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)

The objectives were firstly to assess the evidence that homocysteine is a significant and independent risk factor for vascular disease with special reference to cardiovascular disease, and secondly to evaluate the evidence that a food staple fortified with folic acid will reduce this problem on a population basis. The structure of plasma homocysteine (tHcy) is described. Homocysteine, a highly reactive compound, is synthesized from the amino acid, methionine, and is metabolized by two pathways, the catabolic transsulphuration route via cystathionine beta-synthase (EC 4.2.1.22) and the remethylation path using 5-methyltetrahy-drofolate polyglutamate, the product of 5,10-methylenetetrahydrofolate reductase (MTHFR; EC 1.1.1.171), via the cobalamin dependent enzyme, methionine synthase (MS; EC 2.1.1.13).The mechanisms whereby hyper-tHcy is produced include both increased rates of synthesis and decreased metabolism. The latter may occur owing to nutritional deficiency of the vitamin cofactors which are necessary for the normal function of the metabolic enzymes. In particular, folate is required for methylene reductase, pyridoxal phosphate for cystathionine synthase and cobalamin for methionine synthase. When these vitamins are deficient hyper-tHcy is induced and this occurs especially in the elderly. Alternatively, a variant form of methylene reductase has recently been described which occurs in nearly 10% of the normal population. This variant is associated with hyper-tHcy, especially in situations associated with a low folate nutritional status. Meta-analysis of both retrospective case-control studies, nested prospective case-control surveys and a secondary trial of mortality in postmyocardial infarct patients have shown that the association of hyper-tHcy with vascular disease is beyond doubt. This has been further supported by direct assessments of the degree of vascular disease in the carotid brachial and aortic arteries in relation to tHcy levels. Furthermore, treatment with a cocktail of the vitamin cofactors has produced lowering of tHcy levels and regression of the vascular disease in the carotid arteries of affected individuals. Suggested pathogenic mechanisms in vascular disease induced by hyper-tHcy include vascular endothelial cell dysfunction, smooth muscle proliferation and derangements of normal intravascular regulation mechanisms. A variety of clinical conditions are known to be associated with a high incidence of thromboembolic complications. Some of these are associated with hyper-tHcy. Low physiological doses of folic acid, as well as pharmocological doses, lower tHcy. However, because of the poor bioavailability of food folate (50%) and the considerable chemical instability of the naturally occurring reduced forms of folate, in most people it would require unacceptably high consumption of green vegetables to accomplish the necessary increase in intracellular folate and reduction in tHcy. Accordingly, folic acid, the nonreduced synthetic form of the vitamin, which is 100% bioavailable and chemically extremely stable, should be added to a food staple such as flour to ensure maximum protection for most of the population.
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PMID:Homocysteine as a risk factor for cardiovascular and related disease: nutritional implications. 1909 52

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Homocysteine (Hcy) metabolism involves multiple enzymes; however, tissue Hcy metabolism and its relevance to methylation remain unknown. Here, we established gene expression profiles of 8 Hcy metabolic and 12 methylation enzymes in 20 human and 19 mouse tissues through bioinformatic analysis using expression sequence tag clone counts in tissue cDNA libraries. We analyzed correlations between gene expression, Hcy, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM) levels, and SAM/SAH ratios in mouse tissues. Hcy metabolic and methylation enzymes were classified into two types. The expression of Type 1 enzymes positively correlated with tissue Hcy and SAH levels. These include cystathionine beta-synthase, cystathionine-gamma-lyase, paraxonase 1, 5,10-methylenetetrahydrofolate reductase, betaine:homocysteine methyltransferase, methionine adenosyltransferase, phosphatidylethanolamine N-methyltransferases and glycine N-methyltransferase. Type 2 enzyme expressions correlate with neither tissue Hcy nor SAH levels. These include SAH hydrolase, methionyl-tRNA synthase, 5-methyltetrahydrofolate:Hcy methyltransferase, S-adenosylmethionine decarboxylase, DNA methyltransferase 1/3a, isoprenylcysteine carboxyl methyltransferases, and histone-lysine N-methyltransferase. SAH is the only Hcy metabolite significantly correlated with Hcy levels and methylation enzyme expression. We established equations expressing combined effects of methylation enzymes on tissue SAH, SAM, and SAM/SAH ratios. Our study is the first to provide panoramic tissue gene expression profiles and mathematical models of tissue methylation regulation.
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PMID:Regulation of homocysteine metabolism and methylation in human and mouse tissues. 2030 27


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