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Ammonium Metabolism in Humans

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Ammonium Metabolism in Humans METABOLISM CLINICAL AND EXPERIMENTAL XX (2012) XXX– XXX Available online at www.sciencedirect.com Metabolism www.metabolismjournal.com Ammonium metabolism in humans Maria M. Adeva a,⁎, Gema Souto b, Natalia Blanco c, Cristóbal Donapetry a a Hospital General Juan Cardona b Clinical Center of the National Institutes of Health c United Surgical Partners. La Coruña ARTICLE INFO ABSTRACT Article history: Free ammonium ions are produced and consumed during cell metabolism. Glutamine Received 23 March 2012 synthetase utilizes free ammonium ions to produce glutamine in the cytosol whereas Accepted 16 July 2012 glutaminase and glutamate dehydrogenase generate free ammonium ions in the mitochondria from glutamine and glutamate, respectively. Ammonia and bicarbonate are Keywords: condensed in the liver mitochondria to yield carbamoylphosphate initiating the urea cycle, Metabolic alkalosis the major mechanism of ammonium removal in humans. Healthy kidney produces Glutamate dehydrogenase ammonium which may be released into the systemic circulation or excreted into the Glutamine synthetase urine depending predominantly on acid–base status, so that metabolic acidosis increases Glutaminase urinary ammonium excretion while metabolic alkalosis induces the opposite effect. Brain Hyperammonemia and skeletal muscle neither remove nor produce ammonium in normal conditions, but they are able to seize ammonium during hyperammonemia, releasing glutamine. Ammonia in gas phase has been detected in exhaled breath and skin, denoting that these organs may participate in nitrogen elimination. Ammonium homeostasis is profoundly altered in liver failure resulting in hyperammonemia due to the deficient ammonium clearance by the diseased liver and to the development of portal collateral circulation that diverts portal blood with high ammonium content to the systemic blood stream. Although blood ammonium concentration is usually elevated in liver disease, a substantial role of ammonium causing hepatic encephalopathy has not been demonstrated in human clinical studies. Hyperammonemia is also produced in urea cycle disorders and other situations leading to either defective ammonium removal or overproduction of ammonium that overcomes liver clearance capacity. Most diseases resulting in hyperammonemia and cerebral edema are preceded by hyperventilation and respiratory alkalosis of unclear origin that may be caused by the intracellular acidosis occurring in these conditions. © 2012 Elsevier Inc. All rights reserved. + Abbreviations: NH3, ammonia; NH4, ammonium ions; AST, aspartate aminotransferase; ALT, alanine aminotransferase; BCAT, branched-chain amino acids aminotransferase; KGA, kidney-type glutaminase; GAC, glutaminase C; GAM, glutaminase M; GDH1, glutamate dehydrogenase-1; GDH2, glutamate dehydrogenase-2; NAGS, N-acetylglutamate synthase; CPS1, carbamoylphosphate synthetase-1; OTC, ornithine transcarbamylase; ASL, argininosuccinate lyase; ORNT, mitochondrial ornithine transporter; HHH, hyperornithinemia, hyperammonemia and homocitrullinuria; IMP, inosine monophosphate; ALF, acute liver failure; UCD, urea cycle disorder; CPT1, carnitine palmitoyltransferase-1; CPT2, carnitine palmitoyltransferase-2; CACT, carnitine-acylcarnitine translocase; MCAD, medium-chain acyl-CoA dehydrogenase. ⁎ Corresponding author. Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, La Coruña, Spain. Tel.: +34 664 527 257; fax: +34 981 17 81 59. E-mail address: [email protected] (M.M. Adeva). 0026-0495/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.metabol.2012.07.007 Please cite this article as: Adeva MM, et al, Ammonium metabolism in humans, Metabolism (2012), http://dx.doi.org/10.1016/ j.metabol.2012.07.007 2 METABOLISM CLINICAL AND EXPERIMENTAL XX (2012) XXX– XXX Molecular nitrogen (N2) present in the earth atmosphere has and 11 [8,14]. Glutamine synthetase expression and activity to be reduced to ammonia (NH3) by nitrogen-fixing bacteria have been detected in adult human skin, peripheral lympho- living independently in the soil or in the root of leguminous cytes, liver, brain (predominantly in astrocytes), and the plants before it may be utilized by humans. Ammonia gastrointestinal tract, where the activity is highest in the + dissolves in water to form ammonium ions (NH4) and this stomach, although the esophagus and both small and large form of reduced nitrogen is assimilated into amino acids and intestine have little synthesizing capacity [15,16]. In human other nitrogen-containing molecules. In aqueous solutions, skin, glutamine synthetase expression is predominantly ammonia is a base (any compound accepting hydrogen ions) associated with developing keratinocytes. It is