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)

A disturbance of serine-glycine metabolism in a group of patients who became psychotic after oral intake of serine may be due to any serine-related enzyme abnormality. In order to elucidate this problem, we studied several enzymes in fibroblasts obtained from these patients. First, the enzyme serine hydroxymethyltransferase was investigated. The apparent Km values for serine, L-tetrahydrofolate (H4folate), and pyridoxal 5'-phosphate, as well as the maximal velocities of the forward and backward reactions measured in fibroblasts obtained from patients, were not different from those in the cells from controls. We also measured the activities of another three enzymes of the folic acid cycle, viz., 5,10-methylene-H4folate dehydrogenase, 10-formyl-H4folate synthetase, and 5,10-methenyl-H4folate cyclohydrolase, as well as the enzyme cystathionine beta-synthase. Again, no differences were found among these enzymes in fibroblasts from patients and controls. It can be concluded that the psychotic symptoms occurring after the administration of serine are not the result of any malfunctioning of the enzymes investigated.
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PMID:Serine and folate metabolism in fibroblasts from episodic psychotic patients with psychedelic symptoms. 309 Oct 98

Homocyst(e)ine [H(e)], the sum of homocysteine, homocystine, and the homocysteine-cysteine mixed disulfide, free and protein-bound, has been shown to be associated in retrospective case control studies, and in one prospective study, with vascular disease, including coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease. Elevated levels of homocyst(e)ine severe enough to cause homocystinuria are seen in severe nutritional deficiencies of vitamin B12, folic acid and vitamin B6. Rare genetic disorders of vitamin B12 synthesis of 5'-10'-methylene tetrahydrofolate reductase, or the pyridoxal phosphate-dependent enzyme cystathionine beta-synthase may cause severe hyperhomocyst(e)inemia and homocystinuria. The clinical manifestation of these disorders are mental retardation, neurological disorders, and widespread thromboembolic phenomena. The measurement of H(e) is currently performed using high-pressure liquid chromatography with fluorescence detection. Other methods, especially mass spectroscopy, are also used. Internal standards using increasing concentrations of homocystine and acetylcysteine and several external standards are used to ensure accuracy of the assay. Milder elevations of H(e) have recently been associated with vascular disease, in both men and women. The strength of this association appears to be stronger for peripheral and cerebrovascular disease than for CAD. Nevertheless, several case control studies in Europe, Canada, and the United States have shown that H(e) levels are elevated in CAD patients compared with controls, and H(e) levels are independent of the conventional cardiovascular risk factors (age, gender, lipid and lipoprotein cholesterol levels, hypertension, or cigarette smoking). One prospective study, the Physicians' Health Study, has shown that H(e) levels are slightly but significantly higher in CAD cases vs controls in a population of US physicians.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Measurement of homocyst(e)ine in the prediction of arteriosclerosis. 762 74

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

This review of recent advances covers (1) the metabolism of methionine and its regulation, emphasizing interactions with the three important vitamins folate, cobalamin and pyridoxine; (2) present knowledge of enzymological and moleculargenetic aspects of homozygous deficiencies of the three enzymes which cause elevated homocyst(e)ine; (3) recent clinical findings, post-methionine loading results related to enzyme and mutation studies in obligate heterozygotes for cystathionine beta-synthase deficiency; (4) important new evidence for disturbed homocysteine metabolism in neural tube defects, particularly based on studies of the thermolabile methylene-tetrahydrofolate reductase mutation which is also of importance in vascular disease; (5) the suitability and limitations of animal models that have so far been described.
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PMID:Disorders of homocysteine metabolism. 921 Nov 99

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

Cystathionine beta-synthase (CBS) is an important enzyme for methionine metabolism. A common 844ins68 insertion variant in the CBS gene has been described. This 68-bp duplication of the intron 7-exon 8 boundary within the CBS gene already has been reported to be associated in cis with the T833C mutation. Heterozygosity for CBS deficiency is considered an important cause of hyperhomocysteinemia that strongly relates to cardiovascular disease, as well as homozygosity for another common variant, the C677T mutation of 5,10-methylene tetrahydrofolate reductase. We analysed the prevalence of the 844ins68 variant in the CBS gene in 595 unrelated apparently healthy individuals from nine Italian regions and in 133 patients with coronary artery disease. Our data confirm that the T833C mutation cosegregates in cis with the 844ins68 in all carriers of the insertion. Furthermore, no statistical difference was found in the insertion variant allele frequency between controls and coronary artery disease patients. Our study indicates a microheterogeneity in the distribution of the 844ins68 in the Italian population.
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PMID:Microheterogeneity in the distribution of the 844ins68 in the cystathionine beta-synthase gene in Italy. 1033 41

