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Results for “Cystathionine beta-Synthase”

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At least 19 recordsLinked to original sources
PubMed1977

The molecular defect in a case of (cystathionine beta-synthase)-deficient homocystinuria.

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.

Cross Reactions↗
PubMed1978

Homocystinuria. Evidence for three distinct classes of cystathionine beta-synthase mutants in cultured fibroblasts.

We have compared in vivo pyridoxine responsiveness with in vitro cystathionine beta-synthase activity in extracts of confluent fibroblasts from 14 synthase-deficient patients. Enzyme activity was measured with and without addition of its cofactor, pyridoxal-5'-phosphate, using a radioisotopic assay which detects as little as 0.25% of control activity. Six of seven lines from responsive patients had measurable activity without the added cofactor (0.6-15% of mean control). Two of these lines showed a five- and sevenfold stimulation of cystathionine beta-synthase activity with added pyridoxal-5'-phosphate; in the other four, the cofactor addition increased activity only modestly, as in controls. Two of seven lines from nonresponsive patients had measurable activity (each 3% of mean control) which increased two- and fivefold with the added cofactor. Cystathionine beta-synthase activity was undetectable in one line from a responsive patient and in five lines from nonresponsive ones. To characterize control and mutant synthase further, dissociation constants for pyridoxal-5'-phosphate were estimated and thermostability (54 degrees C) was studied in two control and five mutant lines. In one mutant, both parameters were normal; in the others, the affinity for the cofactor was reduced 3-to 11-fold and thermostability was much impaired. We conclude that at least three general classes of cystathionine beta-synthase mutants exist: those with no residual activity; those with reduced activity and normal affinity for pyridoxal-5' phosphate; and those with reduced activity and a reduced affinity for the cofactor. Pyridoxine responsiveness in vivo cannot be correlated simply with the presence or absence of residual synthase activity in vitro or with stimulation of in vitro enzyme activity by cofactor.

Adolescent↗
PubMed1977

The transsulfuration pathway in Tetrahymena pyriformis.

Four enzymes necessary for the metabolism of methionine by the trans-sulfuration pathway, methionine adenosyltransferase (EC 2.5.1.6), adenosylhomocysteinase (EC 3.3.1.1), cystathionine beta-synthase (EC 4.2.1.22) and cystathionine gamma-lyase (EC 4.4.1.1) were identified in Tetrahymean pyriformis. The ability of these cells to transfer 35S from E135S]methionine to form [35S] cysteine was also observed and taken as direct evidence for the functional existence of this pathway in Tetrahymena. An intermediate in the pathway and an active methyl donor, S-adenosylmethionine, was qualitatively identified in Tetrahymena and its concentration was found to be greater in late stationary phase cells than in early stationary phase cells.

Animals↗
PubMed1977

Sulfur metabolism of a mutant of Cephalosporium acremonium with enhanced potential to utilize sulfate for cephalosporin C production.

Characteristics of a mutant of Cephalosporium acremonium with enhanced potential to utilize sulfate for cephalosporin C production were investigated with sulfur-starved cells. DL-Norleucine showed an inhibitory effect on cephalosporin C and penicillin N production by the mutant in the presence of a sulfur source such as sulfate, sulfite, thiosulfate, and L-cystine, but it exhibited no effect when it was added after a certain period of incubation. On the contrary, antibiotic production by the parent was stimulated by norleucine regardless of the addition time. An increase in the intracellular cysteine pool was found when the cells were incubated with L-methionine or norleucine and sulfate. Enzymatic studies revealed that methionine and norleucine stimulated the cysteine desulfhydrase formation, and this effect was significant in the mutant. Finally the mutant was found to have an enhanced L-serine sulfhydrylase activity. The increase in this enzyme activity in the mutant seems responsible for the increase in the sulfate-utilizing ability and the methionine sensitivity by maintaining a high level of the cysteine pool. Accordingly, the effect of methionine and norleucine is assumed to be exerted through cysteine.

