Folate deficiency affects histone methylation.
Folate deficiency affects histone methylation.
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DOI：
10.1016/j.mehy.2015.12.027
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发表时间：
2016-03
影响因子：
4.7
通讯作者：
Wagner C
中科院分区：
文献类型：
--
作者：
Garcia BA;Luka Z;Loukachevitch LV;Bhanu NV;Wagner C
甲醛与蛋白质产生交联肽链的反应是剧毒的。甲醛是许多酶促反应的代谢产物，这些酶是如何免受甲醛影响的，这个问题在很大程度上仍然没有答案。我们实验室的早期实验表明，两种肝脏线粒体酶，二甲基甘氨酸脱氢酶（DMGDH）和肌氨酸脱氢酶（SDH）催化氧化去甲基化反应（肌氨酸是单甲基甘氨酸的通用名称）。这些酶的酶促产物是去甲基化的底物和甲醛，由去除的甲基产生。DMGDH和SDH都含有FAD，并且都有紧密结合的四氢叶酸（THF），一种叶酸辅酶。四氢呋喃与甲醛可逆结合形成5,10-亚甲基四氢呋喃。当时我们证明纯化后的DMGDH与紧密结合的THF与反应过程中产生的甲醛反应生成5,10-亚甲基THF。这有效地清除了甲醛，保护了酶。近年来，组蛋白尾部的翻译后修饰已被证明对基因表达的表观遗传调控负责。其中一种修饰是赖氨酸残基的甲基化。第一个发现的完成这些修饰组蛋白去甲基化的酶是组蛋白赖氨酸去甲基化酶（LSD1）。LSD1特异性去除组蛋白3第4位二甲基化赖氨酸和单甲基化赖氨酸的甲基。该酶含有紧密结合的FAD，反应产物为去甲基化赖氨酸残渣和甲醛。LSD1去甲基化的机制类似于先前假设的DMGDH的机制，即n -甲基键氧化成亚甲基亚胺，然后水解生成甲醛。这表明THF可能还参与了LSD1反应，清除产生的甲醛。我们的假设是，THF类似于DMGDH和SDH与天然LSD1结合，结合的THF保护FAD类组蛋白去甲基化酶免受5,10-亚甲基THF形成的甲醛生成的破坏性影响。我们目前的初步数据显示，由于饮食叶酸缺乏导致肝脏叶酸减少与组蛋白3甲基化赖氨酸4水平升高有关。这可能是由于叶酸缺乏导致的可用于清除活性部位产生的甲醛的叶酸减少而导致LSD1活性降低的结果。由于LSD1可以调节基因表达，这表明叶酸可能发挥更重要的作用，而不仅仅是作为单碳单位的载体，并且可能是与低叶酸相关的其他疾病的一个因素。
Formaldehyde is extremely toxic reacting with proteins to crosslinks peptide chains. Formaldehyde is a metabolic product in many enzymatic reactions and the question of how these enzymes are protected from the formaldehyde that is generated has largely remained unanswered. Early experiments from our laboratory showed that two liver mitochondrial enzymes, dimethylglycine dehydrogenase (DMGDH) and sarcosine dehydrogenase (SDH) catalyze oxidative demethylation reactions (sarcosine is a common name for monomethylglycine). The enzymatic products of these enzymes were the demethylated substrates and formaldehyde, produced from the removed methyl group. Both DMGDH and SDH contain FAD and both have tightly bound tetrahydrofolate (THF), a folate coenzyme. THF binds reversibly with formaldehyde to form 5,10-methylene-THF. At that time we showed that purified DMGDH, with tightly bound THF, reacted with formaldehyde generated during the reaction to form 5,10-methylene-THF. This effectively scavenged the formaldehyde to protect the enzyme. Recently, post-translational modifications on histone tails have been shown to be responsible for epigenetic regulation of gene expression. One of these modifications is methylation of lysine residues. The first enzyme discovered to accomplish demethylation of these modified histones was histone lysine demethylase (LSD1). LSD1 specifically removes methyl groups from di- and mono-methylated lysines at position 4 of histone 3. This enzyme contained tightly bound FAD and the products of the reaction were the demethylated lysine residue and formaldehyde. The mechanism of LSD1 demethylation is analogous to the mechanism previously postulated for DMGDH, i.e. oxidation of the N-methyl bond to the methylene imine followed by hydrolysis to generate formaldehyde. This suggested that THF might also be involved in the LSD1 reaction to scavenge the formaldehyde produced. Our hypotheses are that THF is bound to native LSD1 by analogy to DMGDH and SDH and that the bound THF serves to protect the FAD class of histone demethylases from the destructive effects of formaldehyde generation by formation of 5,10-methylene-THF. We present pilot data showing that decreased folate in livers as a result of dietary folate deficiency is associated with increased levels of methylated lysine 4 of histone 3. This can be a result of decreased LSD1 activity resulting from the decreased folate available to scavenge the formaldehyde produced at the active site caused by the folate deficiency. Because LSD1 can regulate gene expression this suggests that folate may play a more important role than simply serving as a carrier of one-carbon units and be a factor in other diseases associated with low folate.