Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Hydrogen sulfide (H2S), which is well known as a toxic gas, is produced endogenously from L-cysteine in mammalian tissues. H2S is present at relatively high levels in the brain, suggesting that it has a physiological function. Two other gases, nitric oxide and carbon monoxide, are also endogenously produced and have been proposed as neuronal messengers in the brain. In this work we show the following: (1) an H2S-producing enzyme, cystathionine beta-synthase (CBS), is highly expressed in the hippocampus; (2) CBS inhibitors hydroxylamine and amino-oxyacetate suppress the production of brain H2S; and (3) a CBS activator, S-adenosyl-L-methionine, enhances H2S production, indicating that CBS contributes to the production of endogenous H2S. We also show that physiological concentrations of H2S selectively enhance NMDA receptor-mediated responses and facilitate the induction of hippocampal long-term potentiation. These observations suggest that endogenous H2S functions as a neuromodulator in the brain.
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PMID:The possible role of hydrogen sulfide as an endogenous neuromodulator. 855 35

The DNA sequence of a 26,677 bp fragment from the right arm of chromosome VII from Saccharomyces cerevisiae reveals 18 open reading frames (ORFs) longer than 300 bp. Eight ORFs correspond to previously characterized genes. G6620 is the 3' end of the MOL1 gene coding for a polypeptide similar to stress-inducible proteins from Fusarium; G6630 is the NAT2 gene which encodes a methionine N-acetyltransferase; G6635 is the RPL30B gene coding for the ribosomal protein L30; G6658 is RSR1 encoding a ras-related protein; G6667 is CYS4, the gene for cystathionine beta-synthase; G6670 is identical to ORF2 located close to CYS4; G6673 is PEM1/CHO2 encoding a phosphatidylethanolamine methyltransferase; G7001 is the NSR1 gene coding for a nuclear signal recognition protein. G6664 shares significant homology with the ORF YKR076w from chromosome XI. The other nine ORFs show no significant homology to any protein sequence presently available in the public data bases.
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PMID:The sequence of a 27 kb segment on the right arm of chromosome VII from Saccharomyces cerevisiae reveals MOL1, NAT2, RPL30B, RSR1, CYS4, PEM1/CHO2, NSR1 genes and ten new open reading frames. 858 25

Two separate metabolic pathways that methylate homocysteine to methionine are known in humans, utilizing, respectively, 5-methyltetrahydrofolate and betaine as methyl donors. Deficiency of the folate-dependent methylation system is linked to hyperhomocysteinemia. Our data suggest that this deficiency leads to concurrent metabolic down-regulation of homocysteine transsulfuration that may contribute to hyperhomocysteinemia. By contrast, no instances have been reported of hyperhomocysteinemia resulting from deficiencies of betaine-dependent homocysteine methylation. Long-term betaine supplementation of 10 patients, who had pyridoxine-resistant homocystinuria and gross hyperhomocysteinemia due to deficiency of cystathionine beta-synthase activity, caused a substantial lowering of plasma homocysteine, which has now been maintained for periods of up to 13 years. Betaine had to be taken regularly because the effect soon disappeared when treatment was stopped. In conclusion, depressed activity of the transsulfuration pathway may contribute to hyperhomocysteinemia because of primary deficiencies of enzymes of either the transsulfuration or of the folate-dependent methylation pathways. Stimulation of betaine-dependent homocysteine remethylation causes a commensurate decrease in plasma homocysteine that can be maintained as long as betaine is taken.
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PMID:Human homocysteine catabolism: three major pathways and their relevance to development of arterial occlusive disease. 864 74

Similarly as in other inborn metabolic diseases the cause of hyperhomocysteinaemia are interactions between genetically conditioned changes most frequently due to reduced cystathionine-beta synthase activities and negative factors of the external environment. Negative environmental factors include above all a high dietary animal protein consumption which is the main methionine donor and a low intake of protein of plant origin. Another negative factor is a low intake of foods of plant origin. Fruits and vegetables are among others important sources of folic acid and pyridoxine. Substitution therapy with vitamin preparations is essential in homozygotes and in high risk heterozygotes of cystathionine beta-synthase. This treatment is also necessary during the periconception period in hyperhomocysteinaemic fertile women to reduce the risk of neurotubal defects in their future children. So far investigations are lacking which would provide evidence of a reduced risk of ischaemic heart disease and other cardiovascular diseases in isolated treatment of mildly elevated levels of plasma homocysteine. To elucidate the part played by hyperhomocysteinaemia in hastening of the atherogenetic process further studies are essential, focused on the interaction of elevated homocysteine plasma levels, dyslipoproteinaemias, hyperfibrinogenaemia and other metabolic indicators in this process.
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PMID:[Hyperhomocysteinemia]. 870 82

