Glycine N-methyltransferase and regulation of S-adenosylmethionine levels

Abstract

Methylation is a major biological process. It has been shown to be important in formation of compounds such as phosphatidylcholine, creatine, and many others and also participates in epigenetic effects through methylation of histones and DNA. The donor of methyl groups for almost all cellular methylation reactions is S-adenosylmethionine. It seems that the level of S-adenosylmethionine must be regulated in response to developmental stages and metabolic changes, and the enzyme glycine N-methyltransferase has been shown to play a major role in such regulation in mammals. This minireview will focus on the latest discoveries in the elucidation of the mechanism of that regulation.

FIGURE 1.

Crystal structure of recombinant rat GNMT complexed with 5-methyl-THF. Coordinates of the structure from Protein Data Bank code 2IDK were used for preparation of this figure. Each subunit is denoted A, B, C, and D. Two molecules of folate are shown as yellow spheres. The overall structure was drawn in schematic mode of the PyMOL program. The residues participating in binding AdoMet (Trp³⁹, Arg⁴⁰, Ala⁶⁴, Asp⁸⁵, Asn¹¹⁶, Trp¹¹⁷, and Leu¹³⁶) are drawn as black spheres. The N termini of subunits are denoted Na, Nb, Nc, and Nd. Interaction of the N-terminal fragment of subunit A (green) with the active center of subunit B (red) is clearly seen.

FIGURE 2.

Metabolic pathways related to the regulatory role of GNMT. Two metabolic pathways are shown separated by a dashed line; the ONE CARBON FOLATE POOL and the METHIONINE CYCLE. Indicated on the left of the one-carbon pool are the sources of the one-carbon groups carried by THF; on the right are indicated the metabolic uses of these groups. The methionine cycle includes reactions that transfer methyl groups from methionine to AdoMet and methylation of acceptors. These are followed by regeneration of methionine via methylation of homocysteine by either methionine synthase or betaine-homocysteine methyltransferase. Homocysteine can also be converted to cysteine and, ultimately, to glucose via cystathionine breakdown. The reactions are denoted by numbers: 1, methionine adenosyltransferase; 2, the majority of methyltransferases; 3, GNMT (inhibition by 5-methyl-THF is shown); 4, AdoHcy hydrolase; 5, methionine synthase; 6, 5,10-methylene-THF reductase (with inhibition by AdoMet); 7, betaine-homocysteine methyltransferase; 8, dimethylglycine dehydrogenase; 9, sarcosine dehydrogenase. X refers to the group of methyl acceptors, and CH₃-X refers to the methylated products. Fig. 2 first appeared in Ref. . PE, phosphatidylethanolamine.