Folate in its 5-methyltetrahydrofolate (5-MTHF) form is an essential component required for methionine metabolism.

For that reason folate deficiency has a negative effect on hepatic methionine metabolism, resulting in DNA nucleotide imbalance and increased hepatocellular apoptosis. Endogenous and dietary folate circulating in the blood in the form of 5-MTHF regulates hepatic metabolism, being the substrate with cofactor vitamin B12 for the methionine synthase (MS) reaction. This reaction produces methionine from homocysteine (Hcy). In the alternate salvage pathway for methionine synthesis, choline is the precursor of betaine, which is the substrate for betaine homocysteine methyltransferase (BHMT). The methionine adenosyl transferase (MAT) reaction provides ATP to methionine for creating S-adenosylmethionine (SAM) – main methyl donor in methylation reactions, including DNA methyltransferases. Upon its methyl donation, SAM is converted to S-adenosylhomocysteine (SAH) – substrate for SAH hydrolase required for production of Hcy.

Thus, Hcy can increase SAH levels, and increased levels of Hcy and SAH in the liver, along with decreased SAM synthesis, decrease the SAM/SAH ratio. SAH and Hcy levels are correlated, and being SAH an effective inhibitor of methylation, DNA hypomethylation increases in direct proportion to plasma SAH and Hcy levels. SAM regulates total or reduced glutathione (GSH) by its up-regulation of cystathionine ? synthase and the transsulfuration pathway. GSH is oxidized to its oxidized form (GSSG), and the GSH/GSSG ratio is considered an accurate measure of overall oxidative state.

In addition, SAM provides negative feedback to the methylenetetrahydrofolate reductase (MTHFR) reaction that converts 5,10-methylenetetrahydrofolate (5,10-MTHF) to 5-MTHF. Thus, SAM deficiency accelerates the use of 5,10-MTHF for the MTHFR reaction but decreases its availability for the alternate thymidylate synthetase reaction, which normally maintains the nucleotide balance of deoxyuridine monophosphate (dUMP) and deoxythymidine monophosphate (dTMP).