Figure 3. Roles of metabolites in histone methylation and demethylation.

Methylation of histones and DNA play key roles in keeping the genome in a transcriptionally silent state both locally and globally. Some histone methylation modifications can be activating. Such events are potentially linked to cellular metabolism via S-adenosylmethionine (SAM), which provides the necessary methyl groups for methyltransferases to catalyze histone/DNA methylation as well as non-histone protein methylation (small orange circles indicate methylation marks). Histones are methylated on lysine and arginine residues by histone methyltransferases, HMTs. SAM is produced by SAM synthetases (methionine adenosyl transferase, MAT) via the addition of an adenosine moiety from ATP to methionine. In mammals, dietary folate can be enzymatically converted to 5-methyltetrahydrofolate (5-MTHF). The transfer of a methyl group from 5-MTHF to homocysteine requires Vitamin B₁₂ and results in the synthesis of methionine. Upon donating its high-energy methyl group, SAM becomes S-adenosylhomocysteine (SAH) that is a potent inhibitor of methyltransferases unless broken down by SAH hydrolase (SAHH) into adenosine and homocysteine. Homocysteine can act as a precursor for methionine or cysteine synthesis. Histone demethylases (HDMs) remove methyl groups from histones. Lysine-specific histone demethylase (LSD1) uses FAD as a cofactor whereas JmjC-domain-containing HDMs use α-ketoglutarate (α-KG) as a substrate.