Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.2.1.22 (cystathionine beta-synthase)
 965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deficiency of cystathionine beta-synthase (CBS) is the commonest cause of primary homocystinuria. Homocysteine metabolism is intimately linked with the metabolism of folate, vitamin B12 (cobalamin) and pyridoxine. It is hypothesised that the pathogenesis of neuropsychiatric manifestations in homocystinuria, folate and cobalamin deficiencies are related to imbalance neurotransmitters in the CNS through disturbances in the pathways linking the metabolism of homocysteine and these vitamins. Although neuropsychiatric disorders are relatively common among patients with homocystinuria, it is not well recognised as the causative factor among patients presenting with neuropsychiatric disorders. A 31 year old woman presented with a three week history of delirium and inappropriate and labile affect. There was no history suggestive of drug or alcohol abuse, nutritional deficiency or organic disorders. EEG, cerebral CT, MRI and microbiological investigations did not reveal any organic causes. Because of a diagnosis of pyridoxine-responsive homocystinuria seven years previously, the possibility of homocystinuria was considered and investigated. Laboratory tests revealed macrocytosis and a high concentration of urinary total homocystine. Commencement of pyridoxine at 400 mg/day resulted in disappearance of homocystine in urine within four days with remarkable clinical improvement. Homocystinuria should be considered in the differential diagnosis of unexplained neuropsychiatric disorders in patients who have past or family history of homocystinuria, mental retardation, thromboembolic episodes, vascular diseases or clinical and laboratory features resembling folate and/or vitamin B12 deficiencies. Homocystinuria-associated neuropsychiatric disturbances can easily be treated with pyridoxine in 50% of cases.
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PMID:Homocystinuria and psychiatric disorder: a case report. 1050 67

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

The frequency of the heterozygous 844ins68 mutation of the cystathionine beta-synthase (CBS) gene and of its association with the homozygous C677T transition of the methylenetetrahydrofolate reductase (MTHFR) gene, plasma fasting tHcy, folate and vitamin B12 levels were evaluated in 309 consecutive patients with objectively diagnosed early-onset venous (n = 200) or arterial thromboembolic disease (n = 109) recruited over 25 months in Milan (North Italy) and Naples (South Italy). The above gene polymorphisms were also evaluated in a population of 787 unmatched controls, 204 of whom--similar to patients for age- and sex-distribution--had fasting tHcy, vitamins and activated protein C resistance measured in their plasma. Moderate fasting hyperhomocysteinemia was detected in 15.5% of patients and in 5.9% of 204 controls (Mantel-Haenszel OR after stratification for type of occlusive disease and gender: 2.88; 1.48-5.32). The frequencies of the 677TT mutation of the MTHFR gene and of the heterozygous 844ins68 insertion of the CBS gene were not significantly different in the patient (19.4% and 6.9%) and the control population (16.5% and 7.8%), but the association of the two gene polymorphisms found in 3.9% of patients and in 1.1% of controls - was significantly associated with an increased risk of venous or arterial occlusive diseases (RR = 3.63; 1.48-8.91). The MTHFR 677TT mutation (RR: 6.92; 3.86-12.4) and its association with the 844ins68 insertion (RR: 21.9; 8.35-57.4), but not the isolated insertion (RR: 0.71), were more frequent in patients and controls with fasting hyperhomocysteinemia than in normohomocysteinemic subjects, irrespective of the type of occlusive disease (venous or arterial). When adjusted for determinants of hyperhomocysteinemia in the patient and the control populations (generalized linear model), fasting tHcy levels were significantly higher in subjects with association of the two gene abnormalities (24.2+/-3.8 micromol/L) than in subjects with the MTHFR 677TT mutation only (14.0+/-5.8 micromol/L, p = 0.004). Activated protein C resistance was significantly more prevalent in venous patients (9.9%) than in controls (3.9%, OR = 2.69; 1.08-6.88). Six of 21 venous patients with APC-resistance also had hyperhomocysteinemia (RR = 5.04; 0.68-37.6), but isolated fasting hyperhomocysteinemia retained statistical significance for the association with venous occlusive disease (RR = 2.84; 1.34-6.01). Heterozygosity for the 844ins68 mutation of the CBS gene is not per se a risk factor for premature arterial and/or venous occlusive diseases. However, when detected in combination with thermolabile MTHFR, it increases by almost 4-fold the risk of occlusive diseases (arterial and/or venous), by increasing the risk and the degree of fasting hyperhomocysteinemia.
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PMID:Contribution of the cystathionine beta-synthase gene (844ins68) polymorphism to the risk of early-onset venous and arterial occlusive disease and of fasting hyperhomocysteinemia. 1105 53

