FOLATE VITAMIN-B12 INTERRELATIONSHIPS IN THE CENTRAL-NERVOUS-SYSTEM
FOLATE VITAMIN-B12 INTERRELATIONSHIPS IN THE CENTRAL-NERVOUS-SYSTEM
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DOI：
10.1079/pns19920032
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发表时间：
1992-08-01
影响因子：
7
通讯作者：
SCOTT, JM
中科院分区：
文献类型：
--
作者：
SCOTT, JM
对于贫血如何发生，最广为接受的解释是，维生素 B12 缺乏会干扰叶酸辅助因子的功能，这一点由 Herbert & Zalushy (1962) 提出，通常称为“甲基陷阱假说”。叶酸通常充当接受所谓 CI 单位的辅酶，这些单位通过参与组氨酸、甲酸、肌氨酸和甘氨酸降解的酶或通过将丝氨酸转化为甘氨酸的丝氨酸羟甲基转移酶 (EC 2.1. 2.1) 转移到叶酸上。最后一个反应在数量和功能上都是最重要的，特别是在复制细胞时。此反应和其他反应中产生的 C1 辅因子随后用于生物合成反应。因此，10-甲酰四氢叶酸被用作参与嘌呤生物合成的两种酶的cci因子，而5，10-亚甲基四氢叶酸则参与嘧啶生物合成（图1）。除了在嘌呤和嘧啶以及 DNA 和 RNA 的生物合成中发挥作用外，叶酸还为数十种甲基转移酶提供甲基来源。这是通过将 5, 10-亚甲基四氢叶酸转化为 5-甲基四氢叶酸来完成的，后者通过维生素 B~ 依赖性酶蛋氨酸合酶 (EC 2.1. 1.13) 将同型半胱氨酸甲基化为蛋氨酸（图 1）。然后，这种蛋氨酸可以用 ATP 激活，产生 S-腺苷蛋氨酸 (SAM)，而 SAM 又可以将其甲基提供给甲基转移酶，从而产生甲基化产物和 S-腺苷高半胱氨酸 (SAH)。正常情况下，这种 SAH 不允许在细胞中积累，并且会被酶水解为同型半胱氨酸。然后可以通过蛋氨酸合酶将其再循环回蛋氨酸和 SAM，其中新的甲基由 5-甲基四氢叶酸提供。甲基陷阱假说表明，5，10-亚甲基四氢叶酸向5-甲基四氢叶酸的酶促转化在体内是不可逆的，并且一旦后一种辅因子形成，就需要功能正常的甲硫氨酸合酶才能再次成为其他叶酸辅因子库的一部分。有人认为，维生素 B12 缺乏或蛋氨酸合酶被麻醉气体一氧化二氮等失活时（参见第 221 页），细胞叶酸辅助因子会以 5-甲基四氢叶酸的形式代谢被捕获。细胞无法使该辅因子去甲基化，导致其积累，但以 DNA 和 RNA 生物合成中使用的那些形式为代价。因此，这些细胞将处于一种假性叶酸缺乏状态，最明显的是贫血。细胞会如此轻易地、愚蠢地参与自身的毁灭，乍一看似乎不太可能。然而，Kutzbach & Stokstad (1967) 的发现解决了这个问题，即细胞中 5-甲基四氢叶酸的合成受 SAM 水平的控制。当甲硫氨酸合酶的活性为 https://doi 时，SAM 水平可能会下降。 org/10.1079/PNS19920032 由剑桥大学出版社在线出版
The most accepted explanation as to how the anaemia arises is that vitamin B12 deficiency interferes with the functioning of the folate cofactors as put forward by Herbert & Zalushy (1962) and commonly called the ‘methyl trap hypothesis’. The folates normally function as coenzymes that accept so-called CI units, which are transferred to them by enzymes involved in the degradation of histidine, formate, sarcosine and glycine or by the enzyme serine hydroxymethyltransferase (EC 2.1. 2.1) which converts serine to glycine. This last reaction is quantitatively and functionally the most important, particularly in replicating cells. The C1 cofactors produced in this and the other reactions are then used in biosynthetic reactions. Thus, 10-formyltetrahydrofolate is used as a ccifactor for two of the enzymes involved in purine biosynthesis, while 5, lO-methylenetetrahydro-folate is involved in pyrimidine biosynthesis (Fig. 1). Apart from this role in the biosynthesis of purines and pyrimidines and, thus, DNA and RNA, the folates provide a source of methyl groups for dozens of methyltransferase enzymes. This is done by converting 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate with this latter being used to methylate homocysteine to methionine by the vitamin B~ dependent enzyme methionine synthase (EC 2.1. 1.13)(Fig. 1). This methionine can then be activated with ATP to produce S-adenosylmethionine (SAM) which in turn can donate its methyl group to a methyltransferase giving a methylated product and S-adenosylhomocysteine (SAH). Normally in cells this SAH is not permitted to accumulate and is enzymically hydrolysed to homocysteine. This can then be recycled back to methionine and SAM via methionine synthase with a new methyl group which would be donated by 5-methyltetrahydrofolate. The methyl trap hypothesis suggests that the enzymic conversion of 5, lO-methylenetetrahydrofolate to 5-methyltetrahydrofolate is irreversible in vivo and that once this latter cofactor is formed it requires a functioning methionine synthase for it to become available again as part of the pool of other folate cofactors. It is suggested that in vitamin B12 deficiency or when the enzyme methionine synthase is inactivated by, for example, the anaesthetic gas nitrous oxide (see p. 221), the cellular folate cofactors become metabolically trapped as 5-methyltetrahydrofolate. The inability of a cell to demethylate this cofactor results in its accumulation at the expense of those forms used in DNA and RNA biosynthesis. Thus, such cells would be in a sort of pseudo folatedeficient state most obviously seen as an anaemia. It might at first seem improbable that cells would so readily and foolishly participate in their own destruction. However, this was resolved by the finding by Kutzbach & Stokstad (1967) that the synthesis of 5-methyltetrahydrofolate in cells is controlled by the level of SAM. Falling levels of SAM, as might be expected to occur when the activity of methionine synthase is https://doi. org/10.1079/PNS19920032 Published online by Cambridge University Press