Showing papers on "Urea cycle published in 2010"
TL;DR: It is revealed that lysine acetylation is a prevalent modification in enzymes that catalyze intermediate metabolism, and plays a major role in metabolic regulation.
Abstract: Protein lysine acetylation has emerged as a key posttranslational modification in cellular regulation, in particular through the modification of histones and nuclear transcription regulators. We show that lysine acetylation is a prevalent modification in enzymes that catalyze intermediate metabolism. Virtually every enzyme in glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, the urea cycle, fatty acid metabolism, and glycogen metabolism was found to be acetylated in human liver tissue. The concentration of metabolic fuels, such as glucose, amino acids, and fatty acids, influenced the acetylation status of metabolic enzymes. Acetylation activated enoyl–coenzyme A hydratase/3-hydroxyacyl–coenzyme A dehydrogenase in fatty acid oxidation and malate dehydrogenase in the TCA cycle, inhibited argininosuccinate lyase in the urea cycle, and destabilized phosphoenolpyruvate carboxykinase in gluconeogenesis. Our study reveals that acetylation plays a major role in metabolic regulation.
1,668 citations
TL;DR: This review summarizes what is known about urea sources and availability, use of Urea as an organic N growth source, rates of urea uptake, enzymes involved in urea metabolism (i.e. urea transporters, urease, UALase), and the biochemical and molecular regulation ofUrea transport and metabolic enzymes, with an emphasis on the potential for genomic sequence data to continue to provide important new insights.
Abstract: Urea synthesized commercially and formed naturally as a by-product of cellular metab- olism is an important source of nitrogen (N) for primary producers in aquatic ecosystems. Although urea is usually present at ambient concentrations below 1 µM-N, it can contribute 50% or more of the total N used by planktonic communities. Urea may be produced intracellularly via purine catabolism and/or the urea cycle. In many bacteria and eukaryotes, urea in the cell can be broken down by ure- ase into NH4 + and CO2. In addition, some bacteria and eukaryotes use urea amidolyase (UALase) to decompose urea. The regulation of urea uptake appears to differ from the regulation of urease activ- ity, and newly available genomic sequence data reveal that urea transporters in eukaryotic phyto- plankton are distinct from those present in Cyanobacteria and heterotrophic bacteria with different energy sources and possibly different enzyme kinetics. The diverse metabolic pathways of urea transport, production, and decomposition may contribute to differences in the role that urea plays in the physiology and ecology of different species, and in the role that each species plays in the biogeo- chemistry of urea. This review summarizes what is known about urea sources and availability, use of urea as an organic N growth source, rates of urea uptake, enzymes involved in urea metabolism (i.e. urea transporters, urease, UALase), and the biochemical and molecular regulation of urea transport and metabolic enzymes, with an emphasis on the potential for genomic sequence data to continue to provide important new insights.
234 citations
TL;DR: NRC recommendations may not be adequate to support maximal growth, support arginine-depleting immune responses, and prevent the onset of pulmonary hypertension in broilers reared under rigorous environmental conditions.
Abstract: Arginine is an essential amino acid for chickens due to the absence of a functional urea cycle in birds. Arginine plays critical roles in metabolic pathways associated with growth and immune-compet...
124 citations
TL;DR: It is shown that ammonium exposure alters several amino acid pathways and neurotransmitter systems, cerebral energy, nitric oxide synthesis, axonal and dendritic growth, signal transduction pathways, as well as K(+) and water channels, which may eventually lead to energy deficit, oxidative stress and cell death.
121 citations
TL;DR: Because ammonia generated during fasting is toxic, SIRT5 protein might play a protective role by converting ammonia to non-toxic urea through deacetylation and activation of CPS1, a key enzyme of the urea cycle that catalyzes condensation of ammonia with bicarbonate to form carbamoyl phosphate.
108 citations
TL;DR: The genetics, stroke pathophysiology, clinical presentation, diagnosis, and treatment of Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes, and homocystinuria, organic acidurias, and urea cycle disorders are discussed.
