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)

Abnormal elevation of plasma methionine may result from several different genetic abnormalities, including deficiency of cystathionine beta-synthase (CBS) or of the isoenzymes of methionine adenosyltransferase (MAT) I and III expressed solely in nonfetal liver (MAT I/III deficiency). Classically, these conditions have been distinguished most readily by the presence or absence, respectively, of elevated plasma free homocystine, detected by amino acid chromatography in the former condition, but absent in the latter. During the present work, we have assayed methionine, S-adenosylmethionine, S-adenosylhomocysteine, total homocysteine (tHcy), cystathionine, N-methylglycine (sarcosine), and total cysteine (tCys) in groups of both MAT I/III- and CBS-deficient patients to provide more evidence as to their metabolite patterns. Unexpectedly, we found that MAT I/III-deficient patients with the most markedly elevated levels of plasma methionine also had elevations of plasma tHcy and often mildly elevated plasma cystathionine. Evidence is presented that methionine does not inhibit cystathionine beta-synthase, but does inhibit cystathionine gamma-lyase. Mechanisms that may possibly underlie the elevations of plasma tHcy and cystathionine are discussed. The combination of elevated methionine plus elevated tHcy may lead to the mistaken conclusion that an MAT I/III-deficient patient is instead CBS-deficient. Less than optimal management is then a real possibility. Measurements of plasma cystathionine, S-adenosylmethionine, and sarcosine should permit ready distinction between the 2 conditions in question, as well as be useful in several other situations involving abnormalities of methionine and/or homocysteine derivatives.
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PMID:Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency. 1214 70

Hydrogen sulfide (H2S) is a well-known toxic gas with the smell of rotten eggs. Since the first description of the toxicity of H2S in 1713, most studies about H2S have been devoted to its toxic effects. Recently, H2S has been proposed as a physiologically active messenger. Three groups discovered that the brain contains relatively high concentrations of endogenous H2S. This discovery accelerated the identification of an H2S-producing enzyme, cystathionine beta-synthase (CBS) in the brain. In addition to the well-known regulators for CBS, S-adenosyl-L-methionine (SAM) and pyridoxal-5'-phosphate, it was recently found that Ca2+/calmodulin-mediated pathways are involved in the regulation of CBS activity. H2S is produced in response to neuronal excitation, and alters hippocampal long-term potentiation (LTP), a synaptic model for memory. can also regulate the release of corticotropin-releasing hormone (CRH) from hypothalamus. Another H2S producing enzyme, cystathionine gamma-lyase (CSE), has been identified in smooth muscle, and H2S relaxes smooth muscle in synergy with nitric oxide (NO). Recent progress in the study of H2S as a novel neuromodulator/transmitter in the brain is briefly reviewed.
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PMID:Hydrogen sulfide as a neuromodulator. 1239 53

Some strains of Saccharomyces cerevisiae have detectable activities of L-serine O-acetyltransferase (SATase) and O-acetyl-L-serine/O-acetyl-L-homoserine sulfhydrylase (OAS/OAH-SHLase), but synthesize L-cysteine exclusively via cystathionine by cystathionine beta-synthase and cystathionine gamma-lyase. To untangle this peculiar feature in sulfur metabolism, we introduced Escherichia coli genes encoding SATase and OAS-SHLase into S. cerevisiae L-cysteine auxotrophs. While the cells expressing SATase grew on medium lacking L-cysteine, those expressing OAS-SHLase did not grow at all. The cells expressing both enzymes grew very well without L-cysteine. These results indicate that S. cerevisiae SATase cannot support L-cysteine biosynthesis and that S. cerevisiae OAS/OAH-SHLase produces L-cysteine if enough OAS is provided by E. coli SATase. It appears as if S. cerevisiae SATase does not possess a metabolic role in vivo either because of very low activity or localization. For example, S. cerevisiae SATase may be localized in the nucleus, thus controlling the level of OAS required for regulation of sulfate assimilation, but playing no role in the direct synthesis of L-cysteine.
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PMID:Role of Saccharomyces cerevisiae serine O-acetyltransferase in cysteine biosynthesis. 1258 6

