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)

1. Cystathionine beta-synthase activity isolated from fibroblast cultures obtained from the skin of a normal and a homocystinuric individual were both cross-reactive with normal human liver cystathionine beta-synthase antibody. 2. Isoelectric focusing revealed a substantial difference in the isoelectric points of the normal and abnormal fibroblast enzymes. 3. Treatment of purified samples of normal and abnormal fibroblast enzymes with sodium dodecylsulphate followed by polyacrylamide gel electrophoresis indicated that both normal and abnormal enzymes were composed of two sub-units of molecular weights 53000 and 70000. 4. A combination of urea and sodium dodecylsulphate treatment revealed that the respective 53000 molecular weight sub-units were different. 5. It has been concluded that the molecular defect in the case of pyridoxine non-responsive homocystinuria examined in the present investigation arises as a result of an alteration in the structural gene which codes for the lower molecular weight sub-unit of cystathionine beta-synthase.
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PMID:The molecular defect in a case of (cystathionine beta-synthase)-deficient homocystinuria. 40 47

Three circumstances prompted us to reexamine the relationship between abnormal cystathionine accumulation and possible homocystinuria resulting from this condition: (a) discovery of an infant girl with apparently alternating massive cystathioninuria and homocystinuria; (b) the presence of homocystinuria in some, but not all, previously reported cases of cystathioninuria probably due to gamma-cystathionine deficiency; and (c) the recent demonstration that mammalian cystathionine beta-synthase can cleave cystathionine to homocysteine. The following conclusions were reached: (a) Homocystine may arise as a result of bacterial contamination of a urine sample initially containing cystathionine, but not homocystine. (b) After a methionine load, a cystathioninuric patient may excrete readily detected amounts of homocystine. (c) However, homocystinuria is not a necessary concomitant of even massive cystathioninuria. These findings and some of their implications are briefly discussed.
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PMID:Cystathioninuria and homocystinuria. 112 32

Deficiency of cystathionine beta-synthase (CBS) causes the most common form of inherited homocystinuria. We developed a simple CBS expression system in E. coli to screen for pathogenic mutations in affected individuals. Portions of patient cDNAs were amplified by PCR and used to replace the corresponding segments of normal human CBS cDNA in the bacterial expression plasmid pHCS3. Hybrid CBS was expressed in E. coli and the segments of patient's cDNA which extinguished CBS activity were sequenced to identify the mutation. The first study of a pyridoxine-responsive patient using this screen revealed that of the clones which contained either the middle or the 3'-portion of his cDNA, about half were devoid of catalytic activity. Subsequent sequencing of the affected segments confirmed a compound heterozygosity for a maternal T833-->C transition (I278T) and for a paternal A-->C transversion in the intron 11 splice acceptor. The latter mutation leads to an in-frame deletion of exon 12 (nt 1224-1358, amino acids W408 to G453). This bacterial expression system proved to be a rapid screening method for localizing pathogenic mutations in CBS, allowing us to sequence the affected portions of mutant cDNA within 7-10 days of harvesting cultured fibroblasts.
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PMID:Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta-synthase deficiency. 130 Nov 98

Several inherited metabolic disorders of the transsulfuration pathway are discussed. They are hypermethioninemia, homocystinuria, cystathioninuria, beta-mercaptolactate cysteine disulfideuria and sulfite oxidase deficiency (SOD). Primary coverage is given to homocystinuria and SOD. In the case of homocystinuria, metabolic defects include cystathionine beta-synthase deficiency, methylenetetrahydroforate reductase deficiency, and mutations in cobalamin metabolism. Their main clinical pictures, metabolic abnormalities, and treatment are also described. SOD appears in two cases as an isolated enzyme defect and a combined deficiency of sulfite oxidase and xanthine dehydrogenase that share a common molybdenum cofactor. The clinical, biochemical and neurological features of the two disorders are reviewed.
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PMID:[Inherited metabolic disorders of the transsulfuration pathway]. 140 82

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

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

Cystathionine beta-synthase and gamma-cystathionase, the two major enzymes of the transsulfuration pathway of methionine metabolism, are described. These enzymes are responsible for inborn errors, e.g., homocystinuria and cystathioninuria. The interaction of gamma-cystathionase with the cofactor, substrates and inhibitors of the general formula RONH2 containing structural fragments of substrates has been studied. A non-radioactive avidin-biotin system for the microdetection of gamma-cystathionase in dot blots has been developed. This system was applied for immunoscreening of a rat liver cDNA library in the prokaryotic expression vector lambda gt 11.
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PMID:[Pyridoxal phosphate-dependent enzymes of sulfur amino acid metabolism]. 275 77

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

Homocysteine is a branch-point metabolite, the biological fate of which is linked to vitamin B12, reduced folates and vitamin B6. Various inborn defects in homocysteine metabolism, among which cystathionine beta-synthase deficiency is most common, lead to the clinical condition homocystinuria. A central feature of this clinical state is premature arteriosclerosis. These patients benefit from agents serving as cofactors in homocysteine metabolism which both reduce the homocysteine levels in plasma and the incidence of vascular episodes. Experimental data point to homocysteine as an arteriosclerotic agent. Homocysteine in human plasma exists mainly as mixed disulfides with albumin (70 per cent) and cysteine. New methods determine total plasma homocysteine which includes all these species. Normal values for plasma homocysteine are lower in premenopausal women than in men and postmenopausal women. Impaired homocysteine metabolism seems to exist in 15-30 per cent of patients with premature cardiovascular disease. Moderate homocysteinemia is as a risk factor for cardiovascular disease, independent of conventional risk factors. Apart from homocystinuria, vitamin B12 deficiency causes the most extreme elevations of plasma homocysteine, and it has been established that plasma homocysteine is a more responsive parameter to impaired vitamin B12 function than serum cobalamin. Massive increase in plasma homocysteine level is also observed in folate deficiency, whereas renal failure, some malignant states and psoriasis cause a moderate homocysteinemia. High doses of folic acid reduce plasma homocysteine, and this innocuous mean should be considered as an intervention in patients with increased plasma level. Drugs like methotrexate, some anticonvulsants and 6-azauridine triacetate induce moderate elevation of plasma homocysteine, whereas a reduction is observed after penicillamine administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Plasma homocysteine, a risk factor for premature vascular disease. Plasma levels in healthy persons; during pathologic conditions and drug therapy]. 281 54

The human gene for cystathionine beta-synthase (CBS), the enzyme deficient in classical homocystinuria, has been assigned to the subtelomeric region of band 21q22.3 by in situ hybridization of a rat cDNA probe to structurally rearranged chromosomes 21. The homologous locus in the mouse (Cbs) was mapped to the proximal half of mouse chromosome 17 by Southern analysis of Chinese hamster X mouse somatic cell hybrid DNA. Thus, CBS/Cbs and the gene for alpha A-crystalline (CRYA1/Crya-1 or Acry-1) form a conserved linkage group on human (HSA) chromosome region 21q22.3 and mouse (MMU) chromosome 17 region A-C. Features of Down syndrome (DS) caused by three copies of these genes should not be present in mice trisomic for MMU 16 that have been proposed as animal models for DS. Mice partially trisomic for MMU 16 or MMU 17 should allow gene-specific dissection of the trisomy 21 phenotype.
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PMID:The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17. 289 61


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