Abstract: Several inherited metabolic disorders have been associated with stroke particularly in newborns, children, and young adults. In part 1, we discussed the genetics, stroke pathophysiology, clinical presentation, diagnosis, and treatment of Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. In part 2, we overview homocystinuria, organic acidurias, and urea cycle disorders.
101 citations
TL;DR: It is clear that patients with urea cycle disorders also have altered creatine metabolism, and there is some evidence that this may decrease brain creatine levels which may contribute to the neurological symptoms exhibited by these patients.
89 citations
TL;DR: The cows in the present study experienced a marked metabolic load in early lactation, as presented by changes in plasma metabolites and hormones, and responded accordingly with upregulation and downregulation of almost all candidate genes involved in metabolic processes in the liver.
78 citations
TL;DR: This review discusses the results of neuroimaging studies performed as part of the NIH funded Rare Diseases Clinical Research Center in Urea Cycle Disorders and focuses on biomarkers of brain injury in ornithine transcarbamylase deficiency (OTCD).
66 citations
TL;DR: It is confirmed that all the urea cycle enzyme genes are expressed in the AD brain and the presence of the rare arginase 2 allele rs742869 was associated with an increase in the risk of AD in men and with an earlier age-at-onset for both genders.
Abstract: Since previous observations indicated that the urea cycle may have a role in the Alzheimer's disease (AD) process, we set out to quantify the expression of each gene involved in the urea cycle in control and AD brains and establish whether these genes could be genetic determinants of AD. We first confirmed that all the urea cycle enzyme genes are expressed in the AD brain. The expression of arginase 2 was greater in the AD brain than in the control brain. The presence of the rare arginase 2 allele rs742869 was associated with an increase in the risk of AD in men and with an earlier age-at-onset for both genders. None of the other genes in the pathway appeared to be differentially expressed in the AD brain or act as genetic determinants of the disease.
65 citations
TL;DR: This study identified metabolites previously not known to be associated with insulin resistance and points to the utility of metabolomics analysis in identifying unrecognized biochemical pathways that may be important in understanding the pathophysiology of diabetes.
Abstract: When fed with a high-fat safflower oil diet for 3 wk, wild-type mice develop hepatic insulin resistance, whereas mice lacking glycerol-3-phosphate acyltransferase-1 retain insulin sensitivity. We examined early changes in the development of insulin resistance via liver and plasma metabolome analyses that compared wild-type and glycerol-3-phosphate acyltransferase-deficient mice fed with either a low-fat or the safflower oil diet for 3 wk. We reasoned that diet-induced changes in metabolites that occurred only in the wild-type mice would reflect those metabolites that were specifically related to hepatic insulin resistance. Of the identifiable metabolites (from 322 metabolites) in liver, wild-type mice fed with the high-fat diet had increases in urea cycle intermediates, consistent with increased deamination of amino acids used for gluconeogenesis. Also increased were stearoylglycerol, gluconate, glucarate, 2-deoxyuridine, and pantothenate. Decreases were observed in S-adenosylhomocysteine, lactate, the bile acid taurocholate, and 1,5-anhydroglucitol, a previously identified marker of short-term glycemic control. Of the identifiable metabolites (from 258 metabolites) in plasma, wild-type mice fed with the high-fat diet had increases in plasma stearate and two pyrimidine-related metabolites, whereas decreases were found in plasma bradykinin, α-ketoglutarate, taurocholate, and the tryptophan metabolite, kynurenine. This study identified metabolites previously not known to be associated with insulin resistance and points to the utility of metabolomics analysis in identifying unrecognized biochemical pathways that may be important in understanding the pathophysiology of diabetes.
TL;DR: For either condition, N-carbamylglutamate (NCG), a stable functional analog of NAG, was found to either restore or improve the deficient urea-cycle function.
TL;DR: A comprehensive compilation of clinical CPS1 mutations is provided, and it is discussed how structural knowledge of CPS enzymes in combination with in vitro analyses can be a useful tool for diagnosis of CPS1D.
