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)

Human cystathionine beta-synthase plays a key role in maintaining low intracellular levels of homocysteine and is unique in being a pyridoxal phosphate-dependent enzyme that is a hemeprotein. It catalyzes the beta-replacement of serine and homocysteine to generate the condensation product, cystathionine. While the structure of a truncated catalytic core of the protein has been determined by crystallography, a model for the full-length enzyme has been developed guided by hydrogen-deuterium exchange mass spectrometric and docking studies. In this review, we have utilized the available structural models for human cystathionine beta-synthase to conduct a structure-function analysis of a select group of pathogenic mutations described in patients with hereditary hyperhomocysteinemia.
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PMID:Structural insights into pathogenic mutations in heme-dependent cystathionine-beta-synthase. 1706 88

Cystathionine beta-synthase (CBS) catalyzes the first irreversible step in the transsulfuration pathway and commits the toxic metabolite, homocysteine, to the synthesis of cysteine. Mutations in CBS are the most common cause of severe hereditary hyperhomocysteinemia. The molecular basis of the organ-specific pathologies associated with CBS deficiency is unknown as is the significance of the reported interaction between CBS and Huntingtin protein. In this study, we have used the yeast two-hybrid approach to screen for proteins that interact with CBS and have identified several components of the sumoylation pathway including Ubc9, PIAS1, PIAS3, Pc2, and RanBPM. We demonstrate that CBS is modified by the small ubiquitin-like modifier-1 protein (SUMO-I) under both in vitro and in vivo conditions. Deletion analysis of CBS indicates that the C-terminal regulatory domain is required for interaction with proteins in the sumoylation machinery. Sumoylated CBS is present in the nucleus where it is associated with the nuclear scaffold. The discovery that CBS is a target of sumoylation adds another layer to the complex regulation of this enzyme and reveals a previously unknown residence for this protein, i.e., in the nucleus.
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PMID:Human cystathionine beta-synthase is a target for sumoylation. 1708 6

Rats were fed on a 10% casein (10C) diet, 30% casein (30C) diet, 10C+0.5% methionine diet, or 30C+0.5% methionine diet for 14 d to investigate the relationship between the dietary protein level and plasma homocysteine concentration. The plasma homocysteine concentration was significantly higher in the rats fed on the 10C diet than in the rats fed on the 30C diet, and this phenomenon persisted even under the condition of methionine supplementation. The activity of hepatic cystathionine beta-synthase (CBS) was significantly lower in the rats fed on the 10% casein diets than in the rats fed on the 30% casein diets, irrespective of methionine supplementation. This is the first demonstration of a low-protein diet increasing the plasma homocysteine concentration in experimental animals. It is suggested that the decreased CBS activity might be associated, at least in part, with the hyperhomocysteinemia caused by the low-casein diet.
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PMID:Increased plasma homocysteine concentration in rats from a low casein diet. 1715 55

The effect of dietary supplementation with cysteine on the plasma homocysteine concentration was investigated in rats fed on 10% casein (10C) and 30% casein (30C) diets. The 10C diet significantly increased the plasma homocysteine concentration as compared with the 30C diet. The hyperhomocysteinemia induced by the 10C diet was significantly suppressed by cysteine supplementation even at a 0.3% level, whereas cysteine did not decrease the plasma homocysteine concentration when added to the 30C diet. In contrast, 0.3% methionine supplementation of the 10C diet tended to increase the plasma homocysteine concentration. Cysteine supplementation to rats fed on the 10C diet did not alter the plasma cysteine concentration and the hepatic activities of cystathionine beta-synthase and betaine:homocysteine S-methyltransferase, whereas it significantly decreased the hepatic concentrations of S-adenosylmethionine and betaine. These results suggest that cysteine supplementation might be effective for suppressing the hyperhomocysteinemia induced by a low-protein diet.
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PMID:Cysteine supplementation decreases plasma homocysteine concentration in rats fed on a low-casein diet in rats. 1721 75

