Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism

Luka, Zigmund; Cerone, R.; Phillips, John A.; Mudd, Harvey; Wagner, Conrad

doi:10.1007/s00439-001-0648-4

Cited by 69 publications

(46 citation statements)

References 26 publications

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“…Elevated plasma AdoMet in the present patient demonstrated conclusively that he did not have MAT I͞III deficiency (24). Isolated persistent hypermethioninemia associated with elevated AdoMet may result from a deficiency of glycine N-methyltransferase (GNMT), a defect that has been reported in three children (20,25,26). In these patients, a diagnostically important finding was the absence of N-methylglycine elevation in the face of elevated AdoMet (20).…”

Section: Discussionmentioning

confidence: 61%

S -adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism

Barić

Fumić

Glenn

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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We report studies of a Croatian boy, a proven case of human S-adenosylhomocysteine (AdoHcy) hydrolase deficiency. Psychomotor development was slow until his fifth month; thereafter, virtually absent until treatment was started. He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin. Electron microscopy of muscle showed numerous abnormal myelin figures; liver biopsy showed mild hepatitis with sparse rough endoplasmic reticulum. Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination. Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted (up to 784 M) without tyrosine elevation. Plasma total homocysteine was very slightly elevated for an infant to 14.5-15.9 M. In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy hydrolase was Ϸ3% of control in liver and was 5-10% of the control values in red blood cells and cultured fibroblasts. We found no evidence of a soluble inhibitor of the enzyme in extracts of the patient's cultured fibroblasts. Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine. Leukocyte DNA was hypermethylated. Gene analysis revealed two mutations in exon 4: a maternally derived stop codon, and a paternally derived missense mutation. We discuss reasons for biochemical abnormalities and pathophysiological aspects of AdoHcy hydrolase deficiency.

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Section: Discussionmentioning

confidence: 61%

S -adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism

Barić

Fumić

Glenn

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

205

226

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“…Interestingly, a second major folate-binding protein was up-regulated in the mice on the HM diet, namely 10-formyltetrahydrofolate dehydrogenase, suggesting the possibility that GNMT levels were upregulated because their inhibitor, 5-methyltetrahydrofolate pentaglutamate, was bound to 10-formyltetrahydrofolate dehydrogenase. BHMT comprises ϳ1% of total liver protein (64), and paradoxically its activity has been shown to increase in response to both a methionine-deficient and a methioninerich diet (65). However, Park and Garrow (66) noted that BHMT activity is influenced more by dietary choline and/or betaine than methionine.…”

Section: Discussionmentioning

confidence: 99%

The Nutrigenetics of Hyperhomocysteinemia

DiBello

Dayal

Kaveti

et al. 2010

Molecular & Cellular Proteomics

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Hyperhomocysteinemia has long been associated with atherosclerosis and thrombosis and is an independent risk factor for cardiovascular disease. Its causes include both genetic and environmental factors. Although homocysteine is produced in every cell as an intermediate of the methionine cycle, the liver contributes the major portion found in circulation, and fatty liver is a common finding in homocystinuric patients. To understand the spectrum of proteins and associated pathways affected by hyperhomocysteinemia, we analyzed the mouse liver proteome of gene-induced (cystathionine ␤-synthase (CBS)) and diet-induced (high methionine) hyperhomocysteinemic mice using two-dimensional difference gel electrophoresis and Ingenuity Pathway Analysis. Nine proteins were identified whose expression was significantly changed by 2-fold (p < 0.05) as a result of genotype, 27 proteins were changed as a result of diet, and 14 proteins were changed in response to genotype and diet. Importantly, three enzymes of the methionine cycle were upregulated. S-Adenosylhomocysteine hydrolase increased in response to genotype and/or diet, whereas glycine Nmethyltransferase and betaine-homocysteine methyltransferase only increased in response to diet. The antioxidant proteins peroxiredoxins 1 and 2 increased in wild-type mice fed the high methionine diet but not in the CBS mutants, suggesting a dysregulation in the antioxidant capacity of those animals. Furthermore, thioredoxin 1 decreased in both wild-type and CBS mutants on the diet but not in the mutants fed a control diet. Several urea cycle proteins increased in both diet groups; however, arginase 1 decreased in the CBS ؉/؊ mice fed the control diet. Pathway analysis identified the retinoid X receptor signaling pathway as the top ranked network associated with the CBS ؉/؊ genotype, whereas xenobiotic metabolism and the NRF2-mediated oxidative stress response were associated with the high methionine diet. Our results show that hyperhomocysteinemia, whether caused by a genetic mutation or diet, alters the abundance of several liver proteins involved in homocysteine/methionine metabolism, the urea cycle, and antioxidant defense. Molecular & Cellular Proteomics 9:471-485, 2010.

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“…The role of SAM is to transfer the methyl groups and to use them for formation of many essential compounds as creatine or phosphatidylcholine. It has been previously reported that the increased conflux of GNMT results in the elevated formation of sarcosine through increased utilization of SAM (39). The absence of sarcosine in control samples indicates that it is applicable for diagnosis, due to the reduction in false-positive or negative results (23) similar to proline.…”

Section: N-methyl Transferase (Gnmt) Cleaving Glycine To Sarcosine (mentioning

confidence: 99%

Determination of common urine substances as an assay for improving prostate carcinoma diagnostics

et al. 2014

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Abstract.Recently, interest in the identification of non-invasive markers for prostate carcinoma detectable in the urine of patients has increased. In this study, we monitored the abundance of potential non-invasive markers of prostate carcinoma such as amino acid sarcosine, involved in the metabolism of amino acids and methylation processes, ongoing during the progression of prostate carcinoma. In addition, other potential prostate tumor markers were studied. The most significant markers, prostate-specific antigen (PSA) and free PSA (fPSA), already used in clinical diagnosis, were analyzed using an immunoenzymometric assay. Whole amino acid profiles were also determined to evaluate the status of amino acids in patient urine samples and to elucidate the possibility of their utilization for prostate carcinoma diagnosis. To obtain the maximum amount of information, the biochemical parameters were determined using various spectrophotometric methods. All results were subjected to statistical processing for revealing different correlations between the studied parameters. We observed alterations in most of the analyzed substances. Based on the results obtained, we concluded that the specificity of prostate carcinoma diagnosis could be improved by determination of common urine metabolites, since we compiled a set of tests, including the analysis of sarcosine, proline, PSA and uric acid in the urine. These metabolites were not observed in the urine obtained from healthy subjects, while their levels were elevated in all patients suffering from prostate carcinoma.

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Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism

Cited by 69 publications

References 26 publications

S -adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism

S -adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism

The Nutrigenetics of Hyperhomocysteinemia

Determination of common urine substances as an assay for improving prostate carcinoma diagnostics

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