Showing papers on "Urea cycle published in 1995"

Inborn Metabolic Diseases : Diagnosis and Treatment

Abstract: Part I: Diagnosis and Treatment: General Principles: Classification and clinical Approach to Inherited Metabolic Diseases in Pediatrics.- Clinical approach to Inherited Metabolic Diseases in Adulthood.- Newborn Screening for Inborn Errors of Metabolism.- Diagnostic Procedures and Postmortem Protocol.- Emergency Treatments.- Part II: Disorders of Carbohydrate Metabolism: Glycogen-Storage Diseases and Related Disorders.- Disorders of Galactose Metabolism.- Disorders of the Pentose Phosphate Pathway.- Disorders of Fructose Metabolism.- Persistent Hyperinsulinemic Hypoglycemia.- Disorders of Glucose Transport.- Part III: Disorders of Mitochondrial Energy Metabolism: Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle.- Disorders of Mitochondrial Fatty Acid Oxidation and Related Metabolic Pathways.- Disorders of Ketogenesis and Ketolysis.- Defects of the Respiratory Chain.- Creatine Deficiency Syndromes.- Part IV: Disorders of Amino Acid Metabolism and Transport: Hyperphenylalaninaemias.- Disorders of Tyrosine Metabolism.- Branched-Chain Organic Acidurias/Acidemias.- Disorders of the Urea Cycle and Related Enzymes.- Disorders of Sulfur Amino Acid Metabolism.- Disorders of Ornithine Metabolism.- Cerebral Organic Acid Disorders and other Disorders of Lysine Catabolism.- Nonketotic Hyperglycinemia (Glycine Encephalopathy).- Disorders of Proline and Serine Metabolism.- Transport Defects of Amino Acids at the Cell Membrane.- Part V : Vitamin-Responsive Disorders: Biotin-Responsive Multiple Carboxylase Deficiency.- Disorders of Cobalamin and Folate Transport and Metabolism.- Part VI: Neurotransmitter and Small Peptide Disorders: Disorders of Neurotransmission.- Disorders in the Metabolism of Glutathione and Imidazole Dipeptides.- Trimethylaminuria and Dimethylglycine Dehydrogenase Deficiency.- Part VII: Disorders of Lipid and Bile Acid Metabolism: Dyslipidemias.- Disorders of Cholesterol Synthesis.- Disorders of Bile Acid Synthesis.- Part VIII: Disorders of Nucleic Acid and Heme Metabolism: Disorders of Purine and Pyrimidine Metabolism.- Disorders of Heme Biosynthesis.- Part IX: Disorders of Metal Transport: Disorders in the Transport of Copper, Zinc and Magnesium.- Part X: Organelle-Related Disorders: Lysosomes, Peroxysomes, and Golgi and Pre-Golgi Systems: Disorders of Sphingolipid Metabolism and Ceroid lipofuscinosis.- Pompe Disease, Mucopolysaccharidoses, and Oligosacharidoses.- Peroxisomal Disorders.- Congenital Disorders of Glycosylation.- Cystinosis.

Arginine metabolism in mammals

Abstract: Arginine (ARG), a semiessential amino acid, is taken up by cells using the y + transport system. ARG synthesis occurs from citrulline mainly in the liver and in the kidney. ARG is metabolized either in ornithine and urea mainly in the liver and the intestine or in citrulline and nitric oxide (NO • ) in a large number of cell types. Ornithine derived from arginine can be metabolized in citrulline (in the context of the urea cycle), in glutamate or in polyamines. Arginine taken up by the intestine is transformed into citrulline which is poorly taken up by the liver but mainly by the kidney. In the kidney, citrulline is transformed into arginine and subsequently released for peripheral tissues. Intestinal transformation of arginine into citrulline plays a keyrole in the metabolic adaptation to high/low protein diets. In the liver, arginine metabolism plays a pivotal role in the urea cycle, the rate of which is conditioned not only to metabolize extranitrogen, but also to maintain the acid-base homeostasis. Immune cells exhibit the ability to synthesize both polyamines and NO • which are potent immunomodulators. The modulation and balance between these two pathways remain to be elucidated. In the context of clinical nutrition, the use of ARG supplemented diets may be advocated while keeping in mind that in severe injury with organ failure such regimens could be detrimental. (J. Nutr. Biochem. 6:402-403, 1995.)

