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Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011
3To whom correspondence should be addressed. E-mail: kschalin{at}iastate.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • methionine • S-adenosylmethionine • tissue-specific • glycine N-methyltransferase • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,2
). In its active form as S-adenosylmethionine (SAM)4
, methyl groups serve as a substrate in the transmethylation of proteins, biogenic amines, nucleic acids and phospholipids. Following SAM-dependent transmethylation, the product S-adenosylhomocysteine (SAH) is metabolized to adenosine and homocysteine, the latter being at a metabolic branch point to undergo either transsulfuration to cysteine or remethylation back to methionine. For remethylation, the required methyl group is obtained from either the folate-dependent one-carbon pool [i.e., 5-methyl-tetrahydrofolate (5-methyl-THF)] or betaine, in certain tissues. An adequate supply of methyl groups is critical for health because a lack of dietary methyl groups and/or related cofactors (e.g., folate) can result in neoplastic development (3
–6
).
Because SAH is a potent inhibitor of most methyltransferases (7
), the intracellular ratio of SAM to SAH is considered to be an important index of transmethylation potential (1
,2
). Glycine N-methyltransferase (GNMT) is a key protein in transmethylation because it is believed to function in the regulation of the SAM:SAH ratio. This regulatory mechanism also depends on 1) SAM functioning as an allosteric inhibitor of 5,10-methylene-tetrahydrofolate reductase (MTHFR) (8
,9
) and 2) 5-methyl-THF serving as a ligand of GNMT that upon binding inhibits its enzymatic activity (10
,11
). Under conditions of excess methionine, the concomitant increase in SAM concentrations inhibits MTHFR, thereby reducing the supply of methyl groups as 5-methyl-THF. This reduction in 5-methyl-THF alleviates its inhibition on GNMT and subsequently enables the excess methyl groups from methionine to be disposed of as sarcosine. Conversely, methionine- or methyl group-deficient conditions favor synthesis of 5-methyl-THF and inhibition of GNMT, thereby conserving methyl groups for important transmethylation reactions.
Clearly, regulatory control of GNMT activity by 5-methyl-THF, as well as posttranslational modification of the protein by phosphorylation, plays an important role in the regulation of both folate and methyl group metabolism without altering the abundance of the protein (10
,11
). Factors that can perturb these metabolic pathways and/or the communication between them can have adverse consequences. We have recently demonstrated that retinoid compounds can alter the hepatic activity of GNMT and this regulation occurs at least in part by increasing the abundance of GNMT protein (12
,13
). This may be because of an increase in transcription and/or translation or a decrease in the degradation of GNMT protein. In this study, we provide direct evidence that dietary methionine supply also regulates hepatic GNMT by increasing its abundance. Moreover, the regulation of GNMT activity and protein level by methionine is dose dependent and appears to be tissue specific.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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All experiments involving animals were approved by and conducted in accordance to guidelines established by the Iowa State University Laboratory Animal Resources Committee. Male Sprague Dawley (Harlan Sprague Dawley, Indianapolis, IN) rats (54–74 g) were housed in plastic cages in a room with a 12-h light-dark cycle. They consumed water ad libitum. The composition of the control diet (10% casein plus 0.3% L-methionine) has been previously described (14
).
Experiment series 1: dose-dependent regulation of GNMT by excess dietary methionine
Rats were adapted to the control diet for 5 d and randomly assigned to one of five methionine-supplemented treatment groups (four rats per group): the control diet, the control diet plus 0.5% L-methionine, the control diet plus 1% L-methionine or the control diet plus 2% L-methionine. The total nonprotein free methionine provided by each of these diets was 0.3, 0.8, 1.3 and 2.3%, respectively. Group 5 was a pair-fed control group offered the mean amount of food consumed by the 2% L-methionine group. Rats were fed their respective diets for a total of 10 d, after which they were killed and livers were removed for the subsequent determination of GNMT activity and GNMT protein abundance.
