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:6.3.5.5 (CPS)
1,262 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats given a lethal dose (LD(99.9)) of ammonium acetate (10.8 mmol/kg of body weight) were protected to the extent of 85 and 76% when previously injected with N-carbamoyl glutamate or L-arginine, respectively, at a level of 4 mmol/kg of body weight. At a dose of 1 mmol/kg of body weight, L-arginine protected 24%, while N-carbamoyl-L-glutamate protected 61% of the animals. When a combination of N-carbamoyl-L-glutamate plus L-arginine (1 mmol each per kg of body weight) was injected, 100% of the rats were protected. The efficacy of N-carbamoyl-L-glutamate is related to its role as an activator of mitochondrial carbamoyl phosphate synthetase (EC 2.7.2.5) and its resistance to hydrolysis by tissue acylaminoacid acylase. N-Acetyl-L-glutamate, the naturally occurring and most effective activator of mitochondrial carbamoyl phosphate synthetase, was relatively ineffective in protection against lethal dose of ammonium acetate, because of its ready hydrolysis by acylaminoacid acylase. The findings reported provide a rational basis for the use of N-carbamoyl-L-glutamate plus L-arginine in the prevention and treatment of hyperammonemia in clinical conditions of liver disease and parental infusion of amino acids, and in feeding of urea supplements to ruminants.
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PMID:Ammonia intoxication in rats: protection by N-carbamoyl-L-glutamate plus L-arginine. 450 11

The potential for a considerable formation of ornithine exists in lactating mammary gland because of its arginase content. Late in lactation arginase reaches an activity in the gland higher than that present in any rat tissue except liver. Occurrence of the urea cycle can be excluded since two enzymes for the further reaction of ornithine in the cycle, carbamoyl phosphate synthetase I and ornithine carbamoyltransferase, are both absent from this tissue. Instead, carbamoyl phosphate synthetase II appears early in lactation, associated with accumulation of aspartate carbamoyltransferase and DNA, consistent with the proposed role of these enzymes in pyrimidine synthesis. The facts require another physiological role for arginase apart from its known function in the urea cycle. Significant activity of ornithine aminotransferase develops in mammary gland in close parallel with the arginase. By this reaction, ornithine can be converted into glutamic semialdehyde and subsequently into proline. The enzymic composition of the lactating mammary gland is therefore appropriate for the major conversion of arginine into proline that is known to occur in the intact gland.
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PMID:Function of arginase in lactating mammary gland. 467 4

The concentration of urea in the blood and the rate of urea excretion were markedly elevated in Xenopus maintained in hypertonic saline for 2 to 3 weeks. These changes were accompanied by a twofold increase in the activity of the ornithine-urea cycle as measured in liver slices. The activity of carbamoyl phosphate synthetase rose threefold in frogs adapted to saline. These results suggest that changes in activities of urea cycle enzymes may be important in the adaptation of aquatic organisms to environments of varying salinities.
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PMID:Ornithine-urea cycle activity in xenopus laevis: adaptation in saline. 521 1

Glutamine synthetase and glutamine- and acetylglutamate-dependent carbamoyl-phosphate synthetase, both of which are present in high concentrations in liver of urea-retaining elasmobranchs, have been found to be located exclusively in the mitochondria in liver from the representative elasmobranch Squalus acanthias. This observation is consistent with the view that the function of this unique carbamoyl-phosphate synthetase is related to urea synthesis, and that the initial nitrogen-donating substrate for urea synthesis in these species is glutamine rather than ammonia. The urea cycle enzymes, ornithine carbamoyltransferase and arginase, are also located in the mitochondria, whereas argininosuccinate synthetase and argininosuccinate lyase are located in the cytosol. Glutamine synthetase and arginase are mitochondrial enzymes in uricotelic species, but are normally found in the cytoplasm in ureotelic species. the properties of the elasmobranch arginase, however, are characteristic of arginases from ureotelic species (e.g. the Km for arginine is 1.2 mM, and the enzyme has an Mr congruent to 100,000).
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PMID:Subcellular location of glutamine synthetase and urea cycle enzymes in liver of spiny dogfish (Squalus acanthias). 612 10

High levels of both glutamine synthetase and a unique L-glutamine- and N-acetyl-L-glutamate-dependent carbamoyl phosphate synthetase are present in the mitochondria in livers of marine urea-retaining elasmobranchs (Casey, C. A., and Anderson, P. M. (1982) J. Biol. Chem. 257, 8449-8453). On the basis of these observations it has been suggested that in these species carbamoyl phosphate and, consequently, one of the nitrogen atoms of citrulline and, ultimately, urea, are derived directly from glutamine rather than from ammonia as occurs in mammalian ureotelic species. The purpose of this study was to obtain evidence for this role of glutamine. Isolated hepatic mitochondria from Squalus acanthias incubated with ammonia plus glutamate, ornithine, bicarbonate, inorganic phosphate, and succinate as an energy source were found to synthesize citrulline at a rate comparable to the rate of urea synthesis observed in vivo. Citrulline synthesis proceeds at maximal rates even when the ammonia concentration is as low as 0.05 mM and is stoichiometric with the amount of ammonia initially present. Synthesis from ammonia does proceed in the absence of glutamate, but a much higher concentration of ammonia (congruent to 4 mM) is required to achieve a half-maximal rate. Glutamine can substitute for ammonia plus glutamate as the nitrogen-donating substrate for citrulline synthesis. Selective inhibition of the glutamine-dependent activity of the carbamoyl phosphate synthetase in the isolated mitochondria completely inhibits the ability of the mitochondria to synthesize citrulline from glutamine or from ammonia plus glutamate, whereas selective inhibition of glutamine synthetase inhibits citrulline synthesis from ammonia plus glutamate, but not from glutamine. These observations provide direct evidence that ammonia assimilation for citrulline synthesis (and, therefore, urea synthesis) in these species involves intermediate formation of glutamine.
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PMID:Glutamine-dependent synthesis of citrulline by isolated hepatic mitochondria from Squalus acanthias. 614 86

