Glutamine synthesis

Formation of glutamine is catalyzed by mitochondrial glutamine synthase (Figure 29-7). Since amide bond synthesis is coupled to the hydrolysis of ATP to ADP and P , the reaction strongly favors glutamine synthesis. One function of glutamine is to sequester ammonia in a nontoxic form. 

Figure 29-7. The glutamine synthase reaction strongly favors glutamine synthesis.

Hyperammonemia Type 2. A deficiency of ornithine transcarbamoylase (reaction 2, Figure 29-9) produces this X chromosome-linked deficiency. The mothers also exhibit hyperammonemia and an aversion to high-protein foods. Levels of glutamine are elevated in blood, cerebrospinal fluid, and urine, probably due to enhanced glutamine synthesis in response to elevated levels of tissue ammonia. 

Lydon J, Duke SO, Inhibitots of glutamine synthesis, in Singh BK (ed.). Plant Amino Acids Biochemistry and Biotechnology, Marcel Dekket, New York, pp. 445— 464,1999. 

In this section we discuss the pathways for glutamate and glutamine synthesis. We also discuss some other aspects of the nitrogen cycle. Consideration of the arginine pathway is deferred until the next chapter. 

Examine the bioenergetics of the synthesis of glutamine synthesis from a-ketoglutarate via glutamate synthase or glutamate dehydrogenase (fig. 21.3). Is there a difference ... 

More recently Braganca, Faulkner, and Quastel (B15) showed that this inhibition of acetylcholine synthesis in brain slices by ammonia is consistent only in the diminution of bound acetylcholine. They further showed that the addition of inhibitors of glutamine synthesis, such as methionine sulfoxide, ethionine sulfoxide, and methionine sulfoximine (the toxic product, causing convulsions, formed in flour chemically aged with nitrogen trichloride) would partially reverse the ammonium inhibition. These observations were confirmed and extended to a wide variety of ATP-requiring reactions by Weil-Malherbe. In support of this suggestion was the observation that ammonia is taken up by the brain in hepatic coma (B8). The observations are valid and have been confirmed, but the interpretation of the data and the hypothesis are questionable. A quantitative basis for the evaluation of this mechanism can... 

Fig. 7. Glutamate and glutamine synthesis in relation to the Krebs cycle.

B15. Braganca, B. J., Faulkner, P., and Quastel, J. H., Effects of inhibitors of glutamine synthesis on inhibition of acetylcholine synthesis in brain slices by ammonium ions. Biochim. et Biophys. Acta 10, 83 (1953). 

Hawkins, R.A., Jessy, J., Mans, A.M., De Joseph, M.R. (1993). Effect of reducing brain glutamine synthesis on metabolic symptoms of hepatic encephalopathy. J. Neurochem. 60, 1000-1006. Henderson, R.M., Graf, J., Boyer, J.L. (1989). Inward-rectifying potassium channels in rat hepatocytes. Am. J. Physiol. 256, G1028-G1035. 

Kanamori, K., Parivar, F Ross, B.D. (1993). A 15N NMR study of in vivo cerebral glutamine