Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.2.1.22 (cystathionine beta-synthase)
965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of vitamin B12(B12)-deficiency on the activities of hepatic methionine synthase, homocysteine methyltransferase, and cystathionine beta-synthase was investigated in rats. The rats bred from B12-deficient dams were fed the B12-deficient diets for 150 days after weaning. Growth retardation of the B12-deficient rats was already observed on day 30 and continued through 150 days. But dietary supplementation of 0.5% DL-methionine slightly improved the growth retardation. Urinary excretion of methylmalonic acid increased to about 15 mg/mg creatinine and hepatic B12 concentration declined to about 2 ng/g liver after a 150-day feeding of the B12-deficient diets. Hepatic methionine synthase activity in rats fed the B12-deficient diets supplemented with or without methionine decreased to about 5% of B12-supplemented controls. Hepatic betaine-homocysteine methyltransferase activity showed no significant change caused by B12-deficiency. Hepatic cystathionine beta-synthase activity in rats fed the B12-deficient diets supplemented with or without methionine decreased to about 61% and 27% of their B12-supplemented controls, respectively, but the decrease was partially improved by methionine supplementation. In conclusion, the rats bred from B12-deficient dams showed a severe B12-deficiency after a 150-day feeding of the B12-deficient diets. The decrease of hepatic cystathionine beta-synthase activity was supposed to be due to the adaptation by the defect of methionine resynthesis.
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PMID:Effect of vitamin B12-deficiency on the activity of hepatic cystathionine beta-synthase in rats. 273 4

We investigated the nitrous oxide-induced inactivation of methionine synthase and the concurrent homocysteine (Hcy) export in mutant fibroblasts with defects in the homocysteine catabolizing enzyme, cystathionine beta-synthase, or in methionine synthase, which carries out homocysteine remethylation. The fibroblasts were incubated in various concentrations of methionine to create conditions favoring methionine conservation or catabolism. In cystathionine beta-synthase-deficient cells, high medium methionine partly protected the enzyme against inactivation, as previously found in normal fibroblasts. The Hcy export rate at low methionine levels was low (0.2-0.6 nmol/h/10(6) cells), and increased 2-3-fold at high methionine levels. Nitrous oxide enhanced Hcy export rate at low methionine, so that in the presence of nitrous oxide, the Hcy export became less dependent of methionine. In cb1G cells, the enzyme inactivation was moderate and independent of medium methionine. The Hcy export rate was intermediate (0.5-0.8 nmol/h/10(6) cells) at low methionine levels, and increased moderately (< 2-fold) at high methionine levels or following nitrous oxide exposure. In cb1E mutants, the enzyme activity was not affected by nitrous oxide, and the Hcy export was high (0.8-1.6 nmol/h/10(6) cells) and independent of methionine and nitrous oxide. These data suggest that Hcy remethylation and cystathionine beta-synthase activity are major determinants of Hcy export at low and high methionine, respectively. The low susceptibility of methionine synthase to nitrous oxide in the presence of high methionine or in cb1G or cb1E mutants is probably related to low catalytic turnover.
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PMID:Effect of methionine and nitrous oxide on homocysteine export and remethylation in fibroblasts from cystathionine synthase-deficient, cb1G, and cb1E patients. 813 95

Homocysteine can be methylated to form methionine by the cobalamin- (Cbl) and folate-dependent enzyme, methionine synthase; serum levels of total homocysteine are elevated in greater than 95% of patients with either Cbl or folate deficiency. Homocysteine can also condense with serine to form cystathionine in a pyridoxal phosphate-dependent reaction catalyzed by cystathionine beta-synthase. Cystathionine is subsequently cleaved to cysteine and alpha-ketobutyrate by the pyridoxal phosphate-dependent enzyme gamma-cystathionase. To assess levels of cystathionine in Cbl and folate deficiency, we developed a new capillary gas chromatographic-mass spectrometric assay and measured cystathionine in the serum of normal subjects and patients with clinically confirmed deficiencies of these vitamins. The normal range for serum cystathionine was 65 to 301 nmol/L (median = 126 nmol/L) for 50 normal blood donors. In 30 patients with clinically confirmed Cbl deficiency, values for cystathionine ranged from 208 nmol/L to 2,920 nmol/L (median = 816 nmol/L) and 26 (87%) had levels above the normal range. In 20 patients with clinically confirmed folate deficiency, cystathionine concentrations ranged from 138 nmol/L to 4,150 nmol/L (median = 1,560 nmol/L) and 19 (95%) had values above the normal range. Five homozygotes for cystathionine beta-synthase deficiency had high values for serum-total homocysteine and low or low-normal values for serum cystathionine that ranged from 30 nmol/L to 114 nmol/L even though they were on treatment with pyridoxine and had partially responded. One patient with a defect in the synthesis of 5-CH3-tetrahydrofolate and five patients with defects in the synthesis of CH3-Cbl had high values for serum-total homocysteine and high values for cystathionine that ranged from 311 nmol/L to 1,500 nmol/L even though they were on treatment with folic acid and Cbl, respectively, and had partially responded. We conclude that levels of cystathionine are evaluated in the serum of most patients with Cbl and folate deficiency and that they are useful in the differential diagnosis of an elevated serum-total homocysteine level.
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PMID:Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. 850 76

