SAM, a methyl donor for reactions catalyzed by DNMT, is generated by adding ATP to methionine by the enzyme methionine adenosyl transferase (MAT) (figure 2). After the methyl transfer reaction, SAM forms a byproduct, S-adenosyl homocysteine (SAH), which acts as a potent inhibitor of DNMT and HMTs. SAH then is broken down by SAH hydrolase (SAHH) to form homocysteine, which can either enter a set of reactions called the transsulfuration pathway to form glutathione (GSH) or be remethylated to form methionine (Grillo and Colombatto 2008). For remethylation of homocysteine, a methyl group can be transferred either from N5-methyl tetrahydrofolate (THF) by methionine synthase, or from betaine by betaine homocysteine methyl transferase (BHMT). Excessive ROS formation, which can occur during ethanol metabolism, acutely can deplete GSH. This could promote the transsulfuration of homocysteine to generate new GSH and thus divert the reactions from producing methionine and SAM, thereby decreasing DNA methylation.
