Methyltetrahydrofolate in folate-binding protein glycine N-methyltransferase

In mammals, folate is used as a carrier of one-carbon units (C(1)) in nucleic acids metabolism and biological methylation. Among all forms of folate the most abundant is 5-methyltetrahydrofolate (5-CH(3)-THF), which is of exceptional importance. Its distinctive role among other forms of folate is in its dual function. As a C(1) carrier it is used for synthesis of methionine by remethylation of homocysteine. In addition, 5-CH(3)-THF is bound to and inhibits glycine-N-methyltransferase (GNMT). GNMT is one of the key enzymes in methionine and S-adenosylmethionine (AdoMet) metabolism. It removes excess AdoMet by using it for methylation of glycine. The interaction of 5-CH(3)-THF and GNMT was proposed as an important regulatory mechanism in AdoMet metabolism and biological methylation. The recent discovery of human individuals with mutant GNMT and the study of a mouse model with the GNMT gene knocked out showed that inactivation of that enzyme, indeed, has a significant impact on AdoMet levels in the liver and plasma. The crystal structure of GNMT complexed with 5-CH(3)-THF revealed that there are two folate molecules bound to one tetrameric form of GNMT, which is a basis for establishing of mechanism of inhibition of GNMT. The role of GNMT as a folate-binding protein and how it affects one-carbon folate metabolism is discussed.