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 high incidence of vascular complications in severe hyperhomocysteinaemia in homozygotes for cystathionine beta-synthase deficiency has focused attention upon homocysteine as an atherogenic and thrombophilic agent. For two decades there has been accumulating evidence of mild hyperhomocysteinaemia as risk factor of vascular disease. Pooled data on hundreds of coronary, cerebrovascular and peripheral arterial disease patients show that mild hyperhomocysteinaemia was detectable in about 20-30%. In a recent meta-analysis of 27 studies up to 1994, including about 4000 patients and as many controls, it is calculated that the summary odds ratio of elevated homocysteine levels was 1.7, with 95% confidence interval (CI) 1.5-1.9, for coronary heart disease; it was 2.5, with 95% CI 2.0-3.0, for cerebro-vascular disease; and it was 6.8, with 95% CI 2.9-15.8, for peripheral vascular disease. The relevance of this newly recognized risk factor will be demonstrated by the outcome of the European Comac study on 'Hyperhomocysteinaemia and Vascular Disease', a multicentre case-control study on 800 vascular patients and 750 controls. Despite the selection for epidemiological reasons of a relatively low cut-off level as the criterion for mild hyperhomocysteinaemia in this study-the upper 20% of the distribution of control levels-the relative risk of thus-defined hyperhomocysteinaemia for arterial disease is about 2. This equals the relative risk of hypercholesterolaemia and of smoking; hypertension leads to a higher excess risk. The observed synergistic interaction between hyperhomocysteinaemia and hypertension and smoking may warrant a change in the now generally followed procedure of screening for hyperhomocysteinaemia only if conventional risk factors have not been detected in the patient. Those vascular patients with combined risk factors leading to synergism in their joint effect may profit most from homocysteinelowering intervention.
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PMID:The case for mild hyperhomocysteinaemia as a risk factor. 921 Dec 2

Our studies of cystathionine beta-synthase from Saccharomyces cerevisiae (yeast) are aimed at clarifying the cofactor dependence and catalytic mechanism and obtaining a system for future investigations of the effects of mutations that cause human disease (homocystinuria or coronary heart disease). We report methods that yielded high expression of the yeast gene in Escherichia coli and of purified yeast cystathionine beta-synthase. The absorption and circular dichroism spectra of the homogeneous enzyme were characteristic of a pyridoxal phosphate enzyme and showed the absence of heme, which is found in human and rat cystathionine beta-synthase. The absence of heme in the yeast enzyme facilitates spectroscopic studies to probe the catalytic mechanism. The reaction of the enzyme with L-serine in the absence of L-homocysteine produced the aldimine of aminoacrylate, which absorbed at 460 nm and had a strong negative circular dichroism band at 460 nm. The formation of this intermediate from the product, L-cystathionine, demonstrates the partial reversibility of the reaction. Our results establish the overall catalytic mechanism of yeast cystathionine beta-synthase and provide a useful system for future studies of structure and function. The absence of heme in the functional yeast enzyme suggests that heme does not play an essential catalytic role in the rat and human enzymes. The results are consistent with the absence of heme in the closely related enzymes O-acetylserine sulfhydrylase, threonine deaminase, and tryptophan synthase.
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PMID:Yeast cystathionine beta-synthase is a pyridoxal phosphate enzyme but, unlike the human enzyme, is not a heme protein. 1076 67

Elevated plasma homocysteine is associated with a variety of diseases in humans including coronary heart disease, stroke, peripheral vascular disease, and birth defects. However, the mechanism by which plasma homocysteine affects cells is unknown. We have examined the growth of isogenic wild-type and cystathionine beta-synthase (CBS) deficient yeast in response to homocysteine and its immediate metabolic precursor, S-adenosylhomocysteine (SAH). CBS deficient yeast export significantly more homocysteine into the media than wild-type yeast and have elevated internal pools of homocysteine and SAH. We found that 5 mM homocysteine added to the media had very little effect on the growth of wild-type or CBS deficient yeast, although intracellular homocysteine concentrations increased five- to tenfold. In contrast, as little as 25 microM S-adenosylhomocysteine inhibited the growth of CBS deficient yeast, but had no effect on wild-type yeast. Measurements of the intracellular S-adenosylmethionine (SAM) and SAH indicate that CBS deficient yeast contain reduced SAM/SAH ratios relative to wild-type, and this ratio is further reduced by adding SAH to the media. Growth inhibition by SAH in CBS deficient yeast can be totally reversed by addition of SAM to the media, indicating that the ratio and not absolute level is critical for cell growth. These results suggest that CBS plays a key role in the regulation of the SAM/SAH ratio inside cells and that excessive perturbations of this ratio can inhibit growth. We hypothesize that elevated extracellular homocysteine present in humans may reflect an altered intracellular SAM/SAH ratio and that this may be related to disease pathogenesis.
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PMID:S-adenosylhomocysteine, but not homocysteine, is toxic to yeast lacking cystathionine beta-synthase. 1205 65

Hyperhomocysteinemia (HHcy) is a significant and independent risk factor for cardiovascular disease (CVD) and the underlying mechanism is unclear. We and others have reported that homocysteine (Hcy) is inversely correlated with plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apoA-I) in patients with coronary heart disease (CHD). We confirmed this negative correlation in mice with targeted deletions of the genes for apolipoprotein E (apoE) and cystathionine beta-synthase (CBS). Severe HHcy (plasma Hcy 210 micromol/L) accelerates spontaneous arthrosclerosis in the CBS(-/-)/apoE(-/-) mice, reduces the concentration of circulating HDL, apoA-I, and large HDL particles, inhibits HDL function, and enhances HDL-C clearance. We have demonstrated further that Hcy (0.5-2 mmol/L) reduces apoA-I protein synthesis and secretion, but not RNA transcription in mouse primary hepatocytes. A different mechanism was proposed based on studies using the HepG2 cells showing that Hcy (5-10 mmol/L) inhibits apoA-I transcription via peroxisome proliferator-activated receptor-alpha (PPARalpha)-inhibition-dependent and -independent mechanisms. These studies suggest that Hcy-induced HDL-C and apoA-I inhibition represent a novel mechanism by which Hcy induces atherosclerotic CVD.
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PMID:Hyperhomocysteinemia and high-density lipoprotein metabolism in cardiovascular disease. 1802 Sep 70