We compared biochemical and molecular methods for the identification of heterozygous carriers of mutations in the cystathionine beta-synthase (CBS) gene. Eleven relatives of seven unrelated patients with homocystinuria due to homozygous CBS deficiency and controls were studied with respect to total homocysteine concentrations before and after methionine loading. In addition, we determined CBS activity in cultured skin fibroblasts and tested for the presence of five known mutations by a PCR-based method in these seven patients, their relatives and controls. The results demonstrate that measurement of homocysteine after methionine loading and assay of CBS enzyme activity in cultured fibroblasts identify most but not all heterozygotes. There was significant correlation between homocysteine concentrations and CBS activities only after methionine loading (r = 0.12, 0.48, 0.48 and 0.50 at 0, 4, 6 and 8 h, respectively). Among the homozygous patients, molecular approaches identified five T833C and two G919A mutations out of 14 independent alleles, confirming the studies of others that these represent the two most prevalent mutations. In addition, we found that three of six heterozygotes with the T833 C allele had post-methionine loading homocysteine levels which overlapped with controls and of the other three, one (as well as an obligate heterozygote who did not carry any of the five mutant alleles tested) had CBS activity comparable to that of controls. These findings demonstrate that genotyping is useful as an adjunctive method for the diagnosis of the heterozygous carrier state of CBS deficiency.
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PMID:Molecular and biochemical approaches in the identification of heterozygotes for homocystinuria. 872 13

Fasting and post-methionine load plasma total homocysteine concentrations were investigated in the parents of two homocystinuric patients. Three genetic mutations in the cystathionine beta-synthase gene were found. In the patient of family 1, a frequent Caucasian mutation. T833C, was found on one allele, while the mutation on the other allele has not yet been defined. In the patient of family 2, a mutation C569T, recently described by Sperandeo and colleagues, was found on one allele, while a novel mutation, G346A, was characterized on the other allele. The frequent gene mutation T833C was detected in a heterozygous mother who, surprisingly, exhibited strictly normal fasting and post-methionine load homocysteinaemia. In contrast, in the other family, we found a novel mutation (G346A) in the mother located near Lys 119, the putative binding site of phosphopyridoxal phosphate. This mother exhibited increased fasting and post-methionine load homocysteinaemia. These observations could explain the conflicting results reported for vascular pathologies in parents of homocystinuric patients and direct the search for genetic mutations in these vascular pathologies.
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PMID:Homocysteine response to methionine challenge in four obligate heterozygotes for homocystinuria and relationship with cystathionine beta-synthase mutations. 880 79

The effect of concentrations of sulfur-containing amino acids, activities of cystathionine gamma-lyase and cystathionine beta-synthase, and level of vitamin B6 were examined following menthionine administration in normal rats and chronically uremic rats with 7/8 nephrectomy. In the uremic rats, the serum levels of methionine, cystathionine, cysteine and taurine increased in proportion to the amounts of methionine administered. The increase of taurine content in the serum and liver was particularly marked. Cystathionine beta-synthase activity in the liver increased with the administration, but the serum level of pyridoxal phosphate decreased markedly. The body weight gain of rats decreased with the administration, and the contents of urea and creatinine in serum increased. Thus, vitamin B6 deficiency in chronically uremic rats administered with large amounts of methionine may reduce growth, lower renal function and cause abnormal metabolism of sulfur-containing amino acids.
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PMID:Content of sulfur amino acids and vitamin B6 and related enzyme activities in rats with chronic renal failure fed a high methionine diet. 888 37

Editing of the non-protein amino acid homocysteine, a frequent type of error-correcting process in amino acid selection for protein synthesis by an aminoacyl-tRNA synthetase, results in formation of a cyclic thioester, homocysteine thiolactone. Here it is shown that human cells in which homocysteine metabolism is deregulated by a mutation in the cystathionine beta-synthase gene and/or by an antifolate drug, aminopterin (which prevents remethylation of homocysteine to methionine by methionine synthase), produce more homocysteine thiolactone, in addition to homocysteine, than unaffected cells. The thiolactone is incorporated into cellular and extracellular proteins, in addition to being secreted and hydrolyzed to homocysteine. Experiments with model proteins and amino acids suggest that the mechanism of incorporation involves acylation of side chain amino groups of lysine residues by the activated carboxyl group of the thiolactone. The metabolic conversion of homocysteine to homocysteine thiolactone and the reactivity of the thiolactone toward proteins may explain pathological consequences of elevated levels of homocysteine such as observed in vascular disease.
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PMID:Metabolism of homocysteine thiolactone in human cell cultures. Possible mechanism for pathological consequences of elevated homocysteine levels. 899 83

The cysB gene of A. nidulans was cloned by complementation of a cysB mutation. This is the first cloned eukaryotic genomic sequence coding for cysteine synthase. The gene contains one 71-bp intron and codes for a protein of 370 amino acids. Its N-terminal region has characteristic features of transit peptides, suggesting mitochondrial localisation of the enzyme. The protein shows homology with bacterial and plant cysteine synthases among which it occupies a remote phylogenetic position and apparently represents a distinct subfamily. Transcription of the cysB gene is not appreciably regulated by the concentration of methionine in the growth medium.
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PMID:Cloning and characterization of the Aspergillus nidulans cysB gene encoding cysteine synthase. 910 43

This review of recent advances covers (1) the metabolism of methionine and its regulation, emphasizing interactions with the three important vitamins folate, cobalamin and pyridoxine; (2) present knowledge of enzymological and moleculargenetic aspects of homozygous deficiencies of the three enzymes which cause elevated homocyst(e)ine; (3) recent clinical findings, post-methionine loading results related to enzyme and mutation studies in obligate heterozygotes for cystathionine beta-synthase deficiency; (4) important new evidence for disturbed homocysteine metabolism in neural tube defects, particularly based on studies of the thermolabile methylene-tetrahydrofolate reductase mutation which is also of importance in vascular disease; (5) the suitability and limitations of animal models that have so far been described.
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PMID:Disorders of homocysteine metabolism. 921 Nov 99


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