The Role of Glutamine Synthetase and Glutamate Dehydrogenase in Cerebral Ammonia Homeostasis
- 23 May 2012
- journal article
- review article
- Published by Springer Science and Business Media LLC in Neurochemical Research
- Vol. 37 (11), 2439-2455
- https://doi.org/10.1007/s11064-012-0803-4
Abstract
In the brain, glutamine synthetase (GS), which is located predominantly in astrocytes, is largely responsible for the removal of both blood-derived and metabolically generated ammonia. Thus, studies with [13N]ammonia have shown that about 25 % of blood-derived ammonia is removed in a single pass through the rat brain and that this ammonia is incorporated primarily into glutamine (amide) in astrocytes. Major pathways for cerebral ammonia generation include the glutaminase reaction and the glutamate dehydrogenase (GDH) reaction. The equilibrium position of the GDH-catalyzed reaction in vitro favors reductive amination of α-ketoglutarate at pH 7.4. Nevertheless, only a small amount of label derived from [13N]ammonia in rat brain is incorporated into glutamate and the α-amine of glutamine in vivo. Most likely the cerebral GDH reaction is drawn normally in the direction of glutamate oxidation (ammonia production) by rapid removal of ammonia as glutamine. Linkage of glutamate/α-ketoglutarate-utilizing aminotransferases with the GDH reaction channels excess amino acid nitrogen toward ammonia for glutamine synthesis. At high ammonia levels and/or when GS is inhibited the GDH reaction coupled with glutamate/α-ketoglutarate-linked aminotransferases may, however, promote the flow of ammonia nitrogen toward synthesis of amino acids. Preliminary evidence suggests an important role for the purine nucleotide cycle (PNC) as an additional source of ammonia in neurons (Net reaction: l-Aspartate + GTP + H2O → Fumarate + GDP + Pi + NH3) and in the beat cycle of ependyma cilia. The link of the PNC to aminotransferases and GDH/GS and its role in cerebral nitrogen metabolism under both normal and pathological (e.g. hyperammonemic encephalopathy) conditions should be a productive area for future research.Keywords
This publication has 110 references indexed in Scilit:
- Cerebral Glutamine Metabolism under Hyperammonemia Determined in vivo by Localized 1H and 15N NMR SpectroscopyJournal of Cerebral Blood Flow & Metabolism, 2011
- 13N as a tracer for studying glutamate metabolismNeurochemistry International, 2011
- Compartmentalized Cerebral Metabolism of [1,6-13C]Glucose Determined by in vivo13C NMR Spectroscopy at 14.1 TFrontiers in Neuroenergetics, 2011
- On the reversibility of glutamate dehydrogenase and the source of hyperammonemia in the hyperinsulinism/hyperammonemia syndromeAdvances in Enzyme Regulation, 2010
- Brain Glutamine Synthesis Requires Neuronal Aspartate: A CommentaryJournal of Cerebral Blood Flow & Metabolism, 2010
- Brain Glutamine Synthesis Requires Neuronal-Born Aspartate as Amino Donor for Glial Glutamate FormationJournal of Cerebral Blood Flow & Metabolism, 2010
- Human 13N-ammonia PET studies: the importance of measuring 13N-ammonia metabolites in bloodMetabolic Brain Disease, 2010
- Precursors of glutamic acid nitrogen in primary neuronal cultures: Studies with15NNeurochemical Research, 1990
- Some metabolic effects of ammonia on astrocytes and neurons in primary culturesNeurochemical Pathology, 1987
- TRANSAMINATION OF AMINO ACIDS IN HOMOGENATES OF RAT BRAINJournal of Neurochemistry, 1971