Elevated total plasma homocysteine has been established as an independent risk factor for thrombosis and cardiovascular disease. A strong relationship between plasma homocysteine levels and mortality has been reported in patients with angiographically confirmed coronary artery disease. Homocysteine is a thiol containing amino acid. It can be metabolised by different pathways, requiring various enzymes such as cystathionine beta-synthase and methylenetetrahydrofolate reductase. These reactions also require several co-factors such as vitamin B6 and folate. Medications may interfere with these pathways leading to an alteration of plasma homocysteine levels. Several drugs have been shown to effect homocysteine levels. Some drugs frequently used in patients at risk of cardiovascular disease, such as the fibric acid derivatives used in certain dyslipidaemias and metformin in type 2 (non-insulin-dependent) diabetes mellitus, also raise plasma homocysteine levels. This elevation poses a theoretical risk of negating some of the benefits of these drugs. The mechanisms by which drugs alter plasma homocysteine levels vary. Drugs such as cholestyramine and metformin interfere with vitamin absorption from the gut. Interference with folate and homocysteine metabolism by methotrexate, nicotinic acid (niacin) and fibric acid derivatives, may lead to increased plasma homocysteine levels. Treatment with folate or vitamins B6 and B12 lowers plasma homocysteine levels effectively and is relatively inexpensive. Although it still remains to be demonstrated that lowering plasma homocysteine levels reduces cardiovascular morbidity, surrogate markers for cardiovascular disease have been shown to improve with treatment of hyperhomocystenaemia. Would drugs like metformin, fibric acid derivatives and nicotinic acid be more effective in lowering cardiovascular morbidity and mortality, if the accompanying hyperhomocysteinaemia is treated? The purpose of this review is to highlight the importance of homocysteine as a risk factor, and examine the role and implications of drug induced modulation of homocysteine metabolism.
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PMID:Drugs affecting homocysteine metabolism: impact on cardiovascular risk. 1189 29

Hyperhomocysteinemia is an independent risk factor for vascular disease, frequently observed in patients with severe renal impairment. Hyperhomocysteinemia has never been considered as a possible risk factor in renal artery stenosis. We investigated plasma folate and vitamin B12, methylenetetrahydrofolate reductase (MTHFR) C677T and cystathionine beta-synthase (CBS) 844ins68 polymorphisms, and homocysteine levels before and after methionine (100 mg/kg) loading in 58 patients with angiographically documented renal artery stenosis and mildly impaired renal function. One hundred and two normotensive subjects with angiographically normal coronary arteries and no history or clinical or angiographic evidence of atherosclerosis in other vascular districts, were considered as a control group. Mean total homocysteine levels were significantly higher in patients than in controls (P<0.01), as was the prevalence of hyperhomocysteinemia (51.7% vs. 32.3%, P<0.05). However, MTHFR alleles and genotypes as well as CBS 844ins68 mutation frequencies were similar in the two groups, whereas a lower folate level was observed in the patients. Moreover, patients with MTHFR A/A genotype showed a poorer folate status than control subjects, suggesting that a subclinical folate deficiency may be very frequent in renal artery stenosis, regardless of C677T mutation. In conclusions, hyperhomocysteinemia is common in patients with atheromatous renal artery stenosis; a subclinical folate deficiency seems to be involved, regardless of MTHFR thermolabile or CBS insertion genotypes. Folate supplementation might be useful in the management of overall vascular risk of these patients.
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PMID:Homocysteine and atheromatous renal artery stenosis. 1191 80

Vitamins B12, B6, and folic acid converge at the homocysteine metabolic junction where they support the activities of two key enzymes involved in intracellular homocysteine management, methionine synthase (MS) and cystathionine beta-synthase. The molecular mechanism for the regulation of homocysteine metabolism by B12 supplementation has been investigated in this study. B12 supplementation does not alter mRNA or protein turnover rates but induces translational up-regulation of MS by shifting the mRNA from the ribonucleoprotein to the polysome pool. The B12-responsive element has been localized by deletion analysis using a reporter gene assay to a 70-bp region located at the 3' end of the 5'-untranslated region of the MS mRNA. The cellular consequence of the B12 response is a 2- and 3.5-fold increase in the flux of homocysteine through the MS-dependent transmethylation pathway in HepG2 and 293 cells, respectively. It is speculated that B12-induced up-regulation of MS may have evolved as an adaptive strategy for rapidly sequestering an essential and rare nutrient whose availability may have been limited in the evolutionary history of mammals, a problem that is exacerbated by the absence of this vitamin from the plant kingdom.
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PMID:Nutritional modulation of gene expression and homocysteine utilization by vitamin B12. 1267 Sep 34

