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:2.5.1.47 (cysteine synthase)
625 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione metabolism occurs via interorgan cycles in which hepatic synthesis of reduced glutathione and its transfer to extrahepatic tissues play an important role. To elucidate the physiologic significance of the cycles and tissue thiol status during stress-induced gastric mucosal injury, dynamic aspects of glutathione metabolism were analyzed in rats that were treated with water-immersion restraint. This treatment induced gastric mucosal lesion with concomitant decrease in the levels of perchloric acid-soluble thiols in various tissues, particularly in the liver and stomach. During the treatment, glutathione levels markedly decreased in the liver but not in other tissues. Depletion of hepatic glutathione by buthionine sulfoximine, a specific inhibitor for gamma-glutamyl cysteine synthetase, markedly decreased hepatic glutathione levels and increased the gastric injury. Intraperitoneal injection of reduced glutathione significantly increased plasma levels of glutathione and inhibited the occurrence of gastric injury without affecting intracellular glutathione levels. These results indicate that extracellular glutathione and its interorgan metabolism might play a critical role in the protection of gastric mucosa particularly when animals were challenged with various stress.
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PMID:Inhibition of stress-induced gastric injury in the rat by glutathione. 277 41

We have tested the tumoricidal potency of enzyme immunotoxins constructed of antibodies conjugated to glucose oxidase and to lactoperoxidase. Murine plasmacytoma cells were targeted in vitro with the use of affinity-purified rabbit anti-plasmacytoma membrane antibodies (conjugated to glucose oxidase or lactoperoxidase) or rabbit serum raised against plasmacytoma microsome membranes followed by goat anti-rabbit immunoglobulin conjugates (to glucose oxidase or lactoperoxidase). Cytotoxicity was generated subsequently by incubation of the washed cells in a medium supplemented with glucose and sodium iodide, which were the substrates of these enzymes. This resulted in the presumed metabolic release of highly toxic reduced oxygen species and iodinated derivatives. Targeting of tumor cells with both conjugates, as opposed to one of them alone, produced a synergistic killing effect. The gain of specific versus unspecific cytotoxicity was upwards of 10,000-fold. The killing rates were elevated (t10 values less than 30 min) and linear over time. The resultant reduction in tumor cell viability was in the order of 5 to 6 logs after only 20 to 90 min of incubation in the glucose/NaI medium. Cytotoxicity was enhanced by the gamma-glutamyl cysteine synthetase inhibitor buthionine-S,R-sulfoximine and by the glutathione reductase inhibitor 1,3-bis(2-chloroethyl)-1-nitrosourea, while catalase was inhibitory. The results suggest that these enzyme immunotoxins may be suitable for the ex vivo purging of autologous bone marrow grafts.
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PMID:Immunotoxins containing glucose oxidase and lactoperoxidase with tumoricidal properties: in vitro killing effectiveness in a mouse plasmacytoma cell model. 279 Jul 77

The effect of cellular glutathione depletion on fibrinolytic activity in the arterial wall and on the levels of components of the plasma fibrinolytic system was studied in rabbits. Intraperitoneal administration of buthionine sulphoximine (4.5 mmol/kg body wt), an inhibitor of gamma-glutamyl cysteine synthetase, induced a significant reduction in liver glutathione concentrations with a peak decrease of 51% at 7 hours and a progressive return to normal values. The glutathione concentration in aortic tissue was also significantly reduced 7 h after administration of the depleting agent. Fibrinolytic activity in the arterial wall was inhibited following buthionine sulphoximine administration and only reappeared at 24 hours postinjection. Diethyl maleate administration (3.2 mmol/kg body wt i.p.) also depleted liver and aortic glutathione and inhibited fibrinolysis in the arterial wall. Treatment with both glutathione-depleting agents induced a significant reduction in the functional activity of tissue plasminogen activator (t-PA) (-61% and -27% respectively for buthionine sulphoximine or diethyl maleate) and a significant increase in that of plasminogen activator-inhibitor (PAI) (+61% and +27% respectively), while alpha-2-antiplasmin activity was not modified. Our data suggest a modulatory role of glutathione in the release and/or clearance of the components of the fibrinolytic system in the rabbit.
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PMID:Inhibition of fibrinolysis by cellular glutathione depletion in the rabbit. 292 7

