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)

Precocious atherosclerosis occurs in homocystinuria due to cystathionine beta-synthase deficiency and there is evidence that homocysteine may produce endothelial damage. Mild homocysteinemia has been reported in heterozygotes after methionine loads and it has been suggested that they could have an increased risk of atherogenesis. We measured plasma amino acids before and after a methionine load (100 mg per kg) in 17 obligatory heterozygotes, in 20 men under 50 yr with established ischemic heart disease, and in matched controls, to determine whether methionine loading allows identification of heterozygotes, and whether there is an altered rate of methionine metabolism in patients with premature coronary artery disease. The obligate heterozygotes had higher mean plasma concentrations of methionine and total homocysteine at 4, 8 and 12 hours after the load than their controls, and lower concentrations of total cysteine and taurine in fasting and all post load samples; however, there was considerable overlap of measurements in heterozygotes and their controls even when differential weightings were applied. There were no differences in mean plasma concentrations of methionine, total homocysteine or total cysteine between the patients with ischemic heart disease and their controls at any measurement point. However, two patients with premature coronary artery disease, identical twins, had persistent elevation of total plasma homocysteine and an exaggerated homocysteine response to methionine. Oral folate restored homocysteine concentrations before and after methionine to normal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Homocysteinemia, ischemic heart disease, and the carrier state for homocystinuria. 668 24

We investigated the biosynthesis of cystathionine beta-synthase (EC 4.2.1.22) in a cell-free translation system programmed with rat liver mRNA and in slices of rat liver. The enzyme was recovered by immunoprecipitation and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Only a single mRNA species, coding for a 63,000-dalton polypeptide, was detected when rat liver mRNA was assayed by cell-free translation. On the other hand, two polypeptides were recovered by immunoprecipitation from fresh liver extracts: a predominant Mr = 63,000 polypeptide and a minor Mr = 48,000 polypeptide. When such extracts were incubated at 4 degrees C for 7 days, the synthase activity increased 2-3-fold with a concomitant disappearance of the Mr = 63,000 polypeptide and some increase of the Mr = 48,000 polypeptide. Moreover, the specific activity of synthase containing the smaller subunits was now found to be approximately 60-fold higher than that containing the larger ones. At least in part, this increased specific activity reflected a 30-fold greater affinity for homocysteine. The changes in subunit size and activity could be prevented in vitro by protease inhibitors such as N alpha-p-tosyl-L-lysine chloromethyl ketone, antipain, and leupeptin, but not by several other protease inhibitors. Pulse-chase experiments with slices of rat liver suggested a slow, post-translational conversion of the Mr = 63,000 polypeptide to the Mr = 48,000 polypeptide. Taken together, our findings are consistent with the possibility that the large subunit form of synthase is essentially inactive under physiologic conditions, and that synthase activity is regulated by limited proteolysis.
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PMID:Biosynthesis and proteolytic activation of cystathionine beta-synthase in rat liver. 670 53

Using an in vitro system which contained enzymes, substrates, and other reactants at concentrations which approximated the in vivo conditions in rat liver, we measured the simultaneous product formation by three enzymes which utilize homocysteine. In the control system, 5-methyltetrahydrofolate homocysteine methyltransferase, betaine homocysteine methyltransferase, and cystathionine beta-synthase accounted for 27, 27, and 46%, respectively, of the homocysteine consumed. Subsequent studies demonstrated that the adaptation from a high protein diet to a low protein diet is achieved by a significant increase in betaine homocysteine methyltransferase, and 83% reduction in cystathionine synthase, and a total decrease of 55% in the consumption of homocysteine. S-Adenosylmethionine, by activating cystathionine synthase, contributes significantly to the regulation of the pathway.
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PMID:Methionine metabolism in mammals. Distribution of homocysteine between competing pathways. 674 58

