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)

The mitochondrial matrix subfractions from rat liver, kidney cortex, brain, heart, and skeletal muscle were isolated and their protein components were resolved by two-dimensional polyacrylamide gel electrophoresis, revealing between 120 and 150 components for each matrix subfraction. Excellent resolution was obtained utilizing a pH 5 to 8 gradient in the first dimension and in 8 to 13% exponential acrylamide gradient in the second dimension, increasing the number of mitochondrial matrix proteins observed 3-fold over one-dimensional systems. Protein components tentatively identified by co-migration with pure enzymes and by known tissue distributions are carbamoyl-phosphate synthetase (EC 2.7.2.5), ornithine transcarbamylase (EC 2.1.3.3), glutamate dehydrogenase (EC 1.4.1.3), pyruvate carboxylase (EC 6.4.1.1), citrate synthase (EC 4.1.3.7), fumarase (EC 4.2.1.2), aconitase (EC 4.2.1.3), alpha-ketoglutarate dehydrogenase (EC 1.2.4.2), dihydrolipoyl transsuccinylase (EC 2.3.1.12), lipoamide dehydrogenase (EC 1.6.4.3), glutamate-aspartate aminotransferase (EC 2.6.1.1), and the two subunits of pyruvate dehydrogenase (EC 1.2.4.1). Protein components unambiguously identified by peptide mapping are citrate synthase, aconitase, and pyruvate carboxylase. The inner membrane subfraction from rat liver mitochondria was also resolved two dimensionally; the alpha and beta subunits of ATPase (F1) (EC 3.6.1.3) were identified by peptide mapping.
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PMID:Resolution of rat mitochondrial matrix proteins by two-dimensional polyacrylamide gel electrophoresis. 44 63

We present a diagnostic and therapeutic protocol designed to prevent clinical expression of inborn errors of urea synthesis in the neonatal period, and discuss the long-term developmental outcome of survivors. The families of 32 infants, among 43 identified prenatally as being at risk for a urea cycle disorder, chose to have their infants treated according to a diagnostic and therapeutic protocol, beginning at birth. The therapy was effective in avoiding neonatal hyperammonemic coma and death in seven patients with carbamoyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, and argininosuccinate lyase deficiency. When treated prospectively, five of eight patients with ornithine transcarbamylase deficiency avoided severe hyperammonemia and survived the neonatal period. Two patients with carbamoyl phosphate synthetase deficiency and two with ornithine transcarbamylase deficiency have subsequently died; three additional patients with the latter disorder have received orthotopic liver transplants. Our experience suggests that these surviving patients have had a more favorable neurologic outcome than patients rescued from neonatal hyperammonemic coma. However, all of them require a burdensome medical regimen and may have handicaps that include impairment of development and recurrent episodes of hyperammonemia. Further, those with deficiency of carbamoyl phosphate synthetase or ornithine transcarbamylase have a high mortality rate.
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PMID:Prospective treatment of urea cycle disorders. 172 Apr 58

Activities of the specific enzymes of the inherited hyperammonemic syndromes (carbamoyl-phosphate synthetase CPS), ornithine transcarbamylase (OTC), arginine-succinate-synthetase (ASS), arginine-succinate-lyase (ASL) and arginase (ASE) were measured in a liver biopsy specimen of a 2 years-old girl suffering from chronic hyperammonemia and in the erythrocyte- and leukocyte-homogenisate of her parents. The activity of OTC in liver homogenisate of the patient was 62.9 percent; in the leukocytes of the parents it was 78.5 percent (in mother) and 102 per cent (in the father) as compared to the controls. Our patient proved to be a symptomatic carrier of OTC deficiency and her mother proved to be an asymptomatic carrier.
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PMID:Congenital hyperammonemia: symptomatic carrier girl patient and her asymptomatic heterozygous mother for ornithine transcarbamylase (OTC) deficiency: specific enzyme diagnostic and kinetic investigations for the detection of heterozygous genostatus. 174 44

