Tissue distribution of glycine N-methyltransferase, a major folate-binding protein of liver.

Abstract

Glycine N-methyltransferase (GNMT; S-adenosyl-L-methionine:glycine N-methyltransferase, EC 2.1.1.20)is a major protein in rat liver that binds 5-methyltetrahydrofolate polyglutamate in vivo. This enzyme is believed to function in the regulation of the availability of S-adenosylmethionine, the primary donor ofmethyl groups in the body. The distribution of GNMT in a variety of rat tissues was examined immunohistochemically. In liver, GNMT was most abundant in the periportal region, whereas in kidney it was seen primarily in the proximal convoluted tubules. In pancreas, GNMT was abundant, principally in the exocrine tissue. GNMT was present in the striated duct cells ofthe submaxillary gland. In thejejunum, GNMT was found in the epithelial cells of the vili. Close examination ofthe liver indicated GNMT in the nucleus; this site was confirmed by purification of the nuclei and measurement of enzyme activity. The location of GNMT in the liver and kidney suggests that this enzyme plays a role in gluconeogenesis, while its presence in the exocrine cells suggests it may also be a factor in secretion.Glycine N-methyltransferase (GNMT; S-adenosyl-L-methionine:glycine N-methyltransferase EC 2.1.1.20) is a major protein of rat liver cytosol (1, 2). It catalyzes the methylation of glycine by S-adenosylmethionine (SAM) to form N-methylglycine, also known as sarcosine, and S-adenosylhomocysteine (SAH). Because the enzyme is so abundant, composing 1-3% of liver cytosol from different species (1, 3, 4) and one product of the enzymatic reaction, sarcosine, has no known metabolic role, GNMT has been suggested to function as an alternative mechanism for converting SAM to SAH (5) to maintain the SAM/SAH ratio. The ratio of SAM to SAH is believed important in a variety of reactions involving the methylation of both small and macromolecules (6). GNMT also binds 5-methyltetrahydrofolate (5-MeTHF) polyglutamate endogenously and is one of the cytosolic folate-binding proteins (2). When the folate is bound to GNMT, the enzyme activity is inhibited; this serves physiologically as a mechanism for linking the de novo synthesis of methyl groups via the one-carbon folate pool to the availability of methionine in the diet (7). These metabolic relationships are depicted in Fig.

Metabolic derangement of methionine and folate metabolism in mice deficient in methionine synthase reductase

“…Confirming this role for GNMT, mice completely lacking GNMT due to gene deletion exhibit a ~35-fold increase in AdoMet, with a ~3-fold decrease in AdoHcy [45]. Tissues with high levels of GNMT, such as liver or kidney [46], typically exhibit lower ratios of AdoMet/AdoHcy than do tissues like brain with very low levels of GNMT activity [47]. As shown in Table 3, the lowest AdoMet/AdoHcy ratios in wild type mice are found in liver, while those in kidney and brain are higher, and those in heart the highest of all.…”

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation

“…Deletion of GNMT increased the susceptibility of liver cancer in mice (10). The presence of GNMT in the liver and kidney implies that this protein could participate in gluconeogenesis (12). The function of GNMT in extra hepatic tissues is less clear.…”

“…GNMT also is present in pancreas, prostate, intestinal mucosa, plasma and semen (12)(13)(14)(15)(16)(17). The localization of GNMT in the exocrine cells in the above tissues suggests a potential role in secretion (12). GNMT serves as an alternative mechanism for utilizing S-adenosylmethionine that does not necessarily involve the methylation of physiologically important acceptors (12).…”

“…The function of GNMT in extra hepatic tissues is less clear. GNMT also is present in pancreas, prostate, intestinal mucosa, plasma and semen (12)(13)(14)(15)(16)(17). The localization of GNMT in the exocrine cells in the above tissues suggests a potential role in secretion (12).…”

The important role of glycine N-methyltransferase in the carcinogenesis and progression of prostate cancer

“…6,7 It has been postulated that GNMT is involved in gluconeogenesis in the liver and kidney. 8 Knockdown of GNMT in the prostate cancer cell line by RNA interference attenuated prostate cancer invasion in the cell invasion assay. 5 Their data are suggestive of a link between cancer progression and GNMT activity.…”