Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

Abstract

Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low—typically µM. The remarkable gradient of glutamate in the different cerebral compartments: vesicles > cytosol/mitochondria > extracellular fluid attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate catabolism and synthesis in well-defined cellular and subcellular compartments in the brain. A major route for glutamate and ammonia removal is via the glutamine synthetase (glutamate ammonia ligase) reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter γ-aminobutyrate (GABA) via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (especially aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine amide, the direction of the glutamate dehydrogenase reaction in the brain in vivo is mainly toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia, there is a large increase in cerebral glutamine content, but only small changes in the levels of glutamate and α-ketoglutarate. Thus, the channeling of glutamate toward glutamine during hyperammonemia results in the net synthesis of 5-carbon units. This increase in 5-carbon units is accomplished in part by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate carboxylase. Here, we suggest that glutamate may constitute a buffer or bulwark against changes in cerebral amine and ammonia nitrogen. Although the glutamate transporters are briefly discussed, the major emphasis of the present review is on the enzymology contributing to the maintenance of glutamate levels under normal and hyperammonemic conditions. Emphasis will also be placed on the central role of glutamate in the glutamine-glutamate and glutamine-GABA neurotransmitter cycles between neurons and astrocytes. Finally, we provide a brief and selective discussion of neuropathology associated with altered cerebral glutamate levels.

Minireview on Glutamine Synthetase Deficiency, an Ultra-Rare Inborn Error of Amino Acid Biosynthesis

“…Glutamine—the most abundant free amino acid in the human body—plays a major role in essential metabolic pathways such as nitrogen metabolism, ammonia detoxification, acid–base homeostasis, osmotic regulation, and cell signaling and proliferation [6,7,8,9,10]. …”

“…Glutamine is a precursor for neurotransmitters and a substrate for immune cells [6,11,12,13]. Moreover, it is a precursor for glucose, purines, pyrimidines, adenosine monophosphate, and nicotinamide adenine dinucleotide (NAD + ) [9,14,15,16].…”

“…GS plays a key role in (i) protecting the neurons from excitotoxicity by capturing ammonia and glutamate in the glial cells; and (ii) supplying glutamine for glutamate and GABA synthesis in the glutamine-glutamate-GABA cycle, regulating the excitatory and inhibitory synaptic transmission of neurons (Figure 3) [6,70,71]. Here, we will only briefly discuss the pathophysiology in relation to GS deficiency, but the reader is referred to more dedicated work for complete insight.…”

“…In the brain, ammonia is produced by the reactions of glutaminase and glutamine dehydrogenase [6]. In addition, ammonia from the body circulation can diffuse across the blood-brain barrier, entering astrocytes, where it is normally rapidly detoxified by incorporation into glutamine (Figure 3) [15,47,72].…”

Comparison between thaw-mounting and use of conductive tape for sample preparation in ToF-SIMS imaging of lipids in Drosophila microRNA-14 model

“…MSI is a powerful technique for understanding the biodistributions, accumulation, and metabolisms of drugs and diseases, and hence is being increasingly employed in pharmaceutical research. As evidenced in several studies, [18][19][20] localization of biomolecules is most likely related to their biological functions. Hence, a deep understanding of the spatial distributions of the relevant biomolecular components, as well as the mechanistic effects of exogenous interferences in brain functions, plays a key role during drug discovery.…”