In order to obtain inhibitors of the meso-diaminopimelate-adding enzyme, which participates in the biosynthesis of bacterial peptidoglycan, several N alpha-propionyl-dipeptides of the general formula Pr-L-Ala-ambo-Xaa-OH were synthesized. Xaa represented methionine S,S-dioxide, methionine S-oxide, methionine sulfoximine, and 2-amino-4-phosphonobutyric acid, i.e. transition state analogs of glutamine synthetase and gamma-glutamyl-cysteine synthetase, which catalyze the same type of reaction as our target enzyme. After synthesis, the diastereoisomers were separated by preparative HPLC or t.l.c.; those containing methionine derivatives could be identified thanks to previously synthesized reference compounds. After preincubation with the meso-diaminopimelate-adding activity from Escherichia coli, the LD diastereoisomers displayed moderate inhibitory effects, whereas the LL ones were inefficient. The best inhibition was obtained with one diastereoisomer of Pr-L-Ala-zeta-2-amino-4-phosphonobutyrate, presumably the LD one. A chloromethylketone derivative Pr-L-Ala-D-Glu(CH2Cl)-OH, potential affinity labeler of the meso-diaminopimelate-adding enzyme, was also synthesized. In the assay with preincubation, this compound behaved as the best inhibitor.
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PMID:Synthesis of inhibitors of the meso-diaminopimelate-adding enzyme from Escherichia coli. 307 5

The role of the glutathione (GSH) redox cycle and vitamin E as antioxidant defense systems was studied in normal human cultured skin fibroblasts infected by virulent Mycoplasma pneumoniae. In cells infected for 20 h, catalase activity was inhibited by 75% and the intracellular GSH decreased to 32% of its normal values. GSH peroxidase and oxidized glutathione (reductase activities in the infected cells were unaffected.) GSSG glutathione in the medium of the infected cells rose in accordance with the intracellular GSH decrease. The observed elevation in GSSG/GSH ratio was attributed to the increase in intracellular H2O2 content in M. pneumoniae-infected cells due to the marked inhibition in their catalase activity. The protective effect of the GSH redox cycle in infected cells was studied by depletion of cellular GSH, prior to their infection with M. pneumoniae, using buthionine sulfoximine (BSO), a selective inhibitor of gamma-glutamyl cysteine synthetase. After 16 h of incubation with BSO, the GSH levels were reduced to 38% of their normal value and recovered to 55% during 24 h after removal of the inhibitor. BSO had no effect on GSH peroxidase and catalase activities in either infected or noninfected cells. The level of malonyldialdehyde (an indicator of membrane lipid peroxidation) in BSO-treated cells infected by M. pneumoniae was 1.8 times higher than in infected controls. Cells enriched with 0.25 and 2.25 micrograms of vitamin E per mg of protein prior to their infection by M. pneumoniae revealed the following: a lesser degree of catalase inhibition, 46 and 30%, respectively, versus 64% in infected control cells that were not supplemented with vitamin E; lower levels of malonyldialdehyde, 55 and 20% increments, respectively, versus a 140% increment in infected controls; higher residual activity of lactate dehydrogenase, 76 and 96%, respectively, versus 58% in infected controls. Our data indicate that the oxidative damage induced in M. pneumoniae-infected cells due to the increase in intracellular levels of H2O2 and O2- is limited by the host cell GSH redox cycle and by supplementation with vitamin E.
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PMID:Protective effects of the glutathione redox cycle and vitamin E on cultured fibroblasts infected by Mycoplasma pneumoniae. 308 58

Mice poisoned with acetaminophen were treated with esterase inhibitors, buthionine sulfoximine, and N-acetyl-L-lysine in experiments designed to explore the mechanism of N-acetylcysteine protection in vivo. Three esterase inhibitors, phenylmethylsulfonyl fluoride, bis-(p-nitrophenyl)-phosphate, and diisopropylfluorophosphate, had no effect on the antidote effectiveness of N-acetylcysteine, although each provided partial protection against acetaminophen poisoning. Buthionine sulfoximine, a specific inhibitor of gamma-glutamyl cysteine synthetase, antagonized the antidote effect of N-acetylcysteine. Acetaminophen-induced hepatotoxicity, as measured by plasma alanine aminotransferase activity, and mortality failed to decline, consistent with stimulation of glutathione synthesis as the primary mechanism of antidote protection. N-Acetyl-L-lysine was given at doses up to ten-fold higher than N-acetylcysteine yet had no effect on acetaminophen hepatotoxicity or its prevention by N-acetylcysteine. These results advance the view that N-acetylcysteine acts primarily as a glutathione precursor. They further suggest the esterase inhibitors limit poisoning by acetaminophen and may be useful agents in antagonizing the toxicity of other metabolically activated drugs.
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PMID:Effects of esterase inhibitors and buthionine sulfoximine on the prevention of acetaminophen hepatotoxicity by N-acetylcysteine. 310 95