Transcriptional regulation of genes for ornithine cycle enzymes

Abstract: The omithine cycle [1], also called the urea cycle, is an enzyme system that converts ammonia into urea (for recent reviews, see [2-4]) (Figure 1). Ammonia, which is produced mainly by amino acid metabolism, is toxic to higher animals, and must be excreted or detoxified. Fish and amphibian larvae such as tadpoles excrete ammonia from the gills directly into the surrounding water. Mammalian fetuses transfer ammonia to their mothers. Amphibian metamorphosis and mammalian birth, which lead to independent life on land, are accompanied by induction of the ornithine cycle in the liver. This enables the animals to convert ammonia into urea, which is less toxic and can be stored prior to excretion. Urea synthesized in the liver is transported to the kidney, and then excreted. On the other hand, in birds and terrestrial reptiles, ammonia is converted into uric acid, which is practically water-insoluble and can be stored in a solid form in a shelled egg. The ornithine cycle consists of five enzymes (Figure 1); the first enzyme, carbamoyl-phosphate synthase I (CPS; EC 6.3.4.16), and the second enzyme, ornithine transcarbamylase (OTC; EC 2.1.3.3), are located in the mitochondrial matrix, and the remaining three enzymes, argininosuccinate synthase (AS; EC 6.3.4.5), argininosuccinate lyase (AL; EC 4.3.2.1) and arginase (EC 3.5.3.1), are present in the cytosol. CPS and OTC have provided useful systems for the study of intracellular traffic and the processing of nuclear-gene-encoded mitochondrial proteins [5-8]. Inborn errors in any of the five enzymes can result in insufficient ammonia detoxification, leading to hyperammonaemia (reviewed in [4]). Besides these five enzymes, Nacetylglutamate synthase (EC 2.3.1.1), which catalyses the formation of N-acetylglutamate, an obligatory allosteric activator of CPS, participates in the regulation of urea biosynthesis. This enzyme has been purified and characterized from the rat [9,10] and human [11] liver. A deficiency of this enzyme also results in hyperammonaemia [12]. The ornithine cycle enzymes, except for arginase, that are present in non-hepatic tissues (see below) are mainly involved in arginine biosynthesis (as recent reviews, see introductions of [13,14]). In fact, the ornithine cycle is thought to have evolved from the arginine-synthetic pathway (reviewed in [15]). This notion is substantiated by sequence identities between the ornithine cycle enzymes of mammals and the corresponding arginine-biosynthetic enzymes of micro-organisms such as Escherichia coli and yeast (reviewed in [16]).

Urea cycle intermediate kinetics and nitrate excretion at normal and "therapeutic" intakes of arginine in humans

Abstract: We investigated the effects of a high dietary supplement of arginine on plasma arginine, ornithine, and leucine kinetics and on urea production and excretion in five healthy young adult men. Subjec...

3 Urea Cycle in Fish: Molecular and Mitochondrial Studies

Abstract: Publisher Summary This chapter discusses the molecular and mitochondrial studies of the urea cycle in fish. A significant proportion of energy production in fish involves the catabolism and oxidation of proteins and amino acids. Consistent with their water habitat, the major end product of nitrogen metabolism in most fish is ammonia. Carbamoyl phosphate is the precursor for two major metabolic pathways: the urea cycle and pyrimidine nucleotide biosynthesis. The first step of the urea cycle in mammalian and amphibian ureotelic species is catalyzed by carbamoyl-phosphate synthetase I. The function of CPSase II is to catalyze carbamoyl phosphate formation as the first step in pyrimidine nucleotide biosynthesis. The utilization of the amide group of glutamine for the biosynthesis of carbamoyl phosphate in the glutamine-dependent CPSases involves the reaction of glutamine with a cysteine SH group on the enzyme to form a γ-glutamyl thioester intermediate, releasing ammonia, which reacts with an activated intermediate common to all CPSase. The unique co-functioning of glutamine synthetase and CPSase III in ammonia assimilation in the mitochondrial matrix probably reflects the adaptation of urea synthesis for the dual role of ureoosmotic and ureotelic functions.