Acremonium↗
PubMed1979

Diseases of sulphur metabolism: implications for the methionine-homocysteine cycle, and vitamin responsiveness.

Sixteen inherited human diseases are now recognized, affecting most of the major steps in sulphur metabolism. Studies of patients with three types of homocystinuria have demonstrated unequivocally the major role of cystathionine formation in degradation of homocysteine, and the importance of homocysteine remethylation. Methionine balance studies of normal subjects and of a sarcosine oxidase-deficient subject have shown the predominant role of creatine synthesis in methionine utilization and permitted assessment of the rate of oxidation of the methyl group of methionine. Together, the results demonstrate that once regulatory adjustments have been made the rate of methylneogensis is nicely controlled so that labile methyl groups are made available in amounts just sufficient to meet the needs for methionine. When excess methionine is ingested the four-carbon moiety is diverted into cystathionine, the methyl group is oxidized via sarcosine and the flow of partially oxidized one-carbon units is diverted away from 5-methyltetrahydrofolate toward CO2. Studies of cystathionine synthase-deficient patients demonstrate that the capacity to respond or not to respond to pyridoxine administration is genetically controlled, probably through structural differences in mutant cystathionine synthases. However, the properties of the enzyme crucial in conferring responsiveness have not yet been identified.

Adolescent↗
PubMed1979

Cystathionine synthase in rat brain: regional and time-of-day differences and their metabolic implications.

In relation to concern for probable interrelations of cystathionine synthase (CS, EC 4.2.1.21) and methionine, one-carbon, and 5-hydroxytryptamine metabolism, we have investigated tissue and time-of-day differences in CS activity in the laboratory rat under standardized conditions. Liver, kidney, and pancreas had highest CS activities; nine regions of the CNS had mean activities ranging from 4.5% (lumbosacral cord) to 24.5% (hypothalamus) of mean hepatic activity; pituitary and adrenal glands lacked detectable CS activity. Although significantly lower CS activity occurred in liver (9%, P less than 0.050) and kidney (13%, P less than 0.025) during the interval two hours before to two hours after the daily onset of darkness, no significant changes were found in hypothalamus, cerebellum, or medulla oblongata. Regional CNS differences in CS activity appeared to be without correlation in relation to published data on relative contents of 5-hydroxytryptamine, tryptophan 5-hydroxylase (EC 1.14.16.4), 5,10-Methylene reductase (N5-methyltetrahydrofolate-NAD-oxidoreductase, (EC 1.1.1.78), or 5-methyltetrahydrofolate. Therefore, among CNS regions examined, a critical deficiency in ability to metabolize a homocysteine load is considered to be unlikely under normal conditions.

Animals↗
PubMed2026

Unveiling clinical and genetic landscapes of MMA and CBS: insights from whole exome sequencing in a tertiary care setting.

BACKGROUND: MMA and CBS deficiency are rare autosomal recessive metabolic disorders caused by defects in cobalamin metabolism and cystathionine-beta-synthase activity, respectively. Advanced molecular genetic techniques, have become essential for diagnosing these conditions. This study aimed to analyze the genetic variations in three MMA and four CBS deficiency cases using WES and correlate the findings with clinical, biochemical, and treatment outcomes. METHODS: Clinical evaluation, biochemical testing, neuroimaging, and WES were performed. WES data were analyzed using the reference genome GRCh37, and variants were classified according to ACMG guidelines. Treatment outcomes were monitored for three months post-intervention. RESULTS: In MMA cases, a homozygous pathogenic variant (c.394 C > T, p.Arg132Ter) in MMACHC was identified in all three patients. Biochemical abnormalities included methylmalonic aciduria, elevated homocysteine, and megaloblastic anemia. Hydroxycobalamin therapy improved behavioral, cognitive, and dermatological symptoms, though residual neuropathy persisted in one case. In CBS deficiency, pathogenic variants in CBS (c.992 C > T, p.Ala331Val; c.862 G > A, p.Ala288Thr; c.700 G > A, p.Asp234Asn) were identified. Clinical features included developmental delayed milestones, lens dislocation, and vascular complications. Treatment outcomes varied based on early diagnosis and compliance. CONCLUSION: This study highlights the importance of newborn screening program with WES in diagnosing and managing MMA and CBS deficiency, facilitating early intervention, improving clinical outcomes, and supporting precision medicine approaches. IMPACT: Early newborn screening and diagnosis are critical for effective treatment and improved patient outcomes. Novel clinical and pathogenic variants will expand the current understanding of these disorders. WES enhances the diagnostic precision for MMA and CBS deficiency, facilitating timely intervention and superior clinical management. Accurate and early detection of treatable IEMs through NBS can significantly reduce disease burden and healthcare costs.