Editing of the non-protein amino acid homocysteine, a frequent type of error-correcting process in amino acid selection for protein synthesis by an aminoacyl-tRNA synthetase, results in formation of a cyclic thioester, homocysteine thiolactone. Here it is shown that human cells in which homocysteine metabolism is deregulated by a mutation in the cystathionine beta-synthase gene and/or by an antifolate drug, aminopterin (which prevents remethylation of homocysteine to methionine by methionine synthase), produce more homocysteine thiolactone, in addition to homocysteine, than unaffected cells. The thiolactone is incorporated into cellular and extracellular proteins, in addition to being secreted and hydrolyzed to homocysteine. Experiments with model proteins and amino acids suggest that the mechanism of incorporation involves acylation of side chain amino groups of lysine residues by the activated carboxyl group of the thiolactone. The metabolic conversion of homocysteine to homocysteine thiolactone and the reactivity of the thiolactone toward proteins may explain pathological consequences of elevated levels of homocysteine such as observed in vascular disease.
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PMID:Metabolism of homocysteine thiolactone in human cell cultures. Possible mechanism for pathological consequences of elevated homocysteine levels. 899 83

The link between vascular disease and elevated homocysteine levels has been recognized for more than 30 years, and association with moderately elevated levels has been suspected for 20 years. Homocysteine is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalysed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Homocysteine is also remethylated to methionine by methionine synthase, a vitamin B12 dependent enzyme and by methylenetetrahydrofolate reductase. Environmental factors such as folate, or vitamin B12, or vitamin B6 deficiencies and genetic defects such as cystathionine beta-synthase or abnormality of methylene-tetrahydrofolate reductase or some vitamin B12 metabolism defects may contribute to increasing plasma homocysteine levels. Normal fasting levels of homocysteine lie within the range 6-16 mumol/l. Apart from differences in assay methods, age, sex and nutritional status may affect the plasma levels. Though it is now well known that homocysteine is an independent risk factor for premature vascular disease, the pathogenesis of homocysteine-induced vascular damage is, for the most part, unknown. It may be multifactorial, including direct homocysteine damage to the endothelium, an enhanced low-density lipoprotein peroxidation, an increase of platelet thromboxane A2, or a decrease of protein C activation.
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PMID:[Deregulation of homocysteine metabolism and consequences for the vascular system]. 923 30

Recent genetic studies have led to the characterization of molecular determinants contributing to the pathogenesis of hyperhomocysteinemia. In this article we summarize the current insights into the molecular genetics of severe, moderate and mild hyperhomocysteinemia. We will consider deficiencies of the trans-sulfuration enzyme cystathionine beta-synthase (gene symbol: CBS), and the disturbances of the remethylation enzymes 5, 10-methylenetetrahydrofolate reductase (gene symbol: MTHFR), methionine synthase (gene symbol: MTR), and the recently identified methionine synthase reductase (gene symbol: MTRR). Furthermore, we will focus on clinically important genetic polymorphisms which are highly prevalent and thus of potential general interest.
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PMID:Molecular genetics of homocysteine metabolism. 1068 51

