Burgos-Barragan Guillermo, Wit Niek, Meiser Johannes, Dingler Felix A, Pietzke Matthias, Mulderrig Lee, Pontel Lucas B, Rosado Ivan V, Brewer Thomas F, Cordell Rebecca L, Monks Paul S, Chang Christopher J, Vazquez Alexei, Patel Ketan J
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
Nature. 2017 Aug 31;548(7669):549-554. doi: 10.1038/nature23481. Epub 2017 Aug 16.
The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.
叶酸驱动的一碳（1C）循环是细胞中的一个基本代谢枢纽，它能够合成核苷酸、氨基酸并进行表观遗传修饰。这个循环还可能释放甲醛，甲醛是一种强大的蛋白质和DNA交联剂，生物体大量产生这种物质。在这里，我们表明，补充该循环的必需辅因子四氢叶酸以及其他易氧化的叶酸衍生物会杀死无法解毒甲醛或缺乏DNA交联修复能力的人、小鼠和鸡细胞。值得注意的是，甲醛是由叶酸主链的氧化分解产生的。此外，我们发现人体细胞中的甲醛解毒会产生甲酸，从而促进核苷酸合成。这种一碳单位的供应足以维持无法利用丝氨酸（一碳单位的主要来源）的细胞的生长。这些发现确定了一个意想不到的甲醛来源，更普遍地说，表明这种普遍存在的内源性基因毒素的解毒作用产生了一种良性的一碳单位，它可以维持基本代谢。