Genetic disorders of homocysteine (Hcy) metabolism or a high-methionine diet lead to elevations of plasma Hcy levels. In humans, severe genetic hyperhomocysteinemia results in premature death from vascular complications whereas dietary hyperhomocysteinemia is often used to induce atherosclerosis in animal models. Hcy is mistakenly selected in place of methionine by methionyl-tRNA synthetase during protein biosynthesis, which results in the formation of Hcy-thiolactone and initiates a pathophysiological pathway that has been implicated in human vascular disease. However, whether genetic deficiencies in Hcy metabolism or a high-methionine diet affect Hcy-thiolactone levels in mammals has been unknown. Here we show that plasma Hcy-thiolactone is elevated 59-fold and 72-fold in human patients with hyperhomocysteinemia secondary to mutations in methylenetetrahydrofolate reductase and cystathionine beta-synthase genes, respectively. We also show that mice, like humans, eliminate Hcy-thiolactone by urinary excretion; in contrast to humans, however, mice also eliminate significant amounts of plasma total Hcy (approximately 38%) by urinary excretion. In mice, hyperhomocysteinemia secondary to a high-methionine diet leads to 3.7-fold and 25-fold increases in plasma and urinary Hcy-thiolactone levels, respectively. Thus, we conclude that hyperhomocysteinemia leads to significant increases in the atherogenic metabolite Hcy-thiolactone in humans and mice.
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PMID:Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice. 1732 60

Deficiency in nutritional determinants of homocysteine (HCY) metabolism, such as vitamin B(12) and folate, during pregnancy is known to influence HCY levels in the progeny, which in turn may exert adverse effects during development, including liver defects. Since short hypoxia has been shown to induce tolerance to subsequent stress in various cells including hepatocytes, and as vitamins B deficiency and hypoxic episodes may simultaneously occur in neonates, we aimed to investigate the influence of brief postnatal hypoxia (100% N(2) for 5 min) on the liver of rat pups born from dams fed a deficient regimen, i.e., depleted in vitamins B(12), B(2), folate, and choline. Four experimental groups were studied: control, hypoxia, deficiency, and hypoxia + deficiency. Although hypoxia transiently stimulated HCY catabolic pathways, it was associated with a progressive increase of hyperhomocysteinemia in deficient pups, with a fall of cystathionine beta-synthase activity at 21 days. At this stage, inducible NO synthase activity was dramatically increased and glutathione reductase decreased, specifically in the group combining hypoxia and deficiency. Also, hypoxia enhanced the deficiency-induced drop of the S-adenosylmethionine/S-adenosylhomocysteine ratio. In parallel, early exposure to the methyl-deficient regimen induced oxidative stress and led to hepatic steatosis, which was found to be more severe in pups additionally exposed to hypoxia. In conclusion, brief neonatal hypoxia may accentuate the long-term adverse effects of impaired HCY metabolism in the liver resulting from an inadequate nutritional regimen during pregnancy, and our data emphasize the importance of early factors on adult disease.
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PMID:Influence of preconditioning-like hypoxia on the liver of developing methyl-deficient rats. 1772 45

Alterations in lipid metabolism may play a role in the vascular pathology associated with hyperhomocysteinemia (HHcy). Homocysteine is linked to lipid metabolism through the methionine cycle and the synthesis of phosphatidylcholine (PC) by phosphatidylethanolamine (PE) methyltransferase, which is responsible for the synthesis of 20-40% of liver PC. The goal of the present study was to determine if the reduced methylation capacity in HHcy is associated with alterations in liver phospholipid and fatty acid metabolism. Mice heterozygous for disruption of cystathionine beta-synthase (Cbs+/-) fed a diet to induce HHcy (HH diet) had higher (p<0.001) plasma total homocysteine (30.8+/-4.4 microM, mean+/-S.E.) than C57BL/6 mice (Cbs+/+) fed the HH diet (7.0+/-1.1 microM) or Cbs+/+ mice fed a control diet (2.3+/-0.3 microM). Mild and moderate HHcy was accompanied by lower adenosylmethionine/adenosylhomocysteine ratios (p<0.05), higher PE (p<0.05) and PE/PC ratios (p<0.01), lower PE methyltransferase activity (p<0.001), and higher linoleic acid (p<0.05) and lower arachidonic acid (p<0.05) in PE. Mice with moderate HHcy also had higher linoleic acid and alpha-linolenic acid (p<0.05) and lower arachidonic acid and docosahexaenoic acid (p<0.05) in liver PC. The first step in the desaturation and elongation of linoleic acid and linolenic acid to arachidonic acid and docosahexaenoic acid, respectively, is catalyzed by Delta6-desaturase (encoded by Fads2). We found hypermethylation of the Fads2 promoter (p<0.01), lower Fads2 mRNA (p<0.05), and lower Delta6-desaturase activity (p<0.001) in liver from mice with HHcy. These findings suggest that methylation silencing of liver Fads2 expression and changes in liver fatty acids may contribute to the pathology of HHcy.
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PMID:Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia. 1797 55

