Defects In Methionine Metabolism Research Articles

Anaesthesia Management of a Young Patient with Homocystinuria

Homocystinurea is a rare autosomal recessive genetic disease. It is caused by deficiency in cystathionine-beta synthase leading to defect in methionine metabolism. HIGH LEVEL of plasma homocysteine are associated with vascular injury via mechanism of oxidative damage. Vascular smooth muscle proliferation, promotion of platelet activation and aggregation and disruption of normal procoagulant-anticoagulant balance favoring thrombosis. This is a case of seventeen-year-old girl. Known case of homocystinurea who scheduled for cataract surgery for her dislocated lens. The major anesthetic consideration includes the development of thromboembolism, need to avoid nitrous oxide in balance anesthesia and avoid dehydration, long fasting, hypoglycemia.

Anaesthesia Management of a Young Patient with Homocystinuria

Homocystinurea is a rare autosomal recessive genetic disease. It is caused by deficiency in cystathionine-beta synthase leading to defect in methionine metabolism. HIGH LEVEL of plasma homocysteine are associated with vascular injury via mechanism of oxidative damage. Vascular smooth muscle proliferation, promotion of platelet activation and aggregation and disruption of normal procoagulant-anticoagulant balance favoring thrombosis. This is a case of seventeen-year-old girl. Known case of homocystinurea who scheduled for cataract surgery for her dislocated lens. The major anesthetic consideration includes the development of thromboembolism, need to avoid nitrous oxide in balance anesthesia and avoid dehydration, long fasting, hypoglycemia.

Methionine-Dependence Phenotype in the de novo Pathway in BRCA1 and BRCA2 Mutation Carriers with and without Breast Cancer

Methionine-dependence phenotype (MDP) refers to the reduced ability of cells to proliferate when methionine is restricted and/or replaced by its immediate precursor homocysteine. MDP is a characteristic of human tumors in vivo, human tumor cell lines, and normal somatic tissue in some individuals. It was hypothesized that MDP is a risk factor for developing breast cancer in BRCA (BRCA1 and BRCA2) germline mutation carriers. To test the hypothesis, human peripheral blood lymphocytes of BRCA carriers with and without breast cancer and healthy non-carrier relatives (controls) were cultured for 9 days in medium containing either 0.1 mmol/L L-methionine or 0.2 mmol/L D,L-homocysteine, with the ratio of viable cell growth in both types of medium after 9 days used to calculate the methionine-dependence index (MDI), a measure of MDP. We also tested whether MDP was associated with common polymorphisms in methionine metabolism. Viable cell growth, MDI, and polymorphism frequency in MTRR (A66G and C524T) and MTHFR (A1298C and A1793G) did not differ among the study groups; however, MDI tended to be higher in BRCA carriers with breast cancer than those without and was significantly increased in MTHFR 677T allele carriers relative to wild-type carriers (P=0.017). The presence of MTR A2756G mutant allele and MTHFR C677T mutant allele in carriers was associated with increased breast cancer risk [odds ration, 3.2 (P=0.16; 95% confidence interval, 0.76-13.9) and 3.9 (P=0.09; 95% confidence interval, 0.93-16.3), respectively]. The results of this study support the hypothesis that defects in methionine metabolism may be associated with breast cancer risk in BRCA carriers.

M1760 Bifidobacteria Attenuate the Development of Non-Alcoholic Fatty Liver in Obese Mice

Our laboratory has previously shown that ethanol causes defects in methionine metabolism which result in higher levels of two toxic metabolites, homocysteine and S-adenosylhomocysteine (SAH). These metabolites, in turn, contribute to the development of characteristic features of alcoholic liver injury via impairments in crucial transmethylation reactions. We have further reported that dietary betaine supplementation alleviates ethanol-induced changes in intracellular SAH levels to mitigate steatosis, apoptosis and damaged protein accumulation, thereby preventing the progression to fibrosis and cirrhosis. We have data that shows that this protective effect of betaine is due to its ability to donate methyl groups to homocysteine via reactions catalyzed by the betaine homocysteine methyltransferase (BHMT) enzyme to generate methionine. In our search for alternates to betaine, we found that sulphur-containing analogs of betaine called thetins are alternative methyl-donor substrates of BHMT. The purpose of this study therefore was to compare the efficacy of betaine and one such analog, dimethylacetothetin (DMAT) in preventing alcoholic liver injury. The chronic ethanol feeding model which shows characteristic features of alcoholic liver injury after 4-5 weeks of ethanol exposure was utilized. Male Wistar rats (180-200 g BW) were fed the control or ethanol diet. Additional groups were fed the ethanol diet-supplemented with 1% betaine or 0.5% DMAT. All rats were sacrificed at the end of 4-5 weeks of feeding. Blood was collected and livers were excised and freeze-clamped and stored at -70°C until analyzed. We observed that while both compounds, betaine and DMAT, were effective in reducing fat accumulation in the liver, DMAT was more effective than betaine in preventing alcoholic steatosis (p < 0.05). Betaine supplemented as 1% in ethanol diet reduced the elevated liver triglycerides by ~50% (p < 0.05). However, DMAT at only a 0.5% supplementation reduced the liver triglycerides to levels seen in the control diet-fed animals. The blood ethanol levels were similar in ethanol-fed rats as compared to the betaine or DMAT-supplemented ethanol diet fed groups. We further showed that DMAT is a an exceptionally good substrate for BHMT, is 20 times more effective than betaine in remethylating homocysteine (p < 0.05) and also more efficacious in preventing methionine-induced hyperhomocysteinemia (p < 0.05). To conclude, DMAT should be considered as an alternative therapeutic agent to betaine for the treatment of alcoholic and non-alcoholic liver disease.

