Epigenetics and the toxicity of one-carbon metabolism

One-carbon metabolism is a major metabolic hub that produces one-carbon units for important biosynthetic events as well as for the creation of epigenetic marks. The one-carbon carrier tetrahydrofolate (THF) plays the primary role in this hub, accepting formaldehyde generally from serine and creating one-carbon THF intermediates in a series of events known as the folate or one-carbon cycle. THF derivatives can provide one-carbon units for purine and thymidine synthesis, as well as the methionine cycle, which yields the universal methyl donor S-adenosylmethionine. AdoMet provides methyl groups for epigenetic methylation and is converted to Homocysteine (Hcy), which can enter the transsulfuration route to produce cysteine and, finally, glutathione (GSH), the primary cellular antioxidant. THF's critical function comes at a cost. THF and other folate derivatives are prone to oxidative breakdown, which results in the release of formaldehyde, which can damage DNA - a consequence avoided by the Fanconi Anaemia DNA repair process. Epigenetic demethylations catalyzed by lysine-specific demethylases (LSD) and Jumonji histone demethylases can potentially result in the release of formaldehyde, posing a risk to genome integrity. The toxicity of formaldehyde in animals is restricted by a metabolic pathway centered on the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), which oxidizes formaldehyde conjugated to GSH, eventually producing format. Surprisingly, this format can be a substantial source of one-carbon units, establishing a formaldehyde cycle that may limit the toxicity of one-carbon metabolism and epigenetic demethylations. This paper highlights current breakthroughs in one-carbon metabolism and epigenetics, with an emphasis on the stages that include formaldehyde flow and may result in cytotoxicity affecting human health