Child, Preschool↗
PubMed1979

Protein-bound homocyst(e)ine in normal subjects and in patients with homocystinuria.

A method was developed to quantitate protein-bound homocyst(e)ine using 2-mercaptoethanol. Protein-bound homocyst(e)ine was discovered in the plasma from normal individuals, ranging from 0.5--2.2 nmole/ml. In two obligatory heterozygotes for classical homocystinuria, plasma protein-bound homocyt(e)ine was 3.5 and 4.8 nmole/ml, respectively. Untreated homozygotes showed approximately a 40-fold increase of plasma protein-bound homocyst(e)ine. Furthermore, using conventional methods, no free homocystine was detectable in the supernatant of plasma precipitate from two classical homocystinuric patients treated with pyridoxine, but plasma protein-bound homocyst(e)ine showed a 10-fold increase. Protein-bound homocyst(e)ine was also demonstrated in the liver, kidney, and brain tissues from a patient with methylenetetrahydrofolate reductase deficiency.

Brain↗
PubMedDate not supplied

[Some physical and chemical properties of serinesulfhydrase from chicken liver].

An improved procedure of purification of serinesulfhydrase from chicken liver is described. Preparations of enzyme (700-fold purification with the yield of 40 per cent from total activity) have been obtained homogeneous on polyacrylamide gel electrophoresis. Molecular weight of serinesulfhydrase is 90.000; 1 mole of enzyme contains 2 moles of pyridoxalphosphate and consists apparently of 2 subunits. Amino acid composition of the enzyme is studied. Absorption spectrum of serinesulfhydrase has a maximum at 430 nm what is characteristic of numerous pyridoxal-P enzymes. The position of this maximum does not depend on pH (within its range 6--10) and the presence of L-serine, a primary enzyme substrate. An essential change in the absorption spectrum of enzyme was observed in the presence of some thiol compound--DL-homocysteine, beta-mercaptoethanol and glutathione (cosubstrates of the reaction) and L-cysteine (a primary reaction substrate). It is suggested that this change in the spectrum is due to the action of SH-compounds on the enzyme conformation before the beginning of the enzymatic reaction or on its initial stages.

Amino Acids↗
PubMedDate not supplied

Homocystinuria: pathogenetic mechanisms.

Homocystinuria with elevated plasma homocysteine and methionine levels is the result of deficient activity of cystathionine synthetase, the enzyme catalyzing conversion of homocysteine to cystathionine. It is inherited as an autosomal recessive trait with a worldwide distribution. The major clinical manifestations result from the elevated plasma homocysteine level. The excitotoxic effect of homocysteic acid accounts for mental retardation and seizures. Interference with collagen cross-linking by sulfhydryl groups of homocysteine causes ectopia lentis and skeletal deformities. Sulfation factor-like effects contribute to disruption of vascular endothelium, which is followed by platelet thrombosis and widespread arterial and venous occlusions. Low methionine homocystinuria, with deficient remethylation of homocysteine, results from deranged vitamin B(12) metabolism and from deficient 5,10-methylene-tetrahydrofolate reductase. Administration of azaribine produces homocystinuria by mechanism not yet elucidated.

Animals↗