TL;DR: NAGS deficiency can be successfully treated with NCG and arginine hydrochloride with favourable outcome and molecular diagnostic rather than enzyme analysis should be used in patients with suspected NAGS deficiency.
Abstract: N-Acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder, which may present in the neonatal period with severe hyperammonemia and marked neurological impairment. We report on a Turkish family with a patient who died due to hyperammonemia in the neonatal period. Reduced activity of NAGS and carbamyl phosphate synthetase were found at autopsy. A second child who developed hyperammonemia on the second day of life was immediately treated with arginine hydrochloride, sodium benzoate and protein restriction. After NAGS deficiency was suspected by enzyme analysis, sodium benzoate was replaced by N-carbamylglutamate (NCG). A third child who developed slight hyperammonemia on the third day of life was treated with NCG before enzyme analysis confirmed reduced NAGS activity. Neither of the patients developed hyperammonemia in the following years. After the human NAGS gene was identified, mutation analysis revealed that the older sibling on NCG therapy was homozygous for a 971G>A (W324X) mutation. The parents and the younger sibling were heterozygous. Therapy was continued in the older sibling until now without any adverse effects and favourable neurodevelopment outcome. In the younger sibling, therapy was stopped without any deterioration of urea cycle function. NAGS deficiency can be successfully treated with NCG and arginine hydrochloride with favourable outcome. Molecular diagnostic rather than enzyme analysis should be used in patients with suspected NAGS deficiency.
TL;DR: The results of the present work indicate that the glutaminase activity in periportal hepatocytes is not the rate-controlling step of the glutamine-derived nitrogen flow through the urea cycle, corroborate recent work indicating that ureogenesis is also an important ammonia-detoxifying mechanism in cells situated downstream to the perip Mortal region.
Abstract: Glutaminase predominates in periportal hepatocytes and it has been proposed that it determines the glutamine-derived nitrogen flow through the urea cycle. Glutamine-derived urea production should, thus, be considerably faster in periportal hepatocytes. This postulate, based on indirect observations, has not yet been unequivocally demonstrated, making a direct investigation of ureogenesis from glutamine highly desirable. Zonation of glutamine metabolism was investigated in the bivascularly perfused rat liver with [U-14C]glutamine infusion (0.6 mM) into the portal vein (antegrade perfusion) or into the hepatic vein (retrograde perfusion). Ammonia infusion into the hepatic artery in retrograde and antegrade perfusion allowed to promote glutamine metabolism in the periportal region and in the whole liver parenchyma, respectively. The results revealed that the space-normalized glutamine uptake, indicated by 14CO2 production, gluconeogenesis, lactate production and the associated oxygen uptake, predominates in the periportal region. Periportal predominance was especially pronounced for gluconeogenesis. Ureogenesis, however, tended to be uniformly distributed over the whole liver parenchyma at low ammonia concentrations (up to 1.0 mM); periportal predominance was found only at ammonia concentrations above 1 mM. The proportions between the carbon and nitrogen fluxes in periportal cells are not the same along the liver acinus. In conclusion, the results of the present work indicate that the glutaminase activity in periportal hepatocytes is not the rate-controlling step of the glutamine-derived nitrogen flow through the urea cycle. The findings corroborate recent work indicating that ureogenesis is also an important ammonia-detoxifying mechanism in cells situated downstream to the periportal region.
TL;DR: The design, synthesis, and evaluation of a series of 2-aminoimidazole amino acids represent new leads for the development of arginase inhibitors with promising pharmacological profiles are suggested.
Abstract: Arginase, a key metalloenzyme of the urea cycle that converts l-arginine into l-ornithine and urea, is presently considered a pharmaceutical target for the management of diseases associated with ab...
TL;DR: Exclusively vegetarian diets may not provide an adequate supply of Arg, which is required for maximum production and for the immune system of current broiler lineages, because of the antagonistic relationship between these amino acids.
