Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase
Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase
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DOI：
10.1016/j.ymgme.2007.02.001
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发表时间：
2007-05-01
影响因子：
3.8
通讯作者：
Matthews, Rowena G.
中科院分区：
文献类型：
--
作者：
Elmore, C. Lee;Wu, Xuchu;Matthews, Rowena G.
高同型半胱氨酸血症是一种代谢紊乱，与叶酸库的分布有关，叶酸库为嘌呤和胸苷酸的生物合成以及同型半胱氨酸的再甲基化形成甲硫氨酸提供一碳单位。在人类中，甲硫氨酸合酶缺乏导致甲基四氢叶酸的积累，而嘌呤和胸苷酸生物合成所需的叶酸衍生物则以牺牲为代价。小鼠蛋氨酸合酶活性的完全消除导致胚胎死亡。其他高同型半胱氨酸血症的小鼠模型具有正常或降低的甲基四氢叶酸水平，并且不是胚胎致死性的，尽管它们具有降低的α-Met/β-Hcy比率和受损的甲基化。我们构建了一个小鼠模型，在Mtrr基因中插入一个基因陷阱，指定蛋氨酸合成酶还原酶，蛋氨酸合成酶活性所必需的酶。该模型是一种亚形态，甲硫氨酸合成酶还原酶活性降低，从而避免了与甲硫氨酸合成酶活性缺失相关的致命性。Mtrr（g1/g1）小鼠血浆同型半胱氨酸增加，血浆蛋氨酸减少，组织甲基四氢叶酸增加。出乎意料的是，Mtrr（gt/gt）小鼠在大多数组织中没有显示出α Met/β Hcy比率的降低。不同的高同型半胱氨酸血症遗传小鼠模型中不同的代谢产物谱可能有助于理解同型半胱氨酸升高的生物学效应。(C)2007爱思唯尔公司All rights reserved.
Hyperhomocyst(e)inemia is a metabolic derangement that is linked to the distribution of folate pools, which provide one-carbon units for biosynthesis of purines and thymidylate and for remethylation of homocysteine to form methionine. In humans, methionine synthase deficiency results in the accumulation of methyltetrahydrofolate at the expense of folate derivatives required for purine and thymidylate biosynthesis. Complete ablation of methionine synthase activity in mice results in embryonic lethality. Other mouse models for hyperhomocyst(e)inemia have normal or reduced levels of methyltetrahydrofolate and are not embryonic lethal, although they have decreased ratios of AdoMet/AdoHcy and impaired methylation. We have constructed a mouse model with a gene trap insertion in the Mtrr gene specifying methionine synthase reductase, an enzyme essential for the activity of methionine synthase. This model is a hypomorph, with reduced methionine synthase reductase activity, thus avoiding the lethality associated with the absence of methionine synthase activity. Mtrr(g1/g1) mice have increased plasma homocyst(e)ine, decreased plasma methionine, and increased tissue methyltetrahydrofolate. Unexpectedly, Mtrr(gt/gt) mice do not show decreases in the AdoMet/AdoHcy ratio in most tissues. The different metabolite profiles in the various genetic mouse models for hyperhomocyst(e)inemia may be useful in understanding biological effects of elevated homocyst(e)ine. (C) 2007 Elsevier Inc. All rights reserved.