Alterations in hepatic metabolism of S-amino acids were monitored over one week in male rats treated with a single dose of ethanol (3 g/kg, ip). Methionine and S-adenosylhomocysteine concentrations were increased rapidly, but S-adenosylmethionine, cysteine, and glutathione (GSH) decreased following ethanol administration. Activities of methionine adenosyltransferase, cystathionine gamma-lyase and cystathionine beta-synthase were all inhibited. gamma-Glutamylcysteine synthetase activity was increased from t = 8 hr, but GSH level did not return to control for 24 hr. Hepatic hypotaurine and taurine levels were elevated immediately, but reduced below control in 18 hr. Changes in serum and urinary taurine levels were consistent with results observed in liver. Cysteine dioxygenase activity was increased rapidly, but declined from t = 24 hr. The results show that a single dose of ethanol induces profound changes in hepatic S-amino acid metabolism, some of which persist for several days. Ethanol not only inhibits the cysteine synthesis but suppresses the cysteine availability further by enhancing its irreversible catabolism to taurine, which would play a significant role in the depletion of hepatic GSH.
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PMID:Alterations in hepatic metabolism of sulfur-containing amino acids induced by ethanol in rats. 1262 41

In certain tissues, glutathione biosynthesis is connected to methionine metabolism via the trans-sulfuration pathway. The latter condenses homocysteine and serine to cystathionine in a reaction catalyzed by cystathionine beta-synthase followed by cleavage of cystathionine to cysteine and alpha-ketoglutarate by gamma-cystathionase. Cysteine is the limiting amino acid in glutathione biosynthesis, and studies in our laboratory have shown that approximately 50% of the cysteine in glutathione is derived from homocysteine in human liver cells. In this study, we have examined the effect of pro- and antioxidants on the flux of homocysteine through the trans-sulfuration pathway in the human hepatoma cell line, HepG2. Our studies reveal that pyrrolidine dithiocarbamate and butylated hydroxyanisole enhance the flux of homocysteine through the trans-sulfuration pathway as has been observed previously with the pro-oxidants, H(2)O(2) and tertiary butyl hydroperoxide. In contrast, antioxidants such as catalase, superoxide dismutase and a water-soluble derivative of vitamin E elicit the opposite effect and result in diminished flux of homocysteine through the trans-sulfuration pathway. These studies provide the first evidence for the reciprocal sensitivity of the trans-sulfuration pathway to pro- and antioxidants, and demonstrate that the upstream half of the glutathione biosynthetic pathway (i.e. leading to cysteine biosynthesis) is redox sensitive as is the regulation of the well-studied enzymes in the downstream half (leading from cysteine to glutathione), namely, gamma-glutamyl-cysteine ligase and glutathione synthetase.
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PMID:Redox regulation of homocysteine-dependent glutathione synthesis. 1263 46

Alterations of hepatic glutathione level by betaine were observed previously. In this study effects of betaine administration (1000 mg/kg, i.p.) on S-amino acid metabolism in rats and mice were investigated. Hepatic glutathione level decreased rapidly followed by marked elevation in 24 hr. Concentrations of S-adenosylmethionine, S-adenosylhomocysteine, and methionine were increased whereas cystathionine decreased significantly, suggesting that homocysteine generated in the methionine cycle is preferentially remethylated to methionine rather than being utilized for synthesis of cysteine. Hepatic cysteine concentration declined immediately, but plasma cysteine increased. Effect of betaine on hepatic cysteine uptake was estimated from the difference in cysteine concentration in major blood vessels connected to liver. Cysteine concentration either in the portal vein or abdominal aorta was not altered, however, a significant increase was noted in the hepatic vein, indicating that hepatic uptake of cysteine was decreased by betaine treatment. Activities of glutamate cysteine ligase, cystathionine beta-synthase, and cystathionine gamma-lyase were elevated in 24 hr. Pretreatment with propargylglycine, an irreversible inhibitor of cystathionine gamma-lyase, did not abolish the betaine-induced reduction of hepatic glutathione in 4 hr, however, the elevation at t=24 hr was blocked completely. In conclusion the present results indicate that betaine administration induces time-dependent changes on hepatic metabolism of S-amino acids. Betaine enhances metabolic reactions in the methionine cycle, but inhibits cystathionine synthesis and cysteine uptake, leading to a decrease in supply of cysteine for glutathione synthesis. Reduction in glutathione is subsequently reversed due to induction of cysteine synthesis and glutamate cysteine ligase activity.
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PMID:Effect of acute betaine administration on hepatic metabolism of S-amino acids in rats and mice. 1273 69