We measured blood copper-containing proteins and plasma total copper in 15 patients with homocystinuria (14 with cystathionine beta-synthase deficiency and one with abnormal cobalamin metabolism), in 13 heterozygotes for cystathionine beta-synthase deficiency, and in 44 normal subjects. Plasma total copper was increased in patients with cystathionine beta-synthase deficiency compared with age- and sex-matched controls; the ratio was 1.41 +/- 0.14 for females and 1.39 +/- 0.15 for males (means +/- SD). This was due to corresponding increases in caeruloplasmin concentrations, but levels were unrelated to total plasma homocysteine. Erythrocyte superoxide dismutase levels were normal. The heterozygotes had normal plasma copper and caeruloplasmin levels. The increased copper and caeruloplasmin may contribute to the precocious atherogenesis occurring in homocystinuria by decreasing the adhesion of vascular endothelial cells to the intima. It is unlikely that decreased lysyl oxidase activity due to chelation of copper by homocysteine is important for the pathogenesis of the connective tissue defect in homocystinuria.
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PMID:Increased plasma copper in patients with homocystinuria due to cystathionine beta-synthase deficiency. 682 4

The previously published procedure (Kraus et al. (1978) J. Biol. Chem. 253, 6523-6528) for the purification of cystathionine beta-synthase [L-serine hydro-lyase (adding homocysteine) EC 4.2.1.22], a pyridoxal 5'-phosphate-dependent enzyme from human liver has been modified. The new procedure, starting with a liver homogenate "aged" for 7 days at 4 degrees C, yielded homogeneous enzyme purified over 3000-fold with a much improved yield. "Aging" of the enzyme in crude homogenates yields a form apparently smaller by gel electrophoresis and with significantly increased activity and antigenicity. This species of cystathionine beta-synthase does not form stable complexes with other proteins during purification as does the previously employed, freshly used species. An absorption spectrum and an amino acid composition of the pure enzyme were determined; the amino-terminal residue was shown to be methionine. The isoelectric points of holosynthase and aposynthase were estimated to be 5.2 and 5.6, respectively. Rabbit antiserum raised against the pure cystathionine beta-synthase was characterized using as antigen crude synthase from five different mammalian species as well as the pure human enzyme.
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PMID:Cystathionine beta-synthase from human liver: improved purification scheme and additional characterization of the enzyme in crude and pure form. 683 28

The treatment of homocystinuria that is not responsive to pyridoxine is not usually biochemically or clinically successful, and vascular, ocular, and skeletal complications commonly supervene. Persistent marked homocysteinemia appears to be the most important biochemical disturbance leading to these complications. Ten patients with cystathionine beta-synthase deficiency that was not responsive to pyridoxine and one patient with homocystinuria due to a defect in cobalamin metabolism were treated with 6 g daily of betaine added to conventional therapy, to improve homocysteine remethylation. All patients had a substantial decrease in plasma total homocysteine levels (P less than 0.001) and an increase in total cysteine levels (P less than 0.001). Changes in plasma methionine concentrations were variable. Fasting levels of plasma amino acids became normal in two patients, and in six there was immediate clinical improvement. There were no unwanted effects. We conclude that treatment of homocystinuria that is not responsive to pyridoxine and of disorders of homocysteine remethylation should include betaine in adequate doses to ensure maximum lowering of elevated plasma homocysteine levels.
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PMID:Homocystinuria--the effects of betaine in the treatment of patients not responsive to pyridoxine. 687 13

The activities of cystathionine synthase [L-serine hydro-lyase (adding homocysteine), EC 4.2.1.22], uroporphyrinogen I synthase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8], and glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate:NADP+ 1-oxidoreductase, EC 1.1.1.49) have been measured in phytohemagglutinin-stimulated lymphocytes of young and old human subjects. A significant decrease in activity with age was observed for cystathionine synthase and uroporphyrinogen I synthase but not for glucose-6-phosphate dehydrogenase. These changes could not be related to declining phytohemagglutinin response with aging. Age-related decreases in activity of some enzymes may be relevant for an understanding of the biology of aging. False assignment of heterozygosity, and even homozygosity, for certain genetic disorders, such as homocystinuria, may result when low enzyme levels are detected in the lymphocytes of older people.
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PMID:Effect of chronologic age on induction of cystathionine synthase, uroporphyrinogen I synthase, and glucose-6-phosphate dehydrogenase activities in lymphocytes. 694 Jan 98