High levels of glutamine- and N-acetyl-L-glutamate-dependent carbamoyl phosphate synthetase activity are present in liver extracts of marine species of fish that retain high levels of urea in their tissues for the purpose of osmoregulation. The function of the synthetase in these species appears to be related to urea synthesis.
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PMID:Glutamine- and N-acetylglutamate-dependent carbamoyl phosphate synthetase in elasmobranchs. 624 45

Synthesis of citrulline from ornithine, NH4+, and HCO3- by isolated pig liver mitochondria is inhibited by acetazolamide, a specific inhibitor of carbonic anhydrase, at the same concentrations which inhibit the mitochondrial matrix carbonic anhydrase. At an acetazolamide concentration sufficient to give complete inhibition of matrix carbonic anhydrase, the rate of citrulline synthesis is reduced by 71%, but no further decrease in citrulline is observed at higher concentrations of acetazolamide. Stimulation of O2 uptake by ornithine under conditions of maximal citrulline synthesis is also inhibited by acetazolamide. At pH 6.7, the ratio of citrulline synthesis is depressed relative to the rates observed over the range 7.2-7.7, and acetazolamide inhibits this rate by only 20%. These results support the hypothesis that the physiological role of carbonic anhydrase in liver mitochondria is to supply HCO3- as the substrate for the enzyme carbamoyl phosphate synthetase I, which provides the intermediate carbamoylphosphate in the rate-limiting step of citrulline synthesis. Since the uncatalyzed rate of CO2 hydration is rapid enough that it should not be rate-limiting for the carbamoylphosphate synthetase reaction, carbonic anhydrase appears to regulate access of HCO3- in the synthetase and so should be considered as one of the enzymes participating in the biosynthetic pathway leading to urea formation in the hepatocyte.
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PMID:Contribution of matrix carbonic anhydrase to citrulline synthesis in isolated guinea pig liver mitochondria. 640 83

Valproate (0.5-5 mM) strongly inhibited urea synthesis in isolated rat hepatocytes incubated with 10 mM-alanine and 3 mM-ornithine. Valproate at the same concentrations markedly decreased concentrations of N-acetylglutamate, an essential activator of carbamoyl-phosphate synthetase I (EC 6.3.4.16), in parallel with the inhibition of urea synthesis by valproate. This compound also lowered the cellular concentration of acetyl-CoA, a substrate of N-acetylglutamate synthase (EC 2.3.1.1); glutamate, aspartate and citrulline were similarly decreased. Valproate in a dose up to 2 mM did not significantly affect the cellular concentration of ATP and had no direct effect on N-acetylglutamate synthesis, carbamoyl-phosphate synthetase I and ornithine transcarbamoylase (EC 2.1.3.3) activities.
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PMID:Inhibition of ureagenesis by valproate in rat hepatocytes. Role of N-acetylglutamate and acetyl-CoA. 641 45

A lethal carbamylphosphate synthetase (CPS: EC 6.3.4.16) deficiency (McKusick 23730) was found in a newborn girl; who presented on the second day of life with acute hyperammonaemia, hypotonia, seizures and who died in a coma 6 days after birth. The activity of the mitochondrial urea cycle enzymes, CPS and ornithine transcarbamylase (OTC: EC 2.1.3.3) were measured on a needle biopsy sample taken from liver and showed that CPS was 1.4% of the normal mean (0.09 nmol/min/mg protein) whereas OTC activity was normal (110 nmol/min/mg protein). Immunological analysis of the liver sample showed no detectable immunoreactive CPS and confirmed the presence of normal levels of OTC. RNA was extracted from postmortem liver and in vitro translation experiments showed that there was no translatable CPS mRNA and confirmed that no CPS protein was synthesized in this child. The absence of translatable mRNA is explicable in terms of a genetic defect which results in a failure to synthesize mRNA for CPS, or synthesis of a defective form of mRNA which is not translated.
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PMID:A carbamylphosphate synthetase deficiency with no detectable immunoreactive enzyme and no translatable mRNA. 643 91

Carbamyl phosphate synthetase-I (CPS-I; EC 6.3.4.16), a mitochondrial enzyme of the urea-cycle, was studied in deactivated extracts of rat liver. It has been found to be activated in vitro by dithiothreitol (DTT) and Mg2+ ions. After reduction by DTT, thioredoxins, isolated from rat liver, were able to activate CPS-I by 468%.
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PMID:[In vitro activation by dithiothreitol and thioredoxins of carbamyl phosphate synthetase-I in rat liver]. 644 19


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