Alterations in the hepatic metabolism of S-amino acids were examined in male rats injected with a single dose of ethanol (3 g/kg, i.p.). The hepatic concentrations of methionine and S-adenosylhomocysteine (SAH) were increased, but S-adenosylmethionine (SAM), cysteine, and glutathione (GSH) decreased rapidly following ethanol administration. The activities of methionine adenosyltransferase (MAT), cystathionine beta-synthase (CbetaS) and cystathionine gamma-lyase (CgammaL) were all inhibited. Gamma-glutamylcysteine synthetase (GCS) activity was increased from t = 8 hr, but hepatic glutathione (GSH) level did not return to control for 48 hr. Both hepatic hypotaurine and taurine levels were increased immediately, which were reduced to below control from t = 18 hr. Changes in the serum concentration of taurine were consistent with results observed in the liver. Cysteine dioxygenase (CDO) activity was increased rapidly, but declined from t = 24 hr. The results indicate that an acute dose of ethanol induces significant alterations in the metabolism of S-amino acids in the liver. Ethanol depresses the cysteine availability for GSH synthesis not only by inhibiting the transsulfuration reactions but also by enhancing its irreversible catabolism to taurine via hypotaurine. The physiological significance of this finding is discussed.
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PMID:Effect of acute ethanol administration on S-amino acid metabolism: increased utilization of cysteine for synthesis of taurine rather than glutathione. 1290 7

Tissue concentrations of both homocysteine (Hcy) and cysteine (Cys) are maintained at low levels by regulated production and efficient removal of these thiols. The regulation of the metabolism of methionine and Cys is discussed from the standpoint of maintaining low levels of Hcy and Cys while, at the same time, ensuring an adequate supply of these thiols for their essential functions. S-Adenosylmethionine coordinately regulates the flux through remethylation and transsulfuration, and glycine N-methyltransferase regulates flux through transmethylation and hence the S-adenosylmethionine/S-adenosylhomocysteine ratio. Cystathionine beta-synthase activity is also regulated in response to the redox environment, and transcription of the gene is hormonally regulated in response to fuel supply (insulin, glucagon, and glucocorticoids). The H2S-producing capacity of cystathionine gamma-lyase may be regulated in response to nitric oxide. Cys is substrate for a variety of anabolic and catabolic enzymes. Its concentration is regulated primarily by hepatic Cys dioxygenase; the level of Cys dioxygenase is upregulated in a Cys-responsive manner via a decrease in the rate of polyubiquitination and, hence, degradation by the 26S proteasome.
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PMID:Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. 1518 31

The enzymes of the transsulfuration pathway also have the capacity to catalyze the desulfhydration of cysteine. Recent studies demonstrate a role of the transsulfuration enzymes, cystathionine gamma-lyase and cystathionine beta-synthase, in catalyzing the desulfhydration of cysteine in brain and smooth muscle. The H2S produced from cysteine functions as a neuromodulator and smooth muscle relaxant. In glutamatergic neurons, the production of H2S by cystathionine beta-synthase enhances N-methyl-D-aspartate (NMDA) receptor-mediated currents. In smooth muscle cells, H2S produced by cystathionine gamma-lyase enhances the outward flux of potassium by opening potassium channels, leading to hyperpolarization of membrane potential and smooth muscle relaxation.
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PMID:New roles for cysteine and transsulfuration enzymes: production of H2S, a neuromodulator and smooth muscle relaxant. 1549 68

This study aimed to examine distribution of cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), the hydrogen sulfide (H(2)S)-generating enzymes, and metabolomic alterations in sulfur-containing amino acids in rat testes exposed to stressors. Immunohistochemistry revealed distinct distribution of the two enzymes: CBS occurred mainly in Leydig cells and was also detectable in Sertoli cells and germ cells, whereas CSE was evident in Sertoli cells and immature germ cells involving spermatogonia. The amounts of CSE and CBS in testes did not alter in response to administration of cadmium chloride, an antispermatogenic stressor leading to apoptosis. Metabolome analyses assisted by liquid chromatography equipped with mass spectrometry revealed marked alterations in sulfur-containing amino acid metabolism: amounts of methionine and cysteine were significantly elevated concurrently with a decrease in the ratio between S-adenosylhomocysteine and Sadenosylmethionine, suggesting expansion of the remethylation cycle and acceleration of methyl donation. Despite a marked increase in cysteine, amounts of H(2)S were unchanged, leading to a remarkable decline of the H(2)S/cysteine ratio in the cadmium-treated rats. Under such circumstances, oxidized glutathione (GSSG) was significantly reduced, whereas reduced glutathione (GSH) was well maintained, and the GSH/GSSG ratio was consequently elevated. These results collectively showed that cadmium induces metabolomic remodeling of sulfur-containing amino acids even when the protein expression of CBS or CSE is not evident. Although detailed mechanisms for such a remodeling event remain unknown, our study suggests that metabolomic analyses serve as a powerful tool to pinpoint a critical enzymatic reaction that regulates metabolic systems as a whole.
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PMID:Cadmium exposure alters metabolomics of sulfur-containing amino acids in rat testes. 1589 25


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