Recent epidemiological studies have suggested that hyperhomocysteinemia is associated with increased risk of vascular disease. Homocysteine is a sulphur-containing amino acid whose metabolism stands at the intersection of two pathways: remethylation to methionine, which requires folate and vitamin B12 (or betaine in an alternative reaction); and transsulfuration to cystathionine which requires vitamin B6. The two pathways are coordinated by S-adenosylmethionine which acts as an allosteric inhibitor of the methylenetetrahydrofolate reductase (MTHFR) and as an activator of cystathionine beta-synthase (CBS). Hyperhomocysteinemia arises from disrupted homocysteine metabolism. Severe hyperhomocysteinemia is due to rare genetic defects resulting in deficiencies in CBS, MTHFR, or in enzymes involved in methyl cobalamine synthesis and homocysteine methylation. Mild hyperhomocysteinemia seen in fasting condition is due to mild impairment in the methylation pathway (i.e. folate or B12 deficiencies or MTHFR thermolability). Post-methionine-load hyperhomocysteinaemia may be due to heterozygous cystathionine-beta-synthase defect or B6 deficiency. Patients with homocystinuria and severe hyperhomocysteinemia develop arterial thrombotic events, venous thromboembolism, and more seldom premature arteriosclerosis. Experimental evidence suggests that an increased concentration of homocysteine may result in vascular changes through several mechanisms. High levels of homocysteine induce sustained injury of arterial endothelial cells, proliferation of arterial smooth muscle cells and enhance expression/activity of key participants in vascular inflammation, atherogenesis, and vulnerability of the established atherosclerotic plaque. These effects are supposed to be mediated through its oxidation and the concomitant production of reactive oxygen species. Other effects of homocysteine include: impaired generation and decreased bioavailability of endothelium-derived relaxing factor/nitric oxide; interference with many transcription factors and signal transduction; oxidation of low-density lipoproteins; lowering of endothelium-dependent vasodilatation. In fact, the effect of elevated homocysteine appears multifactorial affecting both the vascular wall structure and the blood coagulation system.
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PMID:[Hyperhomocysteinemia: an independent risk factor or a simple marker of vascular disease?. 1. Basic data]. 1280 8

Homocystinuria due to cystathionine beta-synthase deficiency is the second most treatable aminoacidopathy. The reported incidence varies from 1 in 344,000 worldwide to 1 in 65,000 in Ireland. Untreated patients with homocystinuria have severe hyperhomocysteinaemia. Amongst its pathological sequelae, which include mental retardation, ectopia lentis and osteoporosis, vascular events remain the major cause of morbidity and mortality in untreated patients. Recognized modalities of treatment include pyridoxine, in combination with folic acid and vitamin B12; methionine-restricted, cystine-supplemented diet; and betaine. The natural history of vascular events is such that half will have an event before age 30 years and there is a predicted one event per 25 years at the time of maximal risk. In 158 patients with 2822 patient-years of treatment, there would be a predicted 112 events if left untreated, but instead only 17 vascular events were recorded during treatment (relative risk 0.09, 95% CI 0.036 to 0.228; p < 0.0001). Appropriate chronic treatment to lower hyperhomocysteinaemia is effective in reducing the potentially life-threatening vascular risk in patients with homocystinuria. These findings may also have relevance to the significance of mild hyperhomocysteinaemia that is commonly found in patients with premature vascular disease.
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PMID:Classical homocystinuria: vascular risk and its prevention. 1288 65

Homocysteine (Hcy) is a sulfur-containing amino acid produced when methionine is demethylated. The majority of Hcy undergoes transsulfuration to cysteine by cystathionine beta-synthase (CBS), of which vitamin B6 (pyridoxine) is an essential cofactor. The remainder of Hcy is remethylated by methionine synthase (MS), of which vitamin B12 (cobalamin) is an essential cofactor along with methylenetetrahydrofolate (MTHF). MTHF is generated by the enzyme MTHFR-reductase (MTHFR). High levels of Hcy can result from a variety of aquired factors (deficiency of vitamins B6, B12 and folic acid, high meat diet, smoking and others) or genetic (abnormalities of methionine--homocysteine metabolism). Hyperhomocysteinemia is associated with premature atherosclerosis and venous thromboembolism; so called "cholesterol of XXI. age". Results of many studies suggest that hyperhomocysteinemia, homozygous state for MTHFR gene mutation, folate deficiency are probably risk factors for recurrent fetal loss, intrauterine fetal death, thrombo-embolic disease in pregnancy, neural tube defects and congenital cardiac malformation at infants and other placental diseases (pre-eclampsia, placental abruption and intrauterine growth restriction IUGR). Those irregularities are very interesting and important for obstetricians and gynecologists. The plasma homocysteine values can be modulated by vitamins, vitamin B6 and folic acid in particular. The potential for research and possible prevention in this area is immense.
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PMID:[Hyperhomocysteinemia and pregnancy complications]. 1518 72

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine beta-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy. Studies using animal models of genetic- and diet-induced HHcy have recently demonstrated a causal relationship between HHcy, endothelial dysfunction, and accelerated atherosclerosis. Dietary enrichment in B vitamins attenuates these adverse effects of HHcy. Although oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy, recent in vitro and in vivo studies demonstrate that HHcy induces endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR). This review summarizes the current role of HHcy in endothelial dysfunction and explores the cellular mechanisms, including ER stress, that contribute to atherothrombosis.
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PMID:Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. 1524 79


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