The Effect of Amino Acids on the Metabolic Fate of 15NH4Cl in Isolated Sheep Hepatocytes

Abstract: Ruminants characteristically absorb a large proportion of dietary nitrogen across the portal-drained viscera as ammonia nitrogen which is detoxified by conversion to urea in the liver. In theory, ammonia can supply both nitrogen atoms of the urea molecule via mitochondrial (carbamoyl phosphate) and cyto-plasmic (aspartate) precursor pathways of the ornithine cycle but the effect of amino acids on the flux of nitrogen from ammonia to each of the two urea nitrogen atoms has not been determined. We report a study designed to determine the distribution of [15N] ammonia between [15N1]urea and [15N2]urea in sheep hepatocytes in response to ammonia concentrations (0.33, 0.67 and 1.00 mM) in the presence or absence of amino acids. In the absence of amino acids, the enrichment of [15N2]urea rose more rapidly during incubations than [15N1]urea and attained enrichments of 66–88% within 5 min of incubation. At the end of 2.5 h of incubation, [15N2]urea represented 60% and 90% of the total urea molecules at low and high ammonia concentrations, respectively. The enrichments of glutamate and aspartate were similar to [15N1]urea in the cells at the end of the incubations, even in the presence of unlabelled amino acids, supporting the concept of mitochondrial ammonia being in equilibrium with cytosolic aspartate formation. In the presence of amino acids basal urea synthesis increased but ammonia uptake and 15NH4Cl conversion to urea was less than in the absence of amino acids. The rate of formation of [15N1]urea was greater in incubations containing amino acids but when ammonia concentration in the media was raised only [15N2]urea flux increased with no change in either [15N1]urea or the unlabelled species. Measurement of media amino acid concentrations after 2.5 h of incubation in the presence of amino acids revealed that arginine, glutamine, glycine and alanine were removed while there was net formation of aspartate, threo-nine, serine, glutamate, and the branched chain amino acids. However, less than 12% of the 15N transfer appeared in free amino acids. The increases in basal and unlabelled urea synthesis in the presence of amino acids could be numerically accounted as the sum of arginine and glutamine removal from incubations. It is concluded that in sheep hepatocytes 15NH4Cl removal leads to quantitative formation of [15N2]urea, even in the presence of a physiological mixture of amino acids. The increase in the formation of the [15N1]urea in the presence of amino acids can be explained by the preferential utilisation of the amide nitrogen of glutamine for urea synthesis.

Sources of arginine for induced nitric oxide synthesis in the isolated perfused liver

Abstract: Hepatocytes can be stimulated to express high levels of inducible nitric oxide synthase (iNOS), which utilizes arginine for nitric oxide (NO) synthesis. Hepatocytes also synthesize and catabolize arginine, an intermediate in the urea cycle, raising the possibility that the urea pathway may provide substrate for hepatic NO synthesis. To identify the sources of arginine for iNOS, we measured the release of NO-2 + NO-3 and urea in isolated rat livers perfused in a recirculation model with a Krebs-Henseleit-bicarbonate buffer containing either no added amino acid, arginine, or precursors for urea synthesis. To induce iNOS expression, rats were injected with killed Corynebacterium parvum (C. parvum) or with endotoxin. In livers from C. parvum- and endotoxin-treated rats, we found that 1) an intracellular source of arginine exists that provides substrate to iNOS; 2) additional exogenous arginine increase NO synthesis, demonstrating that endogenous arginine is insufficient for maximal NO synthesis; and 3) an increase in the rate of endogenous arginine synthesis within the urea cycle is inefficient in increasing NO synthesis, demonstrating the independence of the two pathways in the liver.