Experiment series 2: tissue-specific regulation of GNMT by excess dietary methionine
Based on the results from experiment series 1, experiment series 2 used only 1 and 2% methionine-supplemented rats and included pair-fed controls for both groups. After a 5-d acclimation period, two groups consumed ad libitum either the control diet plus 1% L-methionine or the control diet plus 2% L-methionine (1.3 and 2.3% total nonprotein free L-methionine, respectively). The other two groups of rats consumed the control diet but each group was pair-fed the mean amount consumed by the rats fed the 1 and 2% methionine-supplemented diets. After the 10-d treatment period liver, kidney and pancreas samples were removed for the determination of GNMT activity and GNMT protein abundance. Additional liver and kidney samples were removed for the measurement of SAM and SAH.
GNMT analysis
For the determination of GNMT activity (15
), tissue samples from both experiment series 1 and 2 were homogenized in 3 volumes of ice-cold buffer [10 mmol/L sodium phosphate (pH 7), 0.25 mol/L sucrose, 1 mmol/L EDTA, 1 mmol/L sodium azide, 1 mmol/L phenylmethylsulfonylfluoride] and centrifuged at 20,000 x g for 30 min. 2-Mercaptoethanol was added to an aliquot of the resulting supernatant to a final concentration of 10 mmol/L. Total soluble protein concentration of the supernatant was determined by the method of Bradford (16
) using a commercially available kit (Coomassie Plus; Pierce, Rockford, IL) and bovine serum albumin (BSA) as a standard. GNMT activity assays were initiated by the addition of 250 µg protein to a reaction mixture containing 200 mmol/L Tris (pH 9), 5 mmol/L dithiothreitol, 2 mmol/L glycine and 0.2 mmol/L S-adenosyl-L-[methyl-3H]methionine (47.7 kBq/µmol) and incubated at 37°C for 30 min. Unreacted SAM was removed by the addition of activated charcoal and an aliquot of the subsequent supernatant was subjected to liquid scintillation counting. The assay was linear with respect to both protein concentration and incubation time. For the measurement of relative GNMT protein abundance, 75 µg of total protein was denatured, loaded onto a 10–20% gradient polyacrylamide sodium dodecyl sulfate gel and run using a Tris-glycine buffer system. Separated proteins were transferred electrophoretically to nitrocellulose and blocked for 1 h with Tween Tris-buffered saline (TTBS) buffer [20 mmol/L Tris (pH 7.5), 500 mmol/L NaCl, 500 µL/L Tween 20] containing 50 g/L nonfat dry milk. After subsequent washing with TTBS, membranes were incubated overnight at 4°C with affinity-purified polyclonal GNMT antibodies in 10 g/L BSA/TTBS (1/1000). GNMT protein monomer (
32 kDa) was detected using a goat anti-rabbit horseradish peroxidase secondary antibody (Southern Biotechnology Associates, Birmingham, AL) in TTBS (1/5000) and chemiluminescence detection. The relative density of the protein bands was quantified using National Institutes of Health Image (experiment series 1) or SigmaGel (SSPS, Chicago, IL) software (experiment series 2).
Metabolite analysis
Liver and kidney samples from experiment series 2 were homogenized in 4 volumes of 0.4 mol/L perchloric acid for the determination for SAM and SAH concentrations (17
,18
). After centrifugation at 9000 x g for 10 min, the perchloric acid supernatants were neutralized and applied to a C18 SepPak cartridge (Waters, Milford, MA) to obtain SAM and SAH. SAM and SAH were separated and quantified by reversed-phase high-performance liquid chromatography (HPLC) and ultraviolet detection using a mobile phase containing 300 mL/L methanol in 5 mmol/L octane sulfonic acid (pH 4) operated isocratically at 1.2 mL/min. For quantification, standard curves were generated by adding graded levels of SAM and SAH standards to 2-mL aliquots from a pooled hepatic perchloric acid supernatant and analyzed as described above. Compared with standards directly analyzed by HPLC, the recoveries of SAM and SAH from perchloric acid supernatants were 80 and 97%, respectively.