The ability of various concentrations of the differentiation-inducing agent sodium butyrate (NAB, 0-2 mM) to produce radiosensitization in human colon tumor cells when combined with varying concentrations of the irreversible inhibitor of gamma-glutamyl cysteine synthetase, buthionine sulfoximine (BSO, 0-0.75 mM) was studied. We have previously shown that high concentrations of each agent in combination (2 mM NAB + 0.5 mM BSO) produced a supra-additive effect in terms of radiosensitization as indicated by a decrease in the quasi-threshold value (Dq) of the single dose survival curve; we wished to define responses at other concentrations. Cells were adapted in vitro to growth in medium containing NAB for 3 passages prior to x-irradiation and BSO was given acutely 24 hrs before the x-irradiations. The most effective combination was 0.3 mM NAB + 0.75 mM BSO. These data suggest that adaptation of tumor cells to chronic low levels of a differentiation-inducing agent such as NAB followed by administration of BSO just prior to irradiation might be an effective combination in producing increased response of solid tumors.
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PMID:Potentiation of X ray sensitivity by combinations of sodium butyrate and buthionine sulfoximine. 318 35

Nucleotide sequences of the cysK regions of Salmonella typhimurium and Escherichia coli have been determined. A total of 3,812 and 2,595 nucleotides were sequenced from S. typhimurium and E. coli, respectively. Open reading frames of 323 codons were found in both species and were identified as those of cysK by comparison of deduced amino acid sequences with amino- and carboxyl-terminal amino acid analyses of the S. typhimurium cysK gene product O-acetylserine (thiol)-lyase A. The two cysK DNA sequences were 85% identical, and the deduced amino acid sequences were 96% identical. The major transcription initiation sites for cysK were found to be virtually identical in the two organisms, by using primer extension and S1 nuclease protection techniques. The -35 region corresponding to the major transcription start site was TTCCCC in S. typhimurium and TTCCGC in E. coli. The deviation of these sequences from the consensus sequence TTGACA may reflect the fact that cysK is subject to positive control and requires the cysB regulatory protein for expression. Sequences downstream of cysK were found to include ptsH and a portion of ptsI, thus establishing the exact relationship of cysK with these two genes. A 290-codon open reading frame, which may represent the cysZ gene, was identified upstream of cysK.
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PMID:DNA sequences of the cysK regions of Salmonella typhimurium and Escherichia coli and linkage of the cysK regions to ptsH. 329 Jan 98

The development of acquired resistance has limited the effectiveness of chemotherapy in the treatment of ovarian cancer. Experimental model systems were developed to study the mechanisms associated with primary resistance to chemotherapeutic agents and broad cross-resistance (multidrug resistance) which is characteristic of human ovarian cancer. Doxorubicin-resistant cell lines developed in vitro by exposure of a sensitive cell line to increasing concentrations of doxorubicin develop resistance on the basis of a decrease in drug accumulation and have increased expression of the mdr-1 gene. This gene encodes for a membrane glycoprotein and leads to a decreased drug accumulation in drug resistant cell lines. Cell lines established from patients refractory to doxorubicin-containing combinations, however, do not demonstrate a decrease in drug accumulation. Studies are in progress on the measurement of mdr-1 levels in tumors of patients undergoing treatment to determine whether agents, such as verapamil may be useful in the treatment of drug resistant gynecologic cancers. Human ovarian cancer cell lines from drug resistant patients also has been demonstrated to increase levels of glutathione. Lowering of glutathione levels with buthionine sulfoximine (BSO), which irreversibly inhibits the enzyme gamma-glutamyl cysteine synthetase, leads to a marked potentiation of the cytotoxicity of melphalan both in vitro and in vivo in a nude mouse model of human ovarian cancer. Based on those studies, BSO is undergoing toxicologic evaluation before initiation of clinical trials in drug resistant patients. Our studies demonstrate that drug resistance in human ovarian cancer is likely due to interaction of multiple factors. However, biochemical intervention in some of the key steps leading to drug resistance has been demonstrated experimentally feasible and indicates that pharmacologic reversal of drug resistance is a clinical possibility.
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PMID:Multidrug resistance in ovarian cancer. 330 67

Serine acetyltransferase (SAT) from Escherichia coli is subject to feedback inhibition by L-cysteine. A mutant was isolated which excretes L-cysteine because of a lesion in cysE, the structural gene for SAT, rendering the enzyme less feedback sensitive. To analyse the structural basis for this mutation the cysE genes both from wild-type E. coli and the mutant strain were cloned and their nucleotide sequences determined. The cysE gene contained an open reading frame consisting of 819 bp, equivalent to a protein of 273 amino acids. The mutant gene showed a single base change in position 767 resulting in a methionine to isoleucine substitution. A causal connection between this SAT sequence alteration, feedback insensitivity and L-cysteine excretion was demonstrated. The SAT from the wild-type strain was purified. It was composed of a single polypeptide chain migrating in SDS gels according to an Mr of 34,000. As in Salmonella typhimurium, the enzyme was associated in a bifunctional complex with O-acetylserine (thiol)-lyase.
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PMID:L-cysteine biosynthesis in Escherichia coli: nucleotide sequence and expression of the serine acetyltransferase (cysE) gene from the wild-type and a cysteine-excreting mutant. 330 58


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