Prenatal diagnosis of the urea cycle diseases: A survey of the european cases

Abstract: A European survey of prenatal diagnosis cases involving urea cycle diseases was performed. Citrullinemia was the most frequently investigated disease (108 cases). Other diseases are, in order of frequency, argininosuccinic aciduria (75 cases), ornithine transcarbamylase defect (52 cases), carbamoylphosphate synthetase defect (8 cases), triple H (3 cases), and arginase deficiency (1 case). Only one disease (ornithine transcarbamylase defect) is presently diagnosed using molecular biology methods. © 1995 Wiley-Liss, Inc.

Central pontine myelinolysis as a complication of partial ornithine carbamoyl transferase deficiency

Abstract: Central pontine myelinolysis (CPM) is a demyelinating condition of the central pons with or without associated foci of demyelination in extrapontine areas. We present a case of partial ornithine carbamoyl transferase deficiency in a 5-year-old girl which was complicated by CPM. The patient was a previously undiagnosed girl who presented with mild hyperammonemic encephalopathy with a maximum plasma ammonia level of 376 microM on admission. Laboratory testing established the diagnosis of OCT deficiency, and therapy with hydration and protein restriction was successful in returning the plasma ammonia levels to normal. Five days after correction of her hyperammonemia, the patient developed intractable seizures and coma. Serial MRI scans of the brain revealed the evolution of the characteristic findings of CPM. Plasma ammonia and electrolyte concentrations were well controlled throughout this time. This represents the first description of CPM in a patient with a urea cycle defect.

Dietary arginine deficiency and gut ammonium infusion alter flux of urea cycle intermediates across the portal-drained viscera of pigs.

Abstract: The objective of these experiments in pigs were to test the hypotheses that 1) gut synthetic processes could adapt to additional dietary glutamate or ornithine to meet tissue needs for arginine with feeding arginine-deficient diets and 2) acute elevation of ammonium in the hepatic-portal blood leads to increased glutamine production. Arterial [117 +/- 5.3 (arginine-deficient) vs. 78 +/- 5 (arginine-adequate) mumol/L] and portal ammonium concentrations were elevated in pigs fed arginine-deficient diets. Dietary ornithine, which elevated portal-drained visceral flux of ornithine, corrected the urinary orotic aciduria, but not the hyperammonemia seen with feeding arginine-deficient diets. Concentrations or portal drained viscera fluxes of arginine, ornithine, glutamate and glutamine were not altered even though portal and arterial ammonium concentrations were increased 8- and 3.5-fold with mesenteric infusion of ammonium. It was concluded that 1) substitution of glutamate for glycine or alanine does not alter gut production of ornithine, citrulline or arginine; 2) gut citrulline production is not altered by levels of dietary arginine, ornithine or glutamate; 3) increased ammonium challenge does not lead to increased glutamine production even though peripheral ammonium levels increased over threefold; and 4) provision of arginine for tissue needs will have to be met from dietary sources, as adaptations in gut synthetic processes seem to be refractory to dietary arginine status.

Neurological deterioration in patients with urea cycle disorders under valproate therapy--a cause for concern.

Abstract: 1. Coombs RC, Morgan MEI, Durbin GM, Booth IW, McNeish AS (1990) Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Arch Dis Child 65 : 1067-1071 2. Martinussen M, Brubakk A-M, Linker DT, Vik T, Yao A (1994) Mesenteric blood flow velocity and its relation to circulatory adaptation during the first week of life in healthy terms infants. Pediatr Res 36 : 334-339 3. Meyers RI, Alpan G, Lin E, Clyman RI ( 1991) Patent ductus arteriosus, indomethacin, and intestinal distension: effects on intestinal blood flow and oxygen consumption. Pediatr Res 29 : 569-574 4. Miura S, Suematsu M, Tanaka S, Nagata H, Houzawa S, Suzuki M, Kurose I, Serizawa H, Tsuchiya M (1991) Microcirculatory disturbance in indomethacin-induced intestinal ulcer. Am J Physiol 261 : G213-G219 5. Shepherd AP, Riedel GL (1982) Continuous measurements of intestinal mucosal blood flow by laser-Doppler velocimetry. Am J Physiol 242 : G668-G672

Regulation of argininosuccinate synthetase level by corticosteroid and pancreatic hormones during perinatal period

