Structure, function and physiological role of glycine N-methyltransferase

Abstract

Glycine N-methyltransferase (EC 2.1.1.20) catalyzes the transfer of the methyl group of S-adenosylmethionine (AdoMet) to glycine to form S-adenosylhomocysteine and sarcosine. Unlike most AdoMet-dependent methyltransferases, glycine N-methyltransferase is a tetramer of identical subunits. Crystallography of recombinant rat glycine N-methyltransferase indicates that four nearly spherical subunits are arranged to form a flat, square tetramer with a large hole in the centre. The enzyme occurs abundantly in the livers of rat, rabbit and mouse. Glycine N-methyltransferases from rat, rabbit, human and pig livers are shown to have similar amino acid sequences and, with the enzymes from rat and rabbit livers, it is demonstrated that the N-terminal valine is acetylated. Glycine N-methyltransferases from livers exhibit sigmoidal rate behaviour with respect to AdoMet and hyperbolic behaviour with respect to glycine at all pH tested. However, recombinant rat glycine N-methyltransferase which lacks the N-terminal acetyl group shows no cooperativity toward AdoMet at neutral pH, suggesting that elimination of the positive charge at the N-terminus is required for cooperative behaviour. Glycine N-methyltransferase binds 5-methyltetrahydropteroylpentaglutamate tightly, resulting in inhibition of the catalytic activity. The nature of these unique functional features is discussed in the light of the three-dimensional structure of the enzyme. The tissue and subcellular localization of the enzyme and its possible role in methionine metabolism are reviewed.