A moderately elevated plasma total homocysteine (tHcy), whether measured during fasting or post-methionine load (PML), is increasingly being recognized as a risk factor for coronary artery diseases (CAD). However, etiologies for moderately elevated plasma tHcy, particularly with regard to the role of genetic influence on plasma tHcy levels, are still not well understood. In the current investigation, we studied 1025 individuals with respect to the effect of the 68-bp insertion (844ins68 variant) of the cystathionine beta-synthase (CBS) gene, the A(2756)G transition of the B(12)-dependent methionine synthase (MS) gene and the C(677)T transition of the methylenetetrahydrofolate reductase (MTHFR) gene on fasting and 4 h PML tHcy. Of these individuals, 153 (14.9%) were heterozygous for the 68-bp insertion, 329 (32.1%) were heterozygous for the G(2756) allele and 122 (11.9%) were homozygous for the C(677)T transition. Individuals heterozygous for the insertion had significantly lower PML increase in tHcy concentrations, while individuals homozygous for the A(2756)G transition had significantly lower fasting tHcy levels. A 2-way ANOVA showed that there was no interaction between the 844ins68 and the A(2756)G transition for either fasting tHcy or PML increase in tHcy, confirming the fact that the effect of these two genotypes on plasma tHcy levels are additive. The effects are opposite but additive with the C(677)50% of all individuals in this study carried polymorphic traits, which predisposed them to either higher or lower plasma tHcy concentrations, thus providing new evidence of the importance of genetic influences as determinants of tHcy levels.
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PMID:Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels. 1070 24

Elevated concentrations of the amino acid homocysteine and/or folate deficiency have been reported to affect neural development/function in both human patients and animal models. We have investigated the distribution of functional polymorphisms in genes involved in homocysteine/folate metabolism in children with high IQ and in children with average IQ. No differences in the frequencies of genetic variants in the methionine synthase or methylenetetrahydrofolate reductase genes were found. However, the cystathionine beta-synthase (CBS) 844ins68 allele was significantly underrepresented in children with high IQ. The mechanism by which a functional genetic variant in the CBS gene may influence cognitive function remains to be determined.
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PMID:Polymorphisms of genes controlling homocysteine/folate metabolism and cognitive function. 1079 Aug 95

The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation of NMDA receptors could contribute to neuronal damage in homocystinuria and HH(e). Since HH(e) is associated with certain neurodegeneratives diseases, in the present review, the molecular mechanisms involved in neurotoxicity due to Hcy are discussed.
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PMID:[Hyperhomocysteinemia: atherothrombosis and neurotoxicity]. 1079 37

Homocysteine is a key junction metabolite in methionine metabolism. It suffers two major metabolic fates: transmethylation catalyzed by methionine synthase or betaine homocysteine methyl transferase and transsulfuration catalyzed by cystathionine beta-synthase leading to cystathionine. The latter is subsequently converted to cysteine, a precursor of glutathione. Studies with purified mammalian methionine synthase and cystathionine beta-synthase have revealed the oxidative sensitivity of both junction enzymes, suggesting the hypothesis that redox regulation of this pathway may be physiologically significant. This hypothesis has been tested in a human hepatoma cell line in culture in which the flux of homocysteine through transsulfuration under normoxic and oxidative conditions has been examined. Addition of 100 microM H(2)O(2) or tertiary butyl hydroperoxide increased cystathionine production 1.6- and 2.1-fold from 82 +/- 7 micromol h(-)(1) (L of cells)(-)(1) to 136 +/- 15 and 172 +/- 23 micromol h(-)(1) (L of cells)(-)(1), respectively. The increase in homocysteine flux through the transsulfuration pathway exhibited a linear dose dependence on the concentrations of both oxidants (50-200 microM H(2)O(2) and 10-200 microM tertiary butyl hydroperoxide). Furthermore, our results reveal that approximately half of the intracellular glutathione pool in human liver cells is derived from homocysteine via the transsulfuration pathway. The redox sensitivity of the transsulfuration pathway can be rationalized as an autocorrective response that leads to an increased level of glutathione synthesis in cells challenged by oxidative stress. In summary, this study demonstrates the importance of the homocysteine-dependent transsulfuration pathway in the maintenance of the intracellular glutathione pool, and the regulation of this pathway under oxidative stress conditions. Aberrations in this pathway could compromise the redox buffering capacity of cells, which may in turn be related to the pathophysiology of the different homocysteine-related diseases.
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PMID:The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. 1104 66


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