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.
Luka
Zigmund
Z
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
D000595:Amino Acid Sequence; D000818:Animals; D005492:Folic Acid / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D050938:Glycine N-Methyltransferase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D013763:Tetrahydrofolates / Q000737:chemistry / Q000378:metabolism*
D013763:Tetrahydrofolates; D005492:Folic Acid; D050938:Glycine N-Methyltransferase; C005984:5-methyltetrahydrofolate