之间的一碳单元分区的关键联系。甲硫氨酸循环抑制剂防止小鼠胚胎神经管闭合。类似地，不能使用甘氨酸作为叶酸循环的一碳供体导致甘氨酸脱羧酶（Gldc）缺陷胚胎中的NTD。然而，对Mthfr缺失小鼠胚胎的分析表明，S-腺苷甲硫氨酸丰度和神经管闭合都不依赖于来自胚胎或母体叶酸循环的一碳单位。Mthfr缺失或甲硫氨酸处理通过保留叶酸循环内的一碳单位来防止Gldc无效胚胎中的NTD。总的来说，神经管闭合取决于蛋氨酸和叶酸循环的活性，但循环之间的一碳单元转移是不必要的。抑制甲硫氨酸循环活性防止神经管闭合，引起NTDs胚胎和母体MTHFR活性的丧失不能防止神经管闭合甘氨酸是胚胎中通过甘氨酸裂解系统的叶酸循环的1C供体甘氨酸裂解的消除引起NTDs，Leung等人发现胚胎神经管闭合依赖于一种或多种细胞因子的供应，从甘氨酸裂解和甲硫氨酸循环上的叶酸循环的碳单元。相比之下，通过MTHFR将一碳单元从叶酸循环转移到甲硫氨酸循环是不必要的。
Abnormal folate one-carbon metabolism (FOCM) is implicated in neural tube defects (NTDs), severe malformations of the nervous system. MTHFR mediates unidirectional transfer of methyl groups from the folate cycle to the methionine cycle and, therefore, represents a key nexus in partitioning one-carbon units between FOCM functional outputs. Methionine cycle inhibitors prevent neural tube closure in mouse embryos. Similarly, the inability to use glycine as a one-carbon donor to the folate cycle causes NTDs in glycine decarboxylase (Gldc)-deficient embryos. However, analysis of Mthfr-null mouse embryos shows that neither S-adenosylmethionine abundance nor neural tube closure depend on one-carbon units derived from embryonic or maternal folate cycles. Mthfr deletion or methionine treatment prevents NTDs in Gldc-null embryos by retention of one-carbon units within the folate cycle. Overall, neural tube closure depends on the activity of both the methionine and folate cycles, but transfer of one-carbon units between the cycles is not necessary. Inhibition of methionine cycle activity prevents neural tube closure, causing NTDs Loss of embryonic and maternal MTHFR activity does not prevent neural tube closure Glycine is a 1C donor to the folate cycle via the glycine cleavage system in the embryo Ablation of glycine cleavage causes NTDs, preventable by MTHFR inactivity or methionine Leung at al. find that embryonic neural tube closure depends both on the supply of one-carbon units to the folate cycle from glycine cleavage and on the methionine cycle. In contrast, transfer of one-carbon units from the folate cycle to the methionine cycle by MTHFR is dispensable.
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DOI：
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发表时间：
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期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
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作者：
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