Analysis of pathological defects in methionine metabolism using a simple mathematical model

Derangements in methionine metabolism are a hallmark of cancers and homocystinuria, an inborn error of metabolism. In this study, the metabolic consequences of the pathological changes associated with the key pathway enzymes, methionine adenosyl transferase (MAT), glycine N-methyl transferase (GNMT) and cystathionine beta-synthase (CBS) as well as an activation of polyamine metabolism, were analyzed using a simple mathematical model describing methionine metabolism in liver. The model predicts that the mere loss of allosteric regulation of CBS by adenosylmethionine (AdoMet) leads to an increase in homocysteine concentration. This is consistent with the experimental data on the corresponding genetic defects, which specifically impair allosteric activation but not basal enzyme activity. Application of the characteristics of transformed hepatocytes to our model, i.e., substitution of the MAT I/III isozyme by MAT II, loss of GNMT activity and activation of polyamine biosynthesis, leads to the prediction of a significantly different dependence of methionine metabolism on methionine concentrations. The theoretical predictions were found to be in good agreement with experimental data obtained with the human hepatoma cell line, HepG2.

Methionine metabolism in the Buffalo rat following ethanol feeding.

Earlier studies have demonstrated that the Buffalo strain rat may have a defect in the process of methylneogenesis or lack the methyl-transfer enzyme system in the liver involved in methionine biosynthesis. The results of this study demonstrate that the enzyme systems responsible for methionine formation are present in the Buffalo rat and that these systems respond to ethanol feeding in a manner similar to that already shown in the Sprague-Dawley animal. These findings suggest that the previously described defect in methionine metabolism of the Buffalo rat may lie within the mechanism of methylneogenesis.

Elevated overall rates of transmethylation in cell lines from diverse human tumors.

In a study of a diverse set of human tumor cell lines previously shown to all have a defect in methionine metabolism (Stern, P. H., Wallace, C.D. and Hoffman, R.M., J. Cellular Physiology 119, 29-34, 1984), we demonstrate in this report that all have enhanced overall rates of transmethylation compared to normal human fibroblasts. Transmethylation rates were measured by blocking S-adenosylhomocysteine hydrolase and measuring the AdoHcy which accumulates as a result of transmethylation. The enhanced transmethylation rates may be the basis of the above-mentioned defects in methionine metabolism previously reported in human tumor cells, including the basis of the inability of the majority of the tumor cells to grow when methionine is replaced by homocysteine. The excess and unbalanced tRNA methylation observed for the last 25 years in many types of cancer may be at least in part explained by our results of elevated rates of overall transmethylation in cancer cells. The alteration of such a fundamental process as transmethylation in cancer may be indicative of its importance in the oncogenic process.

Homocystinuria

HOMOCYSTINURIA resulting from an inherited defect in methionine metabolism, although a very rare disorder, has been much publicized since its discovery in 1962. 1,2 There is now good evidence that the basic defect is a deficiency of the enzyme cystathionine synthetase, 3,4 preventing the formation of cystathionine from homocystine. The immediate result of this enzyme block is to increase accumulation of homocystine, a nonthreshold amino acid which is rapidly excreted into the urine in the oxidized form as homocystine. The back reaction to methionine, favored by the homocystine accumulation, results in high blood concentrations of the methionine and urinary excretion when tubular reabsorption limit is exceeded. Like other inborn errors of amino acid metabolism, homocystinuria often causes brain damage, the severity varying from minimal intellectual defect to gross cerebral dysfunction. Schimke et al 5 however, judged 16 of 38 patients to be of normal intelligence. Liver biopsies in two of