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. In search of genetic factors causing elevated levels of total homocysteine in plasma (tHcy), we investigated a cohort of consecutively identified, unrelated thrombosis patients (n = 28) having intermediate or severe hyperhomocysteinemia (30 micromol/l<tHcy < or =100 micromol/l, and tHcy > 100 micromol/l, respectively). The methylene-tetrahydrofolate reductase (MTHFR) 677C-->T genotype, and the complete cystathionine beta-synthase (CBS) genotype was determined in all patients. We found that the MTHFR T/T genotype was strongly correlated with intermediate hyperhomocysteinemia, being present in 73.9% of those cases (17 of 23). In three of five patients with severe hyperhomocysteinemia, compound heterozygosity for CBS mutations was detected. Among the mutations, two novel missense mutations: 1265C-->T (S422L) and 1397C-->T (S466L) were detected. The phenotype in those patients was quite mild, thromboembolism apart. This indicates that a search for CBS mutations in patients with severe hyperhomocysteinemia is important to ensure the detection of a possible CBS deficiency, thus enabling treatment. Co-existence of the MTHFR T/T genotype and the common CBS 844ins68 variant was significantly higher among patients (10.7%) as compared to controls (1.2%), indicating that this genotype combination is a thrombotic risk factor (P <0.05). In a few patients, hyperhomocysteinemia could not be explained by this genetic approach, suggesting that other genetic risk factors were implicated.
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PMID:Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic determinants. 1078 Mar 16

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

Hyperhomocysteinemia is a well established risk factor for cardiovascular disease, and multiple factors likely lead to abnormal regulation of plasma homocysteine in patients with diabetes. To examine a possible role for insulin and glucose in homocysteine metabolism, we examined the activity of two important enzymes of homocysteine metabolism in hepatocytes. In various tissues of six mice, methylene tetrahydrofolate reductase (MTHFR) activity was present in all tissues tested and the highest concentration (per gram) was in the brain. In contrast, cystathionine beta-synthase (CBS) activity appeared to be present only in the liver and to a small extent in the kidney. Using HEP G2 cells in culture, MTHFR activity was 3.3+/-0.8 nmol/h when the glucose concentration in the medium was 100 mg/dl and fell to 2.3+/-0.3 nmol/h when glucose was increased to 300 mg/dl. MTHFR activity was 3.4+/-0.3 nmol/h when cells were exposed to an insulin concentration of 5 mU/ml and fell to 2.8+/-0.3 nmol/h when insulin concentration was increased to 200 mU/ml (P<0.01). In contrast CBS activity increased from 0.017 to 0.13 U/ml by increasing the glucose concentration in the medium (P<0.01), but decreased from 0.04 to 0.02 (P<0.01) when the insulin concentration was increased from 5 to 200 mU/ml, respectively. We conclude that CBS and MTHFR have different tissue distributions, with CBS being present predominantly in liver and kidney, and MTHFR found in many tissues. In addition, both insulin and glucose affect the activity of the two enzymes when added to hepatocytes in vitro. If such effects occur in humans with hyperglycemia and hyperinsulinemia, then alterations in homocysteine metabolism may contribute to the accelerated macrovascular disease associated with insulin resistance or type 2 diabetes.
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PMID:The effect of glucose and insulin on the activity of methylene tetrahydrofolate reductase and cystathionine-beta-synthase: studies in hepatocytes. 1158 7

Folic acid is presently the mainstay of treatment for most subjects with elevated plasma homocyst(e)ine concentrations [Plasma or serum homocyst(e)ine, or total homocysteine, refers to the sum of the sulfhydryl amino acid homocysteine and the homocysteinyl moieties of the disulfides homocystine and homocystein-cysteine, whether free or bound to plasma proteins.] Changes in homocyst(e)ine in response to folic acid supplementation are characterized by considerable interindividual variation. The purpose of this study was to identify factors that contribute to heterogeneity in short-term responses to folic acid supplementation. The effects of folic acid supplementation (1 or 2 mg per day) for 3 wk on plasma homocyst(e)ine concentrations were assessed in 304 men and women. Overall, folic acid supplementation increased mean plasma folate 31.5 +/- 98.0 nmol/L and decreased mean plasma homocyst(e)ine concentrations 1.2 +/- 2.4 micromol/L. There was evidence of substantial interindividual variation in the homocyst(e)ine response from -18.5 to +7.1 micromol/L, including an increase in homocyst(e)ine in 20% of subjects (mean increase 1.5 +/- 1.4 micromol/L). Basal homocyst(e)ine, age, male gender, cigarette smoking, use of multivitamins, methylene tetrahydrofolate reductase, and cystathionine beta-synthase polymorphisms accounted for 47.6% of the interindividual variability in the change in homocyst(e)ine after folic acid supplementation, but about 50% of variability in response to folic acid was not explained by the variables we studied.
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PMID:Short-term folic acid supplementation induces variable and paradoxical changes in plasma homocyst(e)ine concentrations. 1183 88


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