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)

Elevated levels of plasma homocysteine are associated with both venous and arterial thrombosis. Homocysteine inhibits the function of thrombomodulin, an anticoagulant glycoprotein on the endothelial surface that serves as a cofactor for the activation of protein C by thrombin. The effects of homocysteine on thrombomodulin expression and protein C activation were investigated in cultured human umbilical vein endothelial cells and CV-1(18A) cells that express recombinant human thrombomodulin. Addition of 5 mM homocysteine to endothelial cells produced slight increases in thrombomodulin mRNA and thrombomodulin synthesis without affecting cell viability. In both cell types, thrombomodulin synthesized in the presence of homocysteine remained sensitive to digestion with endoglycosidase H and failed to appear on the cell surface, suggesting impaired transit along the secretory pathway. In a cell-free protein C activation assay, homocysteine irreversibly inactivated both thrombomodulin and protein C in a process that required free thiol groups and was inhibited by the oxidizing agents diamide or N-ethylmaleimide. By inhibiting both thrombomodulin surface expression and protein C activation, homocysteine may contribute to the development of thrombosis in patients with cystathionine beta-synthase deficiency.
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PMID:Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. 166 Dec 91

The experiments described here were set up (a) to investigate the effect of age and (b) to investigate the effect of giving five diets which varied in methionine and choline or betaine contents on some of the enzymes that metabolize these nutrients in chick liver. Growth and carcass composition of the chicks fed on the different diets were also examined. There was no obvious relationship between age and enzyme activity in young chicks. Only a diet low in methionine (but not one low in choline) showed a significant decrease in growth and a change in carcass composition. The effects of diet on enzyme activity were complex. Choline oxidase (EC 1.1.3.17) activity was affected by the level of choline in the diet, being high when choline was present at high levels, especially when methionine was limiting. 5-Methyltetrahydrofolate homocysteine methyltransferase (EC 2.1.1.3) had a high activity in the livers of chicks fed on a conventional diet compared with those given semi-purified diets. Other enzymes showed minor changes in response to the diet. The diet low in methionine showed a lower activity of cystathionine beta-synthase (EC 4.2.1.22) and slightly higher activities of methionine adenosyltransferase (EC 2.5.1.6) and betaine-homocysteine methyltransferase (EC 2.1.1.5; compared with other diets), suggesting that this diet encouraged re-methylation of homocysteine at the expense of trans-sulphuration to cystathionine. The findings obtained in these studies form a useful basis for further investigation of the metabolic interrelationships between methionine and related nutrients.
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PMID:Changes in body-weight, composition and hepatic enzyme activities in response to dietary methionine, betaine and choline levels in growing chicks. 169 35

Previous work with cultured mammalian cells and perfused laboratory animals suggested to us that hydrolysis of homocysteine thiolactone was catalyzed in these systems. We confirmed this finding by measuring the sulfhydryl-releasing activity of cultured endothelial cells from human umbilical arteries in homocysteine thiolactone solution, pH 7.4, 37 degrees C. The reaction was vigorous and stereospecific and showed saturation kinetics (Km values for L- and D,L-homocysteine thiolactone were 3.9 and 8.2 mmol/l, respectively, and Vmax values were 10.75 and 10.1 mumol/min/10(9) cells, respectively). L-Homocysteine thiolactone was quantitatively converted to homocysteine, as measured by amino acid analysis. Human serum also accelerated the elimination of homocysteine thiolactone, although in this process, the majority of the newly formed sulfhydryl-containing product was precipitable by sulfosalicylic acid, indicating likely homocysteinylation of serum proteins. However, approximately 38% of the sulfhydryl-containing product was not precipitated, and because thiolactone elimination stereospecifically favored the L-enantiomer, a possible subsidiary role for serum-catalyzed hydrolysis of the thiolactone was suggested. No homocysteine thiolactone could be found in serum samples from six patients with acute myocardial infarction, three patients with cystathionine beta-synthase deficiency, and six normal subjects. Thus, humans have active vascular systems for elimination of homocysteine thiolactone, a process that could be responsible for an absence of the compound in serum.
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PMID:Homocysteine thiolactone disposal by human arterial endothelial cells and serum in vitro. 202 4

