The Role of Glutamine Synthetase and Glutamate Deh

Authors: Arthur J L Cooper

Publish Date: 2012/05/23

Volume: 37, Issue: 11, Pages: 2439-2455

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Abstract

In the brain glutamine synthetase GS which is located predominantly in astrocytes is largely responsible for the removal of both bloodderived and metabolically generated ammonia Thus studies with 13Nammonia have shown that about 25  of bloodderived 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 GDHcatalyzed reaction in vitro favors reductive amination of αketoglutarate at pH 74 Nevertheless only a small amount of label derived from 13Nammonia in rat brain is incorporated into glutamate and the αamine 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/αketoglutarateutilizing 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/αketoglutaratelinked 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 lAspartate + 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 eg hyperammonemic encephalopathy conditions should be a productive area for future research

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