present in all forming a conjugated pair with the ammonium ion, according layers of epidermis in young persons and primarily in the + ↔ + to the reversible reaction: NH3 +H NH4 stratum granulosum of elderly persons [17]. Dexamethasone The pKa of the reaction is 9.3, indicating that at this pH and the exposure to ammonium ions strongly induce the + value, the concentration of the ionized (NH4) and unionized activity of glutamine synthetase in spontaneously immortal- (NH3) forms is equal. When the pH of the solution is less than ized human keratinocytes [17]. Glutamine synthetase expres- 9.3, hydrogen ions are incorporated to ammonia to yield sion is also remarkably induced by glucocorticoids in human ammonium ions. Therefore, at physiological plasma and osteoblastic-like cells, while vitamin D inhibits basal and intracellular pH values, virtually only the protonated moiety glucocorticoid-stimulated glutamine synthetase activity by + (NH4) is present in aqueous solutions [1]. The concentration of affecting both the mRNA and protein levels of the enzyme [18]. ammonium in normal human plasma ranges between 11 and In astrocytes, the activity of the enzyme is suppressed by μ 50 mol/L and varies slightly in venous, arterial or capillary increasing the ADP concentration, which may be expected to blood. Free ammonium ions are continually produced and occur when the energy level of the cell is reduced [16]. consumed during cell metabolism in human body tissues. Glutamine synthetase is present at early gestational stages They arise during the breakdown of purine and pyrimidine in human fetuses and placenta [19,20].Humanskeletal derivatives, polyamines, and deamination of several amino muscle is capable of synthesizing glutamine, both during the acids, including glutamine, asparagine, serine, threonine, postprandial period [21,22] and the postabsorptive state [23]. glycine, histidine, lysine, proline, hydroxyproline, homocys- Skeletal muscle of healthy individuals also synthesizes teine, and cystathionine [2]. Some free ammonium ions may glutamine following an intravenous infusion of leucine [21] occasionally be supplied by urease-producing urea-splitting or a mixture of amino acids not containing glutamine [24]. organisms present in saliva [3], gastrointestinal tract [4,5], Congenital deficiency of glutamine synthetase has been urine [6], or other locations [7]. Free ammonium ions are rarely reported. A clinical picture with severe brain malforma- principally consumed to produce glutamine in the cytosol of tions, neonatal seizures, blistering skin lesions, multiorgan some human cells (principally skeletal muscle cells, hepato- failure, and frequent neonatal death has been associated with cytes, keratinocytes, gastrointestinal cells, lymphocytes, and homozygous mutations on the glutamine synthetase gene astrocytes) [8] and to generate carbamoylphosphate predom- [25,26]. Hyperammonemia has not been a consistent finding inantly inside liver mitochondria [9]. Ammonia in gas phase in the few patients reported with congenital glutamine has been detected in human skin [10] and exhaled air [11]. deficiency [25,26]. The activity of glutamine synthetase was The enzymes primarily involved in the metabolism of free markedly diminished with a concomitant reduction in the ammonium ions are the cytosolic enzyme glutamine synthe- amount of glutamine synthetase protein in the liver of two tase [8] and the mitochondrial enzymes glutaminase [12] and patients who had fatal hyperammonemia after orthotopic glutamate dehydrogenase [13]. In a reaction similar to the lung transplantation [27]. There may be a connection between glutaminase reaction, asparaginase yields free ammonium glutamine synthetase expression and some human tumors ions and aspartate from asparagine [2]. In addition, the associated with activating mutations in the gene encoding β- enzyme carbamoylphosphate synthetase-1 catalyzes the catenin, CTNNB1. In children, activating mutations in CTNNB1 condensation of bicarbonate and ammonia to form carba- occur in 80% of hepatoblastoma and 31% of nephroblastoma moylphosphate inside the mitochondrial matrix, starting the tumors. In hepatoblastoma with activated β-catenin, expres- urea cycle in the liver [9]. Aminotransferases (transaminases) sion of glutamine synthetase is detected in tumor areas with are both cytosolic and mitochondrial enzymes engaged in epithelial, but not with mesenchymal differentiation. Gluta- transferring amino groups between amino acid and keto acid mine synthetase expression was not observed in CTNNB1- pairs, without generating or consuming free ammonium ions. mutated nephroblastoma [28]. Important human transaminases include aspartate amino- transferase (AST), alanine aminotransferase (ALT) and branched-chain amino acids aminotransferases (BCAT)
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