In order to ascertain the role of L-serine sulfhydro-lyase (L-serine hydro-lyase (adding homocysteine) EC 4.2.1.22) which also catalyzes sulfhydrylation of O-acetyl-L-serine (Yamagata, S. (1981) J. Bacteriol. 147, 688-690), the enzyme was partially purified from a wild-type strain and three cysteine auxotrophs of Saccharomyces cerevisiae, and the molecular and enzymatic properties of these preparations were compared. The results showed no significant difference in properties investigated, indicating that cysteine synthesis is exclusively performed in this organism through sulfhydrylation of O-acetyl-L-serine, catalyzed not by serine sulfhydro-lyase but by O-acetylserine . O-acetylhomoserine sulfhydro-lyase (Yamagata, S., Takeshima, K. and Naiki, N. (1974) J. Biochem. 75, 1221-1229). Insensitivity of the former enzyme to L-methionine also supported this conclusion.
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PMID:Partial purification and comparison of some properties of L-serine sulfhydro-lyase of Saccharomyces cerevisiae. 703 82

The accumulation of homocyst(e)ine in rats deficient in vitamin B-6 was monitored. Homocysteine and cysteine linked by disulfide bonds to plasma proteins, to red blood cells (RBC) membranes, and free in plasma were analyzed by HPLC separation and electrochemical detection. As the vitamin B-6 deficiency progressed, the concentration of plasma protein-bound and RBC membrane-bound homocysteine increased and that of cysteine decreased. Changes in free homocysteine concentration paralleled those seen in protein-bound homocysteine, but free cystein concentration did not fluctuate throughout the deficiency. Refeeding vitamin B-6 to deficient animals resulted in a return of homocysteine and cysteine concentrations to control levels within 2 days. Bound homocysteine and cysteine and plasma free homocyst(e)ine concentrations in rats deficient in vitamin B-6 were in the same concentration range as those seen in patients with homocystinuria due to cystathionine beta-synthase deficiency. Monitoring changes in plasma protein-bound and free homocysteine concentration during vitamin B-6 deficiency in rats may provide a useful system for the study of cystathionine beta-synthase deficiency and its treatment.
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PMID:Accumulation of homocyst(e)ine in vitamin B-6 deficiency: a model for the study of cystathionine beta-synthase deficiency. 709 45

There is as yet no satisfactory experimental model for homocystinuria due to cystathionine beta-synthase deficiency. We produced homocysteinemia in pigs for up to 60 days by continuously infusing DL-homocysteine thiolactone and compared the changes in the plasma amino acids with the findings in 16 patients with homocystinuria. Vascular morphology was also investigated in the infused animals. In six pigs DL-homocysteine thiolactone, 0.68/kg/day for 13-60 days increased mean levels of methionine from 43.6 to 116.6 mumole/l, homocystine from zero to 67.4, cysteine-homocysteine disulfide from 4.3 to 49.2, taurine from 97.3 to 193.9 and alpha-amino-n-butyric acid from 16.5 to 147.4. Total cysteine did not change although cystine decreased from 50.8 to 26.2 mumole/liter. There were no amino acid changes in four saline infused (control) pigs and no differences in vascular morphology between experimental and control animals. Seven severely affected homocystinuric patients, biochemically, unresponsive to pyridoxine administration, had plasma sulfur-containing amino acid changes of similar magnitude to those in the infused pigs except that taurine concentrations were normal and total cysteine was decreased as it also was in nine pyridoxine responsive patients. In contrast to the pigs, plasma alpha-amino-n-butyric acid was normal in all 16 patients. We conclude that this model provides information about methionine metabolism but that it should be used with caution to study mechanisms in homocystinuria because it does not exactly mimic the human disease and because the thiolactone, which at present must be used as the source of infused L-homocysteine, itself produces changes which could influence results.
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PMID:Experimental homocysteinemia in pigs: comparison with studies in sixteen homocystinuric patients. 709 48


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