The mouse hepatoma BWTG3 has been tested for its ability to grow in three different media that select for traits normally expressed in adult liver: homocysteine medium to select for cystathionine synthase (CS), tyrosine-free medium for phenylalanine hydroxylase (PH), and ornithine medium for carbamylphosphate synthetase-I (CPS-I) and ornithine transcarbamylase (OTC). In no case were the cells immediately capable of bulk growth, showing that all these traits were in some degree deficient. However, the cultures in homocysteine medium and in tyrosine-free medium both gave rise, spontaneously, to growing clones with frequencies of approximately 10(-3) and 10(-5), respectively. The deficiencies of CS and PH were accordingly excluded from further study, in view of their inherent instability. In contrast, no colonies ever formed in ornithine medium. Though neither CPS-I nor OTC were detectable in stock BWTG3 cells, it was found that CPS-I was readily inducible by hormones. The deficiency of OTC, however, appeared to be totally stable showing no reversion in response either to hormones or to azacytidine treatment. This deficiency was investigated by fusing the hepatoma to OTC+ liver cells prepared from normal or sparse-fur (spf) mice. Sparse-fur mice were used because their OTC is mutant and has a distinctive pH-dependence. OTC+ hybrids were readily produced, without the need for any specific selection for OTC, and, in one case at least, with only minimal chromosome segregation. In all the OTC+ hybrids made with spf cells, there was clear reactivation of the wild-type, hepatoma-derived OTC gene.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:BWTG3 hepatoma cells can acquire phenylalanine hydroxylase, cystathionine synthase and CPS-I without genetic manipulation, but activation of the silent OTC gene requires cell fusion with hepatocytes. 186 Sep 1

We describe a male infant with congenital hyperammonaemia due to partial carbamylphosphate synthetase-I (CPS-I) deficiency. At 21 days of age, he had convulsions and at 53 days of age hyperammonaemic coma. Therapy with sodium benzoate, L-arginine, essential amino acids, L-carnitine and peritoneal dialysis lowered the blood ammonia levels, and his clinical manifestations improved. The CPS-I activity in liver tissue obtained by open biopsy was about 25.6% of normal values. The serum and urine free carnitine levels in the patient decreased during the hyperammonaemic crisis and were low at 7 months of age. After oral administration of L-carnitine (10 mg/kg per day) at 7 months of age, the mean blood ammonia levels decreased significantly, accompanied by an increase in serum and urine free carnitine levels. We propose the use of L-carnitine therapy to prevent secondary carnitine deficiency in patients with CPS-I deficiency as well as ornithine transcarbamylase (OTC) deficiency.
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PMID:A case of carbamylphosphate synthetase-I deficiency associated with secondary carnitine deficiency--L-carnitine treatment of CPS-I deficiency. 230 75

Of the two mitochondrial enzymes of the urea cycle, carbamoyl phosphate synthetase (CPS) was and ornithine transcarbamylase (OTC) was not inactivated by the Fe3+-oxygen-ascorbate model system for mixed-function oxidation [R. L. Levine, (1983) J. Biol. Chem. 258, 11828-11833]. The susceptibility of OTC was not increased by its substrates, products, or inhibitors, whereas that of CPS was markedly increased by acetylglutamate (its allosteric activator) when ATP was absent. Thus, acetylglutamate binds in the absence of ATP and exposes to oxidation essential groups of the enzyme. We estimate for this binding a KD value of 1.6 mM, which greatly exceeds the KD values (less than 10 microM) determined in the presence of ATP and bicarbonate. ATP, and even more, mixtures of ATP and bicarbonate protected CPS from inactivation. Acetylglutamate exposes the site for the ATP molecule that yields Pi, and it appears that ATP protects by binding at this site. Experiments of limited proteolysis with elastase suggest that oxidation prevents this binding of ATP and show that it accelerates cleavage of CPS by the protease, thus supporting the idea that oxidation may precede proteolysis. Trypsin, chymotrypsin, and papain also hydrolyze the oxidized enzyme considerably faster than the native enzyme. Our results also support the idea that oxidative inactivation is site specific and requires sites on the enzyme for Me2+ and, possibly, for a nucleotide.
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PMID:Inactivation of mitochondrial carbamoyl phosphate synthetase induced by ascorbate, oxygen, and Fe3+ in the presence of acetylglutamate: protection by ATP and HCO3- and lack of inactivation of ornithine transcarbamylase. 282 12