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

Despite substantial evidence indicating the association of hyperhomocysteinemia (hHcys) and end-stage renal disease (ESRD), the pathogenic role of increased plasma homocysteine (Hcys) levels in the progression of ESRD remains unclear. This review will briefly summarize recent findings regarding the role of hHcys in the development of glomerulosclerosis, the association of hHcys with reduced renal transsulfuration and Hcys-induced changes of redox signaling in the development of glomerulosclerosis in rat kidneys. Based on these results, it is concluded that hHcys is implicated in glomerular sclerosis in hypertension, elevated plasma Hcys in Dahl salt-sensitive (SS) hypertensive rats is due to downregulation of cystathionine beta-synthase (CBS) expression and consequent abnormality of transsulfuration in the kidney compared with normotensive rats. Hcys-induced superoxide (O(2)(*-)) production by activation of NADPH oxidase as a triggering mechanism contributes to the effects of Hcys on the homeostasis of extracellular matrix and consequent sclerosis in the glomeruli, and NADPH oxidase activation by Hcys is associated with enhanced Rac GTPase activity.
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PMID:Hyperhomocysteinemia: association with renal transsulfuration and redox signaling in rats. 1806 50

Cystathionine beta-synthase-deficient mice (Cbs(-/-)) exhibit several pathophysiological features similar to hyperhomocysteinemic patients, including endothelial dysfunction and hepatic steatosis. Heterozygous mutants (Cbs(+/-)) on the C57BL/6J background are extensively analyzed in laboratories worldwide; however, detailed analyses of Cbs(-/-) have been hampered by the fact that they rarely survive past the weaning age probably due to severe hepatic dysfunction. We backcrossed the mutants with four inbred strains (C57BL/6J(Jcl), BALB/cA, C3H/HeJ and DBA/2J) for seven generations, and compared Cbs(-/-) phenotypes among the different genetic backgrounds. Although Cbs(-/-) on all backgrounds were hyperhomocysteinemic/hypermethioninemic and suffered from lipidosis/hepatic steatosis at 2 weeks of age, >30% of C3H/HeJ-Cbs(-/-) survived over 8 weeks whereas none of DBA/2J-Cbs(-/-) survived beyond 5 weeks. At 2 weeks, serum levels of total homocysteine and triglyceride were lowest in C3H/HeJ-Cbs(-/-). Adult C3H/HeJ-Cbs(-/-) survivors showed hyperhomocysteinemia but escaped hypermethioninemia, lipidosis and hepatic steatosis. They appeared normal in general behavioral tests but showed cerebellar malformation and impaired learning ability in the passive avoidance step-through test, and required sufficient dietary supplementation of cyst(e)ine for survival, demonstrating the essential roles of cystathionine beta-synthase in the central nervous system function and cysteine biosynthesis. Our C3H/HeJ-Cbs(-/-) mice could be useful tools for investigating clinical symptoms such as mental retardation and thromboembolism that are found in homocysteinemic patients.
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PMID:Genetic background conversion ameliorates semi-lethality and permits behavioral analyses in cystathionine beta-synthase-deficient mice, an animal model for hyperhomocysteinemia. 1836 86


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