Statistical analysis
Data were subjected to a one-way analysis of variance (ANOVA) (19
). A one-way ANOVA on ranks was performed when the tests for normality and/or equal variance failed. When the differences were significant (P < 0.05) means were compared using Fisher’s least significant difference procedure. For correlation analysis, the Pearson correlation procedure was used. All statistical analyses were performed using SigmaStat (SPSS, Chicago, IL) software.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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As has been documented (20
,21
), there was a retardation of growth in rats fed excess dietary methionine (Fig. 1
). Growth retardation was evident in rats fed 1 and 2% excess dietary methionine but not in those fed 0.5%. This apparent threshold of excess dietary methionine was supported throughout these experiments in that many of the measures exhibited a dose response to excess dietary methionine at levels >0.5%. The toxicity and growth inhibition associated with excess methionine consumption were the result of both a suppression of food consumption and a decrease in food efficiency, the latter supported by the greater weight gain exhibited by the pair-fed group shown in Figure 1
. A similar growth suppression was observed in experiment series 2 as well as a decrease in the relative liver size by rats fed the 2% methionine-supplemented diet (data not shown).
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The hepatic activity of GNMT was 120 and 160% greater in rats fed 2% methionine than in the control (0% supplemental methionine) and pair-fed control groups, respectively (Fig. 2A
). The 1% methionine group also had 74% greater GNMT activity than the pair-fed group although it did not differ from the control group. The control group and rats fed the 0.5% methionine diet also did not differ. Changes in GNMT activity due to excess dietary methionine were reflected in the relative abundance of GNMT protein as determined by band density (Fig. 2
B). Compared with the pair-fed and control groups, the 1% methionine-fed rats had 90 and 140% greater GNMT abundance, respectively, whereas in the 2% methionine group the elevations were 180 and 250%. Similar to GNMT activity, rats supplemented with 0.5% methionine did not differ from the control or pair-fed groups. A representative immunoblot is shown in Fig. 2
above the bar graph where the monomer molecular mass of GNMT is 32 kDa.
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Hepatic GNMT activity and abundance in the methionine dose-response study (experiment series 1) (r = 0.734, P < 0.001; Fig. 3
) suggest that newly synthesized GNMT protein after excess dietary methionine was primarily in its enzymatically active form. This was supported further by the use of disuccinyl suberate as a cross-linking agent to determine the oligomeric state of GNMT. The enzymatic function of GNMT occurs when it is in a homotetramer form, whereas it functions as a binding protein in its homodimer state (22
,23
). Liver extracts obtained from both control and methionine-supplemented rats demonstrated that the majority of GNMT was endogenously present in its active tetrameric (128-kDa) form rather than its monomeric (32-kDa) or dimeric (64-kDa) states (data not shown).
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Compared with the pair-fed controls, hepatic SAM was markedly elevated by excess dietary methionine, 10- and 23-fold in the 1 and 2% methionine-supplemented groups, respectively (Table 1
). SAH was also increased by 31 and 260%, respectively, in liver of rats fed 1 and 2% excess dietary methionine. The changes in SAM and SAH were such that both groups receiving excess dietary methionine had similar sixfold elevations in the SAM:SAH ratio compared with their respective pair-fed controls. The kidney SAM concentration also was increased 72% in rats fed 2% methionine and the SAM:SAH ratio was 68 and 27% greater in those fed 1 and 2% methionine, respectively, compared with their pair-fed controls, increases much less than those in liver.