A yeast strain highly resistant to propargylglycine (an inhibitor of cystathionine gamma-lyase) was isolated from air. It was partially characterized, but it has not been identified with any known yeast species. Its sulphur amino acid metabolism differed from that of other fungi by the lack of the reverse transsulphuration pathway from methionine to cysteine, as no activity of cystathionine beta-synthase or cystathionine gamma-lyase was found. The functional lack of this pathway was confirmed by growth tests and by experiments with [35S]methionine. In contrast to Saccharomyces cerevisiae neither homocysteine synthase nor the sulphate assimilation pathway were repressible by methionine in the new strain; on the contrary, a regulatory effect of cysteine was observed.
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PMID:A yeast with unusual sulphur amino acid metabolism. 207 24

Severe homocysteinemia due to genetic defects either of pyridoxal 5-phosphate (PLP)-dependent cystathionine beta-synthase (CBS) or of enzymes in vitamin B12 and folate metabolism is associated with very early-onset vascular disease. Therefore, we studied homocysteine metabolism in 72 patients presenting before the age of 55 years with occlusive arterial disease of cerebral, carotid, or aorto-iliac vessels. Twenty patients (28%) had basal homocysteinemia; and 26 patients (36%) had abnormal increases of plasma homocysteine after peroral methionine loading, which exceeded the highest value for 46 comparable controls and was within the range for 20 obligate heterozygotes for homocystinuria due to CBS deficiency. Basal plasma homocysteine content was strongly and negatively correlated to vitamin B12 and folate concentrations. Plasma PLP was depressed in most patients but there was no correlation between PLP and homocysteine values. In 20 patients, treatment with pyridoxine hydrochloride (240 mg/day) and folic acid (10 mg/day) reduced fasting homocysteine after 4 weeks by a mean of 53%, and methionine response by a mean of 39%. These data show that a substantial proportion of patients with early-onset vascular disease have impaired homocysteine metabolism, which may contribute to vascular disease, and that the impaired metabolism can be improved easily and without side effects.
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PMID:Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. 240 53

Cystathionine beta-synthase deficiency results in severe homocysteinaemia, precocious arteriosclerosis and frequent thromboembolism. In addition, antithrombin III activity and factor VII are low. Arteriosclerosis seems to be increased in heterozygotes as well (cystathionine beta-synthase gene dosage 50%) but rare in Down syndrome (cystathionine beta-synthase gene dosage 150%). In the present study total plasma homocysteine was high in three homozygotes, slightly increased in 20 obligate heterozygotes but not reduced in nine subjects with Down syndrome when compared to controls. After methionine loading, increases of homocysteine were pathologically high in 14 of 20 heterozygotes but was not, as expected, low in subjects with Down syndrome. Antithrombin III activity and factor VII antigen tended to be low in homozygotes but were normal in heterozygotes. In Down syndrome antithrombin III activity was reduced and factor VII antigen normal. There were no correlations between levels of homocysteine, antithrombin III activity and factor VII antigen. Thus, subjects with Down syndrome seem not to exhibit the expected gene dosage effect on homocysteine metabolism which could explain their reduced proneness to develop arteriosclerosis, nor do antithrombin III activity or factor VII antigen seem to be related to homocysteine metabolism.
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PMID:Homocysteine, factor VII and antithrombin III in subjects with different gene dosage for cystathionine beta-synthase. 253 42

