Glutamate synthesis

Glutamate (Glu)  is the major excitatory neurotransmitter in the nervous system. Glutamate pathways are linked to many other neurotransmitter pathways, and glutamate receptors are found throughout the brain and spinal cord in neurons and glia. 

Glutamate is a key substance in the brain, being involved in metabolism, pathology, and neurotransmission and is an essential source of energy. It is involved in the synthesis of proteins and peptides, as well as other compounds and in the detoxication of ammonia in the brain. Important regulatory processes are cellular uptake mechanisms for Glu and precursor substances, compartmentalization and enzymes involved in the synthesis, and degradation of Glu. It is now generally accepted that the Glu–Gln cycle has an important function in the brain. 

The neurotransmitter glutamate can be synthesized from glutamine by the action of phosphate-activated glutaminase. It appears, however, that glutamate derived from glutamine via this route is produced intramitochondrially and may subsequently undergo a transamination catalyzed by the mitochondrial isoform of aspartate aminotransferase. The α-ketoglutarate thus formed is translocated out of the mitochondria by the dicarboxylate carrier and transaminated in the cytoplasm by the cytoplasmic isoform of aspartate aminotransferase. 

Alternatively, glutamate may be formed from α-ketoglutarate and alanine catalyzed by alanine aminotransferase. This cytoplasmic glutamate is transported into vesicles by vesicular glutamate transporters. Three vesicular glutamate transporters have been cloned and they exhibit differential expression in glutamatergic neurons in various brain regions. This has important implications with regard to characterization of subpopulations of glutamatergic neurons. Glutamate metabolism, which to a large extent takes place in astroglial cells, is catalyzed either by glutamine synthetase or glutamate dehydrogenase.

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