The effects of corticosteroids and pancreatic hormones on two mitochondrial enzymes of ureagenesis, carbamyl phosphate synthetase-I (CPS-I) and ornithine transcarbamylase (OTC), were investigated and compared in fetal rat liver. Supplementing hydrocortisone acetate (50 micrograms) to 18.5-day-old fetuses significantly increased CPS-I activity (by 36%) and decreased OTC activity (by 23%). An actinomycin D supply (2 micrograms) to 18.5-day-old fetuses prematurely increased OTC activity and decreased fetal insulin level (by 42%). This treatment had no effect on CPS-I activity. Glucagon supply (25 micrograms) during the late fetal period increased both activities within 2 h, while dibutyryl-cAMP enhanced OTC activity 17 h later. These results suggested that the fetal development of CPS-I activity was under the control of corticosteroids and glucagon. In contrast, corticosteroid hormones produced an inhibitory effect on OTC activity. This might be explained by the permissive effect of corticosteroids on insulin action, since insulin might act as a repressor in utero of enzyme development. Thus, the paradoxical effect of actinomycin D on OTC activity was probably due to the decrease in fetal insulinemia.
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PMID:Effects of corticosteroids and pancreatic hormones on carbamyl phosphate synthetase-I and ornithine transcarbamylase activities in fetal rat liver. 299 95

A partial carbamylphosphate synthetase (CPS: EC 6.3.4.16) deficiency (McKusick 23730) was found in a male child who presented with generalized convulsions, rickets and apnoeic attacks at six months of age. By his second year he showed serious developmental delay and a gut biopsy revealed an absence of CPS activity with an elevated ornithine transcarbamylase activity. Analysis of the gut biopsy sample on SDS-polyacrylamide gels, followed by electrophoretic transfer to a nitrocellulose filter probed with monospecific antibodies to CPS showed that the child had normal levels of immunoreactive enzyme, but instead of one band corresponding to normal CPS with a subunit size of 165,000 u, the patient had three immunoreactive bands, one larger and two smaller than that found in normal controls. The genetic defect in this child therefore results in an unusual form of CPS being made which has markedly reduced enzyme activity.
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PMID:Immunological evidence for a carbamylphosphate synthetase lesion resulting in the formation of enzyme with altered sub-unit size. 310 74

Foetal hepatocytes obtained from rats at different stages were cultured in order to investigate the inducibility of the five urea-cycle enzymes by glucagon and dibutyryl cyclic AMP (Bt2cAMP). When 18.5-day-old hepatocytes were cultured for 3 days with 10(-7) M glucagon, the activities of carbamoyl phosphate synthetase (CPS), argininosuccinase (ASL) and arginase were increased by 1.4-, 1.8- and 1.9-fold, respectively, as compared to controls. These effects were mimicked by 10(-4) M Bt2cAMP, but the activities of ornithine transcarbamylase (OTC) and argininosuccinate synthetase (ASS) were never changed by the addition of these compounds. Hepatocytes cultured at earlier stages were not responsive to glucagon unless dexamethasone was added simultaneously, suggesting that this steroid might induce some steps necessary for glucagon action. Bt2cAMP was effective as early as day 16.5 without requiring the presence of steroids. In addition, the effect of the cyclic nucleotide appeared additive or synergistic with that of dexamethasone. The simultaneous addition of actinomycin D did not affect the glucagon-induced increase in enzyme levels, thus suggesting a post-transcriptional effect of the hormone on the foetal enzyme activities. Insulin itself did not have any effect on the basal level of the enzyme activities and had only a moderate inhibitory effect on glucagon-induced ASL activity. This slight effect of insulin is in contrast with the marked inhibitory effect of dexamethasone on this enzyme activity that we described previously.
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PMID:Induction of the five urea-cycle enzymes by glucagon in cultured foetal rat hepatocytes. 332 26

We investigated the distribution of the nuclear encoded mitochondrial enzymes, carbamylphosphate synthetase (CPS; EC 6.3.4.16) and ornithine transcarbamylase (OTC; EC 2.1.3.3) in liver by immunocytochemistry on ultrathin sections using the protein A-gold technique. Both enzymes were found to be present as aggregates in the cytoplasm of hepatocytes, in association with ER membranes adjacent to mitochondria. Clusters of the enzymes were also found inside the mitochondria. The aggregation of these enzymes was found only with antibodies to CPS and OTC and not with antibodies against albumin or with IgG from unimmunized serum, nor were aggregates found in cells other than hepatocytes. The results are suggestive of localized uptake of clusters of enzyme or co-translational uptake of enzyme at discrete localizations and that endoplasmic reticulum (ER) associations may be necessary for uptake of the percursor forms of CPS and OTC. The possible involvement is discussed of micropinosomes which are seen associated with inner membrane, intermembrane space and outer membrane in mitochondria obtained from a perinuclear pellet where ER and mitochondria are frequently found in close association.
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PMID:Import of carbamylphosphate synthetase and ornithine transcarbamylase into mitochondria of rat liver: detection of aggregates of enzyme in cytoplasm and mitochondria using immunoelectron microscopy with the protein A-gold method. 352 29


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