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Changes in the activity of GNMT by methionine differed in the three primary tissues reported to contain the protein (Table 2
). Overall, changes in GNMT activity in the liver and kidney due to treatment were similar to the corresponding alterations in intracellular SAM concentrations (Table 1)
. For liver, the increases in GNMT activity and abundance shown here for experiment series 2 were similar to those in the experiment series 1 dose-response study (Fig. 2)
. One exception was that GNMT activity in the 1% methionine group was significantly greater (40%) than in its pair-fed control group. Again, the changes in hepatic GNMT activity were reflected in the relative abundance of the protein in the liver. Kidney was less responsive to excess dietary methionine; only rats fed the 2% methionine diet had a significant increase (79%) in GNMT activity. No discernible immunoreactive band was observed at the proper molecular weight for kidney samples and thus we could not determine whether the abundance of GNMT protein reflects the changes in renal GNMT activity. The basis for the GNMT antibody not reacting with renal GNMT protein is unknown and previous work in the literature has not reported tissue-specific differences in the molecular weight of GNMT. For pancreatic tissue, neither the activity of GNMT nor its abundance was altered by the dietary treatments.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–27
) have shown that hepatic GNMT activity reflects the changes in methionine supply, a relationship that is dependent on the allosteric and posttranslational control that exists between the folate-dependent one-carbon pool and methyl group metabolism to regulate GNMT activity without altering the abundance of the protein (10
,11
). However, our novel finding indicates that transcriptional/translational regulation and/or protein degradation likely plays an important role in the hepatic response of GNMT to methionine, as indicated by the increase in GNMT protein in response to excess dietary methionine. Ogawa and Fujioka (27
) also observed this in an immunotitration of rabbit GNMT antiserums against liver supernatants derived from control and high-methionine (3%)-fed rats. Our studies expand on this earlier finding by 1) directly and quantitatively demonstrating that activation of GNMT by methionine involves an increase in the abundance of the 32-kDa monomer; 2) demonstrating that the methionine-inducible regulation of GNMT was a dose-dependent process above a threshold level of excess dietary methionine; and 3) showing that GNMT regulation by excess dietary methionine was liver specific. For alterations in GNMT activity, the only other report demonstrating that changes in GNMT abundance was involved in the regulation of GNMT activity was our earlier work reporting that retinoid compounds markedly elevated the activity and abundance of hepatic GNMT (12
,13
). Recently, we have reported that retinoid-mediated regulation of GNMT activity and abundance was also liver specific (28
). GNMT is a bifunctional protein that is also involved in detoxification processes. The 32-kDa protein, as a homotetramer, possesses GNMT activity, whereas the dimeric form of the protein functions as a polycyclic aromatic hydrocarbon-binding protein (22
,23
). For the latter, it has been demonstrated that the gene is inducible by benzo-a-pyrene following its transfection into Chinese hamster ovary cells (29
). The only other report of transcriptional/translational control of GNMT was the observation that it is sexually dimorphic in mice and is regulated by growth hormone (30
).
GNMT has been shown to be present in large quantities in both the kidney and pancreas in addition to the liver (7
,31
,32
). We have found in these studies that the regulation of GNMT by methionine was tissue specific. Kidney GNMT exhibited some response to dietary methionine but appeared to be much less sensitive than liver. This is surprising, because others have shown that the kidney represents a tissue that is resistant to alterations in methyl group supply (33
–36
), although no information on renal GNMT regulation exists. In contrast to our results for kidney samples, pancreatic tissue was unresponsive to methionine supplementation. A number of reports have shown that regulation of methyl group metabolism and GNMT in the pancreas is similar to those of hepatic GNMT (24
,36
–38
). Taken together, these results represent an interesting finding with respect to the known characteristics of methionine and folate metabolism in these three tissues. As summarized by Finkelstein (39
), the response of the liver to changes in methionine availability is catabolic, whereas the kidney aims to conserve methionine. This is due primarily to the tissue-specific kinetic properties of the enzymes involved in folate and methyl group metabolism. For example, methionine adenosyltransferase (MAT), the enzyme that catalyzes the activation of methionine to SAM, exists in a number of kinetically distinct isoforms. Hepatic MAT has the ability to respond to changes in methionine supply and begins to catabolize the excess methionine by converting it to SAM (33
,39
–41
). In contrast, the kidney form of MAT is typically saturated at physiological methionine concentrations (39
).
