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01-06-2013 | Original Paper

Mammalian glutaminase isozymes in brain

Authors: Javier Márquez, Carolina Cardona, José A. Campos-Sandoval, Ana Peñalver, Marta Tosina, José M. Matés, Mercedes Martín-Rufián

Published in: Metabolic Brain Disease | Issue 2/2013

Abstract

Glutamine/glutamate homeostasis must be exquisitely regulated in mammalian brain and glutaminase (GA, E.C. 3.5.1.2) is one of the main enzymes involved. The products of GA reaction, glutamate and ammonia, are essential metabolites for energy and biosynthetic purposes but they are also hazardous compounds at concentrations beyond their normal physiological thresholds. The classical pattern of GA expression in mammals has been recently challenged by the discovery of novel transcript variants and protein isoforms. Furthermore, the interactome of brain GA is also starting to be uncovered adding a new level of regulatory complexity. GA may traffic in brain and unexpected locations, like cytosol and nucleus, have been found for GA isoforms. Finally, the expression of GA in glial cells has been reported and its potential implications in ammonia homeostasis are discussed.

Albrecht J, Norenberg MD (2006) Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 44:788–794PubMedCrossRef

Aledo JC, Gómez-Fabre PM, Olalla L, Márquez J (2000) Identification of two human glutaminase loci and tissue-specific expression of the two related genes. Mammal Genome 11:1107–1110CrossRef

Baverel G, Michoudet C, Martin G (1984) Role of fatty acids in simultaneaus regulation of flux through glutaminase and glutamine synthetase in rat kidney cortex. In: Häussinger D, Sies H (eds) Glutamine metabolism in mammalian tissues. Springer, Berlin, pp 187–202CrossRef

Bragg AD, Amiry-Moghaddam M, Ottersen OP et al (2006) Assembly of a perivascular astrocyte protein scaffold at the mammalian blood–brain barrier is dependent on alpha-syntrophin. Glia 53:879–890PubMedCrossRef

Buschdorf JP, Chew LL, Zhang B et al (2006) Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels. J Cell Sci 119:3337–3350PubMedCrossRef

Elgadi KM, Meguid RA, Qian M et al (1999) Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing. Physiol Genomics 1:51–62PubMed

Häussinger D, Gerok W, Sies H (1982) Regulation of flux through glutaminase and glutamine synthetase in isolated perfused rat liver. Biochim Biophys Acta 755:272–278CrossRef

Häussinger D, Kircheis G, Fischer R, Schliess F, vom Dahl S (2000) Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low grade cerebral edema. J Hepatol 32:1035–1038PubMedCrossRef

Hertz L (1979) Functional interactions between neurons and astrocytes I. Turnover and metabolism of putative amino acid transmitters. Prog Neurobiol 13:277–323PubMedCrossRef

Kvamme E, Svenneby G, Hertz L, Schousboe A (1982) Properties of phosphate activated glutaminase in astrocytes cultured from mouse brain. Neurochem Res 7:761–770PubMedCrossRef

Márquez J, Sánchez-Jiménez F, Medina MA et al (1989) Nitrogen metabolism in tumor bearing mice. Arch Biochem Biophys 268:667–675PubMedCrossRef

Márquez J, López de la Oliva AR, Matés JM et al (2006) Glutaminase: a multifaceted protein not only involved in generating glutamate. Neurochem Int 48:465–71PubMedCrossRef

Márquez J, Matés JM, Segura JA et al (2010) Brain glutaminases. Biomol Concepts 1:3–15CrossRef

Martín-Rufián M, Tosina M, Campos-Sandoval JA et al (2012) Mammalian glutaminase Gls2 gene encodes two functional alternative transcripts by a surrogate promoter usage mechanism. PLoS One 7:e38380. Epub 2012 Jun 5. PMID: 22679499

Norenberg MD, Martínez-Hernández A (1979) Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 161:303–310PubMedCrossRef

Olalla L, Aledo JC, Bannenberg G, Márquez J (2001) The C-terminus of human glutaminase L mediates association with PDZ domain-containing proteins. FEBS Lett 488:116–122PubMedCrossRef

Olalla L, Gutiérrez A, Campos JA et al (2002) Nuclear localization of L-glutaminase in mammalian brain. J Biol Chem 277:38939–38944PubMedCrossRef

Olalla L, Gutiérrez A, Jiménez AJ et al (2008) Expression of scaffolding PDZ protein GIP (Glutaminase-Interacting-Protein) in mammalian brain. J Neurosci Res 86:281–292PubMedCrossRef

Olde Damink SW, Jalan R, Redhead DN, Hayes PC et al (2002) Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPPS. Hepatology 36:1163–1171PubMedCrossRef

Quesada AR, Medina MA, Márquez J et al (1988) Contribution by host tissues to circulating glutamine in mice inoculated with Ehrlich ascites tumor cells. Cancer Res 48:1551–1553PubMed

Rama Rao KV, Jayakumar AR, Norenberg MD (2005) Differential response of glutamine in cultured neurons and astrocytes. J Neurosci Res 79:193–199PubMedCrossRef

Romero-Gómez M, Ramos-Guerrero R, Grande L, de Terán LC et al (2004) Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy. J Hepatol 41:49–54PubMedCrossRef

Romero-Gómez M, Jover M, Del Campo JA, Royo JL et al (2010) Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis. Ann Intern Med 153:281–288PubMedCrossRef

Szeliga M, Matyja E, Obara M et al (2008) Relative expression of mRNAs coding for glutaminase isoforms in CNS tissues and CNS tumors. Neurochem Res 33:808–813PubMedCrossRef

Szeliga M, Obara-Michlewska M, Matyja E et al (2009) Transfection with liver-type glutaminase (LGA) cDNA alteres gene expression and reduces viability, migration and proliferation of T98G glioma cells. Glia 57:1014–1023PubMedCrossRef

Thangavelu K, Pan CQ, Karlberg T et al (2012) Structural basis for the allosteric inhibitory mechanism of human kidney-type glutaminase (KGA) and its regulation by Raf-Mek-Erk signaling in cancer cell metabolism. Proc Natl Acad Sci USA 109:7705–7710PubMedCrossRef

Wang JB, Erickson JW, Fuji R et al (2010) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18:207–219PubMedCrossRef

Title: Mammalian glutaminase isozymes in brain
Authors: Javier Márquez
Carolina Cardona
José A. Campos-Sandoval
Ana Peñalver
Marta Tosina
José M. Matés
Mercedes Martín-Rufián
Publication date: 01-06-2013
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 2/2013
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-012-9356-0

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Mammalian glutaminase isozymes in brain

Abstract

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Abstract

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