One-carbon metabolism is a central metabolic hub that provides one-carbon units for essential biosynthetic reactions and for writing epigenetics marks. The leading role in this hub is performed by the one-carbon carrier tetrahydrofolate (THF), which accepts formaldehyde usually from serine generating one-carbon THF intermediates in a set of reactions known as the folate or one-carbon cycle. THF derivatives can feed one-carbon units into purine and thymidine synthesis, and into the methionine cycle that produces the universal methyl-donor S-adenosylmethionine (AdoMet). AdoMet delivers methyl groups for epigenetic methylations and it is metabolized to homocysteine (Hcy), which can enter the transsulfuration pathway for the production of cysteine and lastly glutathione (GSH), the main cellular antioxidant. This vital role of THF comes to an expense. THF and other folate derivatives are susceptible to oxidative breakdown releasing formaldehyde, which can damage DNA -a consequence prevented by the Fanconi Anaemia DNA repair pathway. Epigenetic demethylations catalysed by lysine-specific demethylases (LSD) and Jumonji histone demethylases can also release formaldehyde, constituting a potential threat for genome integrity. In mammals, the toxicity of formaldehyde is limited by a metabolic route centred on the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), which oxidizes formaldehyde conjugated to GSH, lastly generating formate. Remarkably, this formate can be a significant source of one-carbon units, thus defining a formaldehyde cycle that likely restricts the toxicity of one-carbon metabolism and epigenetic demethylations. This work describes recent advances in one-carbon metabolism and epigenetics, focusing on the steps that involve formaldehyde flux and that might lead to cytotoxicity affecting human health.

一碳代谢是一个中央代谢枢纽，为重要的生物合成反应和写入表观遗传学标记提供一碳单位。该中心的主导作用是由单碳载体四氢叶酸 (THF) 发挥的，它通常从丝氨酸接受甲醛，在一系列称为叶酸或单碳循环的反应中生成单碳 THF 中间体。 THF 衍生物可以将一碳单元送入嘌呤和胸苷合成中，并送入甲硫氨酸循环中，从而产生通用的甲基供体S-腺苷甲硫氨酸 (AdoMet)。 AdoMet 为表观遗传甲基化提供甲基，并代谢为同型半胱氨酸 (Hcy)，同型半胱氨酸 (Hcy) 可以进入转硫途径，产生半胱氨酸，最后产生谷胱甘肽 (GSH)（主要的细胞抗氧化剂）。 THF 的这一重要作用是有代价的。 THF 和其他叶酸衍生物容易氧化分解，释放出甲醛，从而损伤 DNA，而范可尼贫血 DNA 修复途径可以防止这种后果。由赖氨酸特异性去甲基化酶 (LSD) 和 Jumonji 组蛋白去甲基化酶催化的表观遗传去甲基化也会释放甲醛，对基因组完整性构成潜在威胁。在哺乳动物中，甲醛的毒性受到以乙醇脱氢酶 5 (ADH5/GSNOR) 为中心的代谢途径的限制，该酶氧化与 GSH 结合的甲醛，最终生成甲酸。值得注意的是，这种甲酸盐可能是一碳单位的重要来源，从而定义了一个可能限制一碳代谢和表观遗传去甲基化毒性的甲醛循环。 这项工作描述了单碳代谢和表观遗传学的最新进展，重点关注涉及甲醛通量并可能导致影响人类健康的细胞毒性的步骤。