Abstract: Due to the lack of a complete urea cycle, uricotelic species, such as broilers, are not able to synthesize de novo arginine (Arg), thus depending exclusively on dietary Arg. High levels of dietary lysine (Lys) increase the demand for Arg because of the antagonistic relationship between these amino acids. The Arg-Lys antagonism promotes an expressive increase in the renal Arg activity and consequently induces the degradation of Arg and the decrease in the activity of glycine amidinotransferase, an enzyme that uses Arg in the synthesis of muscle creatin. Arg is considered an important modulator of immunological and physiological processes. The degradation of Arg produces ornithine, a precursor of polyamines that are key to cell division, DNA synthesis, and cell cycle regulation. Arg participates in the synthesis of nitric oxide (NO), a highly reactive free radical in cells and membranes and participates in several cell processes, including in neurotransmission and immune response. Arg is also considered a potent secretagogue of insulin, growth hormone, and IGF-I in the blood stream. Exclusively vegetarian diets may not provide an adequate supply of Arg, which is required for maximum production and for the immune system of current broiler lineages.
TL;DR: The results show that grafts with a cold ischemia time exceeding 15 h and steatosis should not be accepted for hepatocyte transplantation, and livers from non-heart-beating donors are apparently a potential suitable source of hepatocytes, which could enlarge the liver donor pool.
TL;DR: It is recommended that unexplained or nonresponsive neuropsychiatric/neurodevelopmental symptoms appearing during childhood or adolescence be followed by a study of ammonia and amino acid plasmatic levels to rule out a urea cycle disorder.
Abstract: Inherited urea cycle disorders represent one of the most common groups of inborn errors of metabolism. Late-onset urea cycle disorders caused by partial enzyme deficiencies may present with unexpected clinical phenotypes. We report 9 patients followed up in our hospital presenting late-onset urea cycle disorders who initially manifested neuropsychiatric/neurodevelopmental symptoms (the most prevalent neuropsychiatric/neurodevelopmental diagnoses were mental retardation, attention-deficit hyperactivity disorder [ADHD], language disorder, and delirium). Generally, these clinical pictures did not benefit from pharmacological treatment. Conversely, dietary treatment improved the symptoms. Regarding biochemical data, 2 patients showed normal ammonium but high glutamine levels. This study highlights the fact that neuropsychiatric/neurodevelopmental findings are common among the initial symptomatology of late-onset urea cycle disorders. The authors recommend that unexplained or nonresponsive neuropsychiatric/neurodevelopmental symptoms appearing during childhood or adolescence be followed by a study of ammonia and amino acid plasmatic levels to rule out a urea cycle disorder.
TL;DR: Urea kinetics in cattle fed grain-based diets were largely related to the amount of N consumed, and ruminal microbes were more dependent on N recycling when the protein supplement was largely resistant to ruminal degradation.