Our data confirm this description of liver methionine metabolism; however, they also indicate that there exists an unidentified signal that results in an increase in GNMT protein abundance in response to changes in methionine concentration. Methionine, SAM, or another metabolite related to methyl group metabolism may mediate changes, directly or indirectly, in GNMT expression, translation or turnover of the protein. The changes in enzymatic GNMT activity observed in the kidney appear to be related to the intracellular concentrations of SAM. However, this may reflect only positive modulation of GNMT by SAM (42
,43
) because we were unable to determine the renal abundance of GNMT in response to excess dietary methionine. For pancreas, little information exists with respect to excess dietary methionine. It has been shown to be similar to the liver in a number of metabolic respects, including its response to a deficiency of methyl groups and/or folate (24
,37
,38
,43
). Although it does not possess the hepatic form of MAT, an increase in pancreatic SAM following dietary methionine supplementation has been reported in rats (36
) but not in the AR42J pancreatic cell line (44
). In sheep with diabetes, a condition that markedly increases hepatic GNMT activity, no change was found in pancreatic GNMT activity (45
). Regardless, we found that both the activity and abundance of pancreatic GNMT was unresponsive to excess dietary methionine. Thus, a number of important differences appear to be present in hepatic and pancreatic GNMT and methyl group metabolism. In support of this, we have recently found that both the kidney and pancreas are insensitive to modulation of GNMT and methyl group metabolism by retinoid compounds in contrast to the marked response in liver (28
).
In summary, we have clearly shown that regulation of GNMT by methionine involves a mechanistic component that results in an increase of GNMT protein abundance. Previous work with respect to GNMT regulation has shown that modulation of its activity is accomplished by regulation of existing protein. This includes allosteric regulation by SAM, inhibition by folate ligands and posttranslational modification of the protein by phosphorylation (10
,11
,42
,43
). An increase in GNMT protein abundance by excess dietary methionine may involve an increase in transcription or mRNA stabilization or a decrease in GNMT degradation. The relative contributions of these mechanisms to GNMT regulation, whether modulated by methionine supply or retinoid administration, remain a focus for future work. Likewise, understanding the contrasting regulation of GNMT in different tissues may begin to provide insight into the role of GNMT in those locations.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 M.J.R. and M.H.M. contributed equally to this work.
4 Abbreviations: 5-methyl-THF, 5-methyl-tetrahydrofolate; ANOVA, analysis of variance; BSA, bovine serum albumin; GNMT, glycine N-methyltransferase; HPLC, high-performance liquid chromatography; MAT, methionine adenosyltransferase; MTHFR, 5,10-methylene-tetrahydrofolate reductase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; TTBS, Tween Tris-buffered saline.
Manuscript received 30 March 2002. Initial review completed 20 June 2002. Revision accepted 26 June 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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 C. L. Ulrey, L. Liu, L. G. Andrews, and T. O. Tollefsbol The impact of metabolism on DNA methylation Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R139 - R147. [Abstract] [Full Text] [PDF]
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R. Zhang, J. Ma, M. Xia, H. Zhu, and W. Ling Mild Hyperhomocysteinemia Induced by Feeding Rats Diets Rich in Methionine or Deficient in Folate Promotes Early Atherosclerotic Inflammatory Processes J. Nutr., April 1, 2004; 134(4): 825 - 830. [Abstract] [Full Text] [PDF]
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M. J. Rowling and K. L. Schalinske Retinoic Acid and Glucocorticoid Treatment Induce Hepatic Glycine N-Methyltransferase and Lower Plasma Homocysteine Concentrations in Rats and Rat Hepatoma Cells J. Nutr., November 1, 2003; 133(11): 3392 - 3398. [Abstract] [Full Text] [PDF]
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V. R. Young Introduction to the 2nd Amino Acid Assessment Workshop J. Nutr., June 1, 2003; 133(6): 2015S - 2020. [Abstract] [Full Text] [PDF]
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