The Role of Glutamine Synthetase and Glutamate Dehydrogenase in Cerebral Ammonia Homeostasis

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.

The Astrocyte: Powerhouse and Recycling Center

“…Lacking glutamine synthase, neurons cannot process the excess of nitrogen, which returns to astrocytes as NH 4 þ , NH 3 , or in the form of amino acids ( Fig. 1) (Bak et al 2006;Cooper 2012;Rothman et al 2012). NH 4 þ enters astrocytes through K þ channels and transporters (Nagaraja and Brookes 1998;Kelly and Rose 2010) to be returned to neurons as glutamine.…”

Inhibition of human glutamine synthetase by L-methionine-S,R-sulfoximine—relevance to the treatment of neurological diseases

“…Thus, certain pathological states involving elevations in either ammonia or glutamate might benefit from regulation of glutamine synthetase. Elevations in cerebral ammonia result in increased levels of glutamine within astrocytes (Brusilow et al 2010, Cooper 2012a, 2012b). Glutamine is a significant osmolyte, and therefore, the increase in its concentrations adds to the brain swelling characteristic of hyperammonemia, particularly in the acute form of this condition (Desjardins et al 1999, Tok et al 2009, Brusilow et al 2010, Mardini et al 2011, Cudalbu et al 2012).…”

Expression of human GLUD1 and GLUD2 glutamate dehydrogenases in steroid producing tissues

“…In mammalian liver, the organ known to express GDH at very 54 high levels, the enzyme can reach equilibrium, whereas, in other tissues, GDH is shown to 55 operate mainly in the direction of glutamate oxidation (Cooper, 2012;Treberg et al, 2014). .…”