Abstract: We studied the effects of supplementing N as distillers dried grains with solubles (DDGS) or urea to steers consuming corn-based diets. Six ruminally and duodenally cannulated steers (244 kg) were used in 2 concurrent 3 × 3 Latin squares and fed 1 of 3 corn-based diets: control (10.2% CP), urea (13.3% CP), or DDGS (14.9% CP). Periods were 14 d, with 9 d for adaptation and 5 d for collection of urine and feces. Urinary 15 N 15 N-urea enrichments, resulting from venous infusions of 15 N 15 N-urea, were used to measure urea kinetics. Dry matter intake (6.0 kg/d) was not affected by treatment, but N intake differed (99, 151, and 123 g/d for the control, DDGS, and urea treatments, respectively). Urea-N synthesis tended to be greater (P = 0.09) for DDGS (118 g/d) than for the control treatment (52 g/d), with the urea treatment (86 g/d) being intermediate. Urea-N excreted in the urine was greater (P < 0.03) for the DDGS (35 g/d) and urea treatments (29 g/d) than for the control treatment (13 g/d). Gastrointestinal entry of urea-N was not statistically different among treatments (P = 0.25), but was numerically greatest for DDGS (83 g/d), intermediate for urea (57 g/d), and least for the control (39 g/d). The amount of urea-N returned to the ornithine cycle tended to be greater (P = 0.09) for the DDGS treatment (47 g/d) than for the urea (27 g/d) or control treatment (16 g/d). The fraction of recycled urea-N that was apparently used for anabolism tended (P = 0.14) to be greater for the control treatment (0.56) than for the DDGS treatment (0.31), with the urea treatment (0.45) being intermediate, but no differences were observed among treatments in the amount of urea-N used for anabolism (P = 0.66). Urea kinetics in cattle fed grain-based diets were largely related to the amount of N consumed. The percentage of urea production that was captured by ruminal bacteria was greater (P < 0.03) for the control treatment (42%) than for the DDGS (25%) or urea treatment (22%), but the percentage of duodenal microbial N flow that was derived from recycled urea-N tended (P = 0.10) to be greater for the DDGS treatment (35%) than for the urea (22%) or control treatment (17%). Thus, ruminal microbes were more dependent on N recycling when the protein supplement was largely resistant to ruminal degradation.
TL;DR: The results show that hyperhomocysteinemia, whether caused by a genetic mutation or diet, alters the abundance of several liver proteins involved in homocysteine/methionine metabolism, the urea cycle, and antioxidant defense.
TL;DR: It is proposed that fuel partitioning in vitamin A deficiency may shift from fatty acids to protein catabolism as an energy source and provide an explanation for the role of vitamin A in protein turnover, development, and growth.
Abstract: Chronic vitamin A deficiency induces a substantial delay in the rates of weight and height gain in both humans and experimental animals. This effect has been associated with an impaired nutrient metabolism and loss of body protein. Therefore, we analyzed the effect of vitamin A deficiency on endogenous proteolysis and nitrogen metabolism and its reversibility with all-trans retinoic acid (RA). Male weanling rats, housed in pairs, were pair-fed a vitamin A-deficient (VAD) or control diet until they were 60 d old. A group of deficient rats were further treated with daily intraperitoneal injections of all-trans RA for 10 d. Final body and tissue (i.e. liver and heart) weights were significantly lower and tissue:body weight ratios were similar in VAD rats and in controls. Conversely, the epididymal white fat:body weight ratio and the plasma concentrations of alanine aminotransferase and adiponectin were significantly higher in VAD rats, which also had hepatic macrovesicular lipid accumulations. Plasma and gastrocnemius muscle 3-methylhistidine, urine nitrogen, and plasma and urine urea concentrations were all significantly higher in the VAD group. The expression of the genes encoding urea cycle enzymes and their activities increased in VAD livers. These changes were partially reverted by all-trans RA. We propose that fuel partitioning in vitamin A deficiency may shift from fatty acids to protein catabolism as an energy source. Our results emphasize the importance of vitamin A on the energy balance control system and they provide an explanation for the role of vitamin A in protein turnover, development, and growth.
TL;DR: Alternative pathway therapy with sodium phenylbutyrate causes a substantial impact on the metabolism of branched chain amino acids in patients with urea cycle disorders, implying that better titration of protein restriction can be achieved with branching chain amino acid supplementation in these patients who are on alternative pathway therapy.
01 Jun 2010
TL;DR: A case of severe hyperammonemia with subsequent brain herniation in an adult man after renal transplantation after successful surgery and an initially uneventful postoperative course, the patient developed significant mental status changes associated with seizure activity.