The addition of L-cysteine to hepatic cytosols causes inactivation of tyrosine aminotransferase. We have studied the mechanism of inactivation and the effect of streptozotocin-induced diabetes in the rat on the inactivation of tyrosine aminotransferase in the presence of fractions prepared from livers and kidneys. Diabetes increased the rate at which tyrosine aminotransferase was inactivated after addition of cysteine to hepatic cytosols. The inactivation was due to the production of thiocysteine (which contains sulfane sulfur) from cystine as a result of desulfuration catalyzed by gamma-cystathionase. Diabetes increased the content of cystathionine beta-synthase and gamma-cystathionase in liver. As a result, cytosols from diabetic animals converted homocysteine, cystathionine, cysteine and cystine to sulfane at an elevated rate, with resulting inactivation of tyrosine aminotransferase. In contrast, inactivation in kidney fractions was not affected by diabetes. Incubation with an inhibitor of gamma-cystathionase (propargylglycine) prevented inactivation of tyrosine aminotransferase. These results show that the potential for the formation of sulfane sulfur by the enzymes of the transsulfuration pathway is enhanced by chronic diabetes.
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PMID:Experimental diabetes increases the formation of sulfane by transsulfuration and inactivation of tyrosine aminotransferase in cytosols from rat liver. 256 58

Thrombogenesis and accelerated atherogenesis occur in the homocystinurias, both those due to recessively inherited cystathionine beta-synthase deficiency and to disorders of remethylation of homocysteine to methionine. The evidence strongly implicates high levels of plasma homocysteine as the mediator. Homocysteine damages cultured human venous and arterial endothelial cells and enhances detachment from their substrate, changes not found with comparable concentrations of other amino acids tested. Homocysteine is oxidized in vitro to homocystine in an oxygen-dependent reaction producing hydrogen peroxide. Since the effects of homocysteine in cell cultures can be prevented by catalase, hydrogen-peroxide-induced injury may be the mechanism responsible. Five different laboratories have documented an association between mild homocysteinaemia and premature vascular disease. The majority of affected patients are heterozygotes for cystathionine beta-synthase deficiency whose endothelial cells may have an enhanced susceptibility to injury by homocysteine. Mild homocysteinaemia also occurs in chronic renal failure in which vascular disease is prominent. Mechanisms linking mild homocysteinaemia and possible vascular effects are not yet understood, but could involve prostaglandins and oxidized low-density lipoprotein, and possibly also free radicals.
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PMID:Mechanisms of thrombogenesis and accelerated atherogenesis in homocysteinaemia. 268 Aug 9

In three different studies we tested the hypothesis that early-onset vascular disease is associated with impaired homocysteine metabolism which could contribute to the development of arteriosclerosis and thrombosis. In patients with occlusive vascular disease before the age of 60, a post-methionine load increase of plasma homocysteine exceeding the highest value for comparable healthy control subjects was found in 1 of 21 with myocardial infarction (5%), 14 of 37 with aorto-iliac disease (38%), and 17 of 53 with cerebrovascular disease (32%). This might indicate heterozygosity for homocystinuria due to cystathionine beta-synthase deficiency. Concentrations of serum vitamin B12 and red cell folate had an important modulating effect on plasma homocysteine concentrations in the fasting state.
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PMID:Plasma homocysteine and methionine tolerance in early-onset vascular disease. 268 Aug 11

Homocysteine interacts in a complex way in the plasma with cysteine and plasma proteins. To explore the interrelations between free and protein-bound homocysteine and cysteine during short- and long-term changes in plasma levels, free and bound homocysteine and cysteine were measured in 13 patients with homocystinuria due to cystathionine beta-synthase deficiency. Levels were measured during oral methionine loads (4 g/m2 body surface area) and after oral betaine (3 g twice daily). In six pyridoxine-responsive patients, free and bound levels of homocysteine and cysteine, measured 4 to 24 hours after oral methionine, changed in a parallel manner. Similar close tracking occurred in fasting plasma samples collected from two pyridoxine-nonresponsive patients before and during betaine therapy. Oral betaine given to seven pyridoxine-nonresponsive patients decreased free and bound homocysteine and increased free and bound cysteine toward normal levels during monitoring periods of up to 300 days. In these studies as the level of homocysteine decreased, the proportion of protein-bound homocysteine and cysteine increased. The present study establishes that changes in bound and free levels of either homocysteine or cysteine track closely in the short-term (four hours or less) and generally also in the long-term (up to 300 days).
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PMID:Free and protein-bound homocysteine and cysteine in cystathionine beta-synthase deficiency: interrelations during short- and long-term changes in plasma concentrations. 276 10


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