Figure 3.

Histone methylation reaction and one-carbon metabolism. S-adenosylmethionine (SAM) is synthesized from ATP and methionine (Met) by methionine adenosyltransferase (MAT). Histone methyltransferases (HMTs), such as H3K4 KMTs, utilize SAM as a cofactor to transfer a methyl group to the histone substrate, yielding S-adenosylhomocysteine (SAH) and a methylated histone. In the methionine cycle, SAH is converted to homocysteine (Hcy) via S-adenosylhomocysteine hydrolase (SAHH), followed by the re-methylation of Hcy back to methionine via either methionine synthase (MS) utilizing a methyl group from 5-methyltetrahydrafolate (5-meTHF) or by betaine-homocysteine S-methyltransferase (BHMT) utilizing a methyl group from betaine. In the folate cycle, folic acid is reduced to tetrahydrofolate (THF), which can then accept a one-carbon unit from serine (Ser) or glycine (Gly), producing 5-meTHF. Threonine (Thr) is also involved in modulating SAM concentrations, as it provides both glycine and acetyl-CoA required for optimal synthesis of SAM.