Abstract: We present a case of severe hyperammonemia with subsequent brain herniation in an adult man after renal transplantation. After successful surgery and an initially uneventful postoperative course, the patient developed significant mental status changes associated with seizure activity. His condition rapidly deteriorated, requiring mechanical ventilation and cardiovascular support. Laboratory studies at that time demonstrated an increased serum ammonia level without evidence of liver or kidney dysfunction. Further investigation revealed an increased orotic acid level in the urine, suggesting a urea cycle disorder (UCD). Despite aggressive therapy, the patient's condition continued to deteriorate. Magnetic resonance imaging demonstrated severe brain edema with no cerebral perfusion; after consultation with the family, care was withdrawn. The combination of hyperammonemia and elevated urine orotic acid with normal liver and kidney function suggested a UCD. It is important to note that patients with a UCD may be free of symptoms for many years. Several factors are able to trigger the disease in adulthood, leading to encephalopathy and death. In this case, the patient's seizures were initially assumed to be a side effect of immunosuppressive therapy. Further diagnostic measures were only performed late in the course of the disease, which delayed the diagnosis of UCD.
TL;DR: This case illustrates how late presentation of OTC deficiency in a non-specialist centre can be difficult to differentiate from drug abuse, psychiatric illness or encephalopathy.
Abstract: There is a lack of awareness of acutely presenting inborn errors of metabolism in adults, of which the X-linked urea cycle defect ornithine transcarbamylase (OTC) deficiency is an example, many comparatively mild mutations having been identified. In male hemizygotes clinical manifestations and age at presentation vary and depend on the mutation. In female heterozygotes the clinical spectrum depends on the extent to which the abnormal gene is expressed. Milder versions of the defect may not cause clear clinical symptoms and may remain unrecognized until the person is subjected to an unusually high nitrogen load when they develop severe hyperammonaemia. During acute episodes liver enzymes may be normal or only slightly elevated and occasionally accompanied by coagulopathy, but the key finding is hyperammonaemia. Boys with these milder forms may exhibit abnormal behaviour and be diagnosed with attention deficit hyperactivity disorder. This case illustrates how late presentation of OTC deficiency in a non-specialist centre can be difficult to differentiate from drug abuse, psychiatric illness or encephalopathy. Failure to measure blood ammonia in adults with unexplained key symptoms - particularly prolonged vomiting without diarrhoea and altered mental state/hallucinations, or to recognize the significance of elevated blood ammonia without evidence of liver decompensation can lead to delayed or missed diagnosis.
TL;DR: This case illustrates the importance of screening patients with idiopathic ALF for a metabolic disorder, and a prompt diagnosis and timely treatment enabled a patient with a second episode of ALF to recover fully without the need for liver transplantation.
01 Jan 2010
TL;DR: Isotopes have enabled an appreciation of the degree to which ureagenesis is compromised in patients with urea cycle defects, and the use of isotopes affords an ideal tool with which to gauge the efficacy of therapeutic interventions to augment residual flux through the cycle.
TL;DR: This newly developed LC-MS/MS represents a robust, sensitive, and rapid method that allows simultaneous determination of the five compounds in plasma and urine from children with inborn errors of urea synthesis.
Abstract: Inborn errors of urea metabolism result in hyperammonemia Treatment of urea cycle disorders can effectively lower plasma ammonium levels and results in survival in the majority of patients Available medications for treating urea cycle disorders include sodium benzoate (BA), sodium phenylacetate (PAA), and sodium phenylbutyrate (PBA) and are given to provide alternate routes for disposition of waste nitrogen excretion In this study, we develop and validate a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of benzoic acid, phenylacetic acid, phenylbutyric acid, phenylacetylglutamine, and hippuric acid in plasma and urine from children with inborn errors of urea synthesis Plasma extracts and diluted urine samples were injected on a reverse-phase column and identified and quantified by selected reaction monitoring (SRM) in negative ion mode Deuterated analogues served as internal standards Analysis time was 7 min Assay precision, accuracy, and linearity and sample stability were determined using enriched samples Quantification limits of the method were 100 ng/ml (03-08 μmol/L) for all analytes, and recoveries were >90% Inter- and intraday relative standard deviations were <10% Our newly developed LC-MS/MS represents a robust, sensitive, and rapid method that allows simultaneous determination of the five compounds in plasma and urine