Kidney glutamate dehydrogenase

Figure 8.29 The initial reactions of glutamine metabolism in kidney, intestine and cells of the immune system. The initial reaction in all these tissues is the same, glutamine conversion to glutamate catalysed by glutaminase the next reactions are different depending on the function of the tissue or organ. In the kidney, glutamate dehydrogenase produces ammonia to buffer protons. In the intestine, the transamination produces alanine for release and then uptake and formation of glucose in the liver. In the immune cells, transamination produces aspartate which is essential for synthesis of pyrimidine nucleotides required for DNA synthesis otherwise it is released into the blood to be removed by the enterocytes in the small intestine or by cells in the liver.

There the glutamine is sequentially deamidated by glutaminase and deaminated by kidney glutamate dehydrogenase. 

Ammonia is normally condensed with 2-oxoglutarate and thus converted to glutamate via the enzyme glutamate dehydrogenase this enzyme is of highest activity in the liver and kidney. Glutamate is produced from 2-oxoglutarate and ammonia as follows ... 

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. ... 

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. 

Glutamate dehydrogenase plays a major role in amino acid metabolism. It is a zinc protein, requires NAD+ or NADP+ as coenzyme, and is present in high concentrations in mitochondria of liver, heart, muscle, and kidney. It catalyzes the (reversible) oxidative deamination of L-glutamate to a-ketoglutarate and NH3. The initial step probably involves formation of a-iminoglutarate by dehydrogenation. This step is followed by hydrolysis of the imino acid to a keto acid and NH3 ... 

Ammonia is produced by oxidative and nonoxidative deaminations catalyzed by glutaminase and glutamate dehydrogenase (Chapter 17). Ammonia is also released in the purine nucleotide cycle. This cycle is prominent in skeletal muscle and kidney. Aspartate formed via transamination donates its a-amino group in the formation of AMP the amino group is released as ammonia by the formation of IMP. 

Often there is no good clinical test available to determine the exact type of hepatic lesion, short of liver biopsy. There are certain patterns of enzyme elevation that have been identified and can be helpful (Table 38-3). ° The specificity of any serum enzyme depends on the distribution of that enzyme in the body. Alkaline phosphatase is found in the bile duct epithelium, bone, and intestinal and kidney cells. 5-Nucleotidase is more specific for hepatic disease than alkaline phosphatase, because most of the body s store of 5 -nucleotidase is in the liver. Glutamate dehydrogenase is a good indicator of centrolobular necrosis because it is found primarily in centrolobular mitochondria. Most hepatic cells have extremely high concentrations of transaminases. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are commonly measured. Because of their high concentrations and easy liberation from the hepato-cyte cytoplasm, AST and ALT are very sensitive indicators of necrotic lesions within the liver. After an acute hepatic lesion is established, it may take weeks for these concentrations to return to normal. ... 

F. 42.8. Metabolism of glutamine and other fuels in the kidney. To completely oxidize glutamate carbon to CO2, it must enter the TCA cycle as acetyl CoA. Carbon entering the TCA cycle as a-Ketoglutarate (a-KG) exits as oxaloacetate and is converted to phosphoenolpyru-vate (PEP) by PEP carboxykinase. PEP is converted to pyruvate, which may be oxidized to acetyl CoA. PEP also can be converted to serine, glucose, or alanine. GDH = glutamate dehydrogenase PEPCK = phosphoenolpyruvate carboxykinase TA = transaminase OAA = oxaloacetate. 

The major enzyme involved in the formation of ammonia in the liver, brain, muscle, and kidney is glutamate dehydrogenase. It catalyzes the reaction in which anunonia is condensed with 2-oxoglutarate to form glutamate (Sec. 14.1). 

The operation of this cycle has been shown in mammalian muscle (8), brain (98), and kidney (99). It is an alternative to glutamate dehydrogenase for allowing release of ammonia. The multiple functions attributed to the cycle, and experimental evidence related to it, are too involved to consider in detail in this article, and the topic has already... 

Glutamic acid is oxidized to completion by the kidney and liver cyclo-phorase suspensions of Green and co-workers (P). The oxidation is associated with aerobic phosphorylation, and requires the presence of adenosine 5 -phosphate (AMP), Mg++, and P. Since aged preparations are stimulated by DPN+ it appears highly probable that cyclophorase preparations contain L-glutamate dehydrogenase and enzymes of the TCA cycle. 

The third reaction, the oxidation of cysteine sulfinate, proceeds differently in Proteus vulgaris and in animal tissues. As shown by Singer and Kearney 18,20) the Proteus enzyme system oxidizes it directly to cysteate. This oxidation requires a pyridine nucleotide coenzyme which appears to be closely related to DPN+ 23). On the other hand, in rat liver mitochondria a soluble enzyme system oxidizes L-cysteine sulfinate in the presence of DPN+ to j8-sulfinylpyruvate and NH3 20). This reaction is analogous to that catalyzed by glutamic dehydrogenase [see Eq. (7)]. There is some indication that kidney n-amino acid oxidase can also oxidize cysteine sulfinate 24). Among these pathways of cysteine sulfinate metabolism the transaminative one is of the greatest importance. 

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