Abstract: The urea cycle takes place in the hepatocyte of ureothelic animals. The conversion of ammonia into urea involves five reactions. The first 2 take place in the matrix of the mitochondria, the last 2 occur in the cytosol. Argininosuccinate synthetase (AS) is the third reaction of the urea cycle. It catalyses the condensation of citrulline and aspartate into arginonosuccinate. We have previously reported that rat AS activity was present in the cytosol and the outer membrane of the mitochondria. We have shown that, at the activity level, the colocation of AS was changing during fetal and neonatal development and was under the control of corticosteroid and pancreatic hormones. However, an unresolved issue was whether both AS had the same specific activity and that their location was changing during ontogenesis or that the specific activities of mitochondrial and cytosolic enzymes were different and/or modified during this period. In the present report, we compared the compartmentalization of AS activity and protein level in the fetus, the new-born and the adult rat and the role of corticosteroid and pancreatic hormones. Specific activities of both AS remained unchanged during ontogenesis. Glucocorticoids induced an increase in mitochondrial AS while glucagon appeared to induce a concomitant decrease in the level of mitochondrial AS and an increase in cytosolic AS.

Prospects for gene therapy in ornithine carbamoyltransferase deficiency and other urea cycle disorders

Abstract: Although individually inborn errors of metabolism are rare, collectively they contribute significantly to morbidity and mortality in the pediatric age group. There are several reasons why, out of these inborn errors of metabolism, urea cycle disorders have emerged as potentially good candidates for the development of gene therapy. Studies have initially focused on ornithine carbamoyltransferase (OCT) deficiency in part because there are mouse models of this disease and in part because this disease is particularly resistant to current therapies. Both in vivo and ex vivo approaches to gene therapy are being developed for the treatment of urea cycle disorders. Ex vivo gene therapy is appealing because of the long-term expression that can be achieved, but there are clear limitations to this approach. In vivo gene therapy using adenoviral vectors is attractive for several reasons, including the fact that the virus can be administered by intravenous injection, the high levels of expression observed after a single injection, and the rapidity of that expression. Studies of transgene expression in the mouse models of OCT deficiency (OCTD) have been encouraging, but have also provided evidence that the immune system may be involved in mediating two limiting aspects of this technology, transient gene expression and inflammation. Although deletions in adenoviral early genes should limit adenoviral late gene expression and subsequent viral replication, there is in vitro and in vivo evidence of late gene expression after infection with adenoviruses deleted of some of the early genes. Future studies will focus on systematically defining the components of the virus that are recognized by the immune system and mutating these gene products. The development of an approach to gene therapy that safely, stably, and efficiently transduces gene expression holds the promise of revolutionizing the treatment of inborn errors of urea synthesis. © 1995 Wiley-Liss, Inc.

Urea Cycle Defects

Abstract: There are five well-documented urea cycle defects: Carbamyl phosphate synthetase deficiency (CPSD) Ornithine transcarbamylase deficiency (OTCD) Argininosuccinate synthetase deficiency (ASSD), also called citrullinemia Argininosuccinate lyase deficiency (ASLD), also called argininosuccinic aciduria Arginase deficiency, also called hyperargininemia.

Treatment of ammonia intoxication in rats through the use of amino acids from the urea cycle.

Abstract: To evaluate the effectiveness of the treatment of severe ammonia intoxication with amino acids from the urea cycle (arginine, citrulline and ornithine) and alpha-ketoglutarate, 371 rats were used. The rats were poisoned with a lethal ip dose (99.9%) of ammonium acetate. Five min later they were treated with bidistilled water (control) or with standard urea-cycle mixed amino acid solutions containing 2, 4 or 6 mM arginine/kg bw as the marker basic amino acid or 2 mM arginine + 4 mM alpha-ketoglutarate/kg bw. The clinical picture and plasma urea concentration were followed. All 4 treatment groups had higher survival rates (20.83%-35.71%) than did the controls (1.18%). Surviving animals had a less severe clinical picture and presented fewer convulsive episodes than did fatally-poisoned rats. The higher doses of arginine increased the mean survival time of rats which died. The overall mean plasma urea concentration in surviving rats was higher (75.1 +/- 10.8 mg/dL) than in fatally-poisoned rats (44.4 +/- 4.9 mg/dL). Treatment with urea-cycle amino acids increased hepatic detoxication of ammonia; however, there was no relationship between the doses used and survival rates. There was no apparent synergism between urea-cycle amino acids and alpha-ketoglutarate.

Neurotransmitter alterations in congenital hyperammonemia

Abstract: Inborn errors of metabolism are associated with a significant risk of mental retardation and other developmental disabilities. Only rarely, is the mechanism of the neural injury clearly understood. This is particularly true for those inborn errors of metabolism associated with hyperammonemia, principally urea cycle disorders and organic acidemias. Previously, it was assumed that elevated ammonia levels alone could account for the brain injury. However, in vitro studies suggest that ammonia is not particularly toxic to intact neurons. Furthermore, there does not appear to be a direct linkage between the peak blood ammonia level during hyperammonemic coma and subsequent neurodevelopmental outcome. There is, however, a correlation between duration of hyperammonemic coma and outcome, suggesting a secondary, time-influenced mechanism of neural injury. Recent research has focused on excitotoxicity as a possible inducer of neural injury in congenital hyperammonemia. In addition to developmental disabilities, affected children exhibit behavioral abnormalities. An alteration in serotonin metabolism has been proposed as an explanation for these aberrant behaviors during less severe episodes of hyperammonemia. This review focuses on the neurotransmitter abnormalities occuring in congenital hyperammonemia and on new approaches to protecting the brain during hyperammonemic crises. © 1995 Wiley-Liss, Inc.

Nucleotide pool imbalances in the livers of patients with urea cycle disorders associated with increased levels of orotic aciduria.

Abstract: Liver samples obtained at autopsy from patients with ornithine transcarbamylase (OTC) deficiency, a urea cycle disorder that is associated with high levels of orotic acid biosynthesis and excretion were analysed for nucleotide pools As a control, liver samples from patients with a deficiency of mitochondrial carbamyl phosphate synthetase (CPS-I) which is not associated with increased levels of orotic acidurias were also analysed The results show that liver tissue from OTC deficiency patients exhibited an increased ratio of uridine nucleotides to adenosine nucleotides, while in CPS-I deficiency patients, no such increase was noted This study indicates that genetic disorders that are associated with increased loads of orotic acid exhibit abnormally high ratios of uridine to adenosine nucleotides in the liver This type of imbalance is analogous to that seen in the liver of rats and mice exposed to an orotic acid supplemented or an arginine-deficient diet under liver tumor promoting conditions It is likely that an imbalance in nucleotide pools may have a significant role in the pathophysiology associated with these disorders

Review Arginine metabolism in mammals

Abstract: Arginine (ARG), a semi-essential amino acid, is taken up by cells using the y+ transport system. ARG synthesis occurs from citrulline mainly in the liver and in the kidney. ARG is metabolized either in ornithine and urea mainly in the liver and the intestine or in citrulline and nitric oxide (NO’) in a large number of cell types. Ornithine derivedfrom arginine can be metabolized in citrulline (in the context of the urea cycle), in glutamate or in polyamines. Arginine taken up by the intestine is transformed into citrulline which is poorly taken up by the liver but mainly by the kidney. In the kidney, citrulline is transformed into arginine and subsequently released for peripheral tissues. Intestinal transformation of arginine into citrulline plays a key-role in the metabolic adaptation to highllow protein diets. In the liver, arginine metabolism plays a pivotal role in the urea cycle, the rate of which is conditioned not only to metabolize extra-nitrogen, but also to maintain the acid-base homeostasis. Immune cells exhibit the ability to synthesize both polyamines and NO’ which are potent immunomodulators. The modulation and balance between these two pathways remain to be elucidated. In the context of clinical nutrition, the use of ARG supplemented diets may be advocated while keeping in mind that in severe injury with organ failure such regimens could be detrimental. (J. Nutr. Biochem. 6:402-403, 1995.)