Glutamate dehydrogenase brain

Several explanations centre on the enzyme glutamate dehydrogenase, which is assumed to catalyse a nearequilibrium reaction in brain mitochondria ... 

Fig. 1.3 Reactions showing synthesis of glutamate in brain. Aspartate aminotransferase (1) glu-taminase (2) glutamate dehydrogenase (3) GABA aminotransferase (4) alanine aminotransferase (5) ornithine aminotransferase (6) Al-pyrroline 5-carboxylic acid dehydrogenase (7) and asparagine synthetase (8)...

The major enzyme involved in the formation of ammonia in the liver, brain, muscle, and kidney is glutamate dehydrogenase, which catalyzes the reaction in which ammonia is condensed with 2-oxoglutarate to form glutamate (Sec. 15.1). Small amounts of ammonia are produced from important amine metabolites such as epinephrine, norepinephrine, and histamine via amine oxidase reactions. It is also produced in the degradation of purines and pyrimidines (Sec. 15.6) and in the small intestine from the hydrolysis of glutamine. The concentration of ammonia is regulated within narrow limits the upper limit of normal in the blood in humans is 70/tmol L-1. It is toxic to most cells at quite low concentrations hence there are specific chemical mechanisms for its removal. The reasons for ammonia toxicity are still not understood. The activity of the urea cycle in the liver maintains the concentration of ammonia in peripheral blood at 20/ molL. ... 

In peripheral tissues, two enzymes, namely glutamate dehydrogenase and glutamine synthetase, are important in the removal of reduced nitrogen, and particularly so in the brain, which is highly susceptible to free ammonia. 

Aoki, C., Milner, T.A., Sheu, K.F., Blass, J.P., Pickel, V.M. (1987). Regional distribution of astrocytes with intense immrmoreactivity for glutamate dehydrogenase in rat brain implications for neiuon-glia interactions in glutamate transmission. J. Neurosci. 7 2214-31. 

Plaitakis, A., Zaganas, I. (2001). Regulation of human glutamate dehydrogenases implications for glutamate, ammonia and energy metabolism in brain. J. Neurosci. Res. 66 899-908. 

Glutamate dehydrogenase (EC 1.4.1.3 L-glutamate NAD(P) oxidoreductase, deaminating GLD) is a mitochondrial enzyme found mainly in the liver, heart muscle, and kidneys, but small amounts occur in other tissue, including brain and skeletal muscle tissue, and in leukocytes. 

Behavioral disorders such as anorexia, sleep disturbances, and pain insensitivity associated with hyperammonemia have been attributed to increased tryptophan transport across the blood-brain barrier and the accumulation of its metabolites. Two of the tryptophan-derived metabolites are serotonin and quinolinic acid (discussed later). The latter is an excitotoxin at the N-methyl-D-aspartate (NMDA) glutamate receptors. Thus, the mechanism of the ammonium-induced neurological abnormalities is multifactorial. Normally only small amounts of NH3 (i.e., NH4 ) are present in plasma, since NH3 is rapidly removed by reactions in tissues of glutamate dehydrogenase, glutamine synthase, and urea formation. 

Madl JE, Clements JR, Beitz AJ, Wenthold RJ, Larson AA (1988) Immunocytochemical localization of glutamate dehydrogenase in mitochondria of the cerebellum and ultrastructural study using a monoclonal antibody. Brain Res 452 396-402. 

Fig. 38.5. Summary of the sources of NH4 for the urea cycle. All of the reactions are irreversible except glutamate dehydrogenase (GDH). Only the dehydratase reactions, which produce NH4 from serine and threonine, require pyridoxal phosphate as a cofactor. The reactions that are not shown occurring in the muscle or the gut can all occur in the liver, where the NH4 generated can be converted to urea. The purine nucleotide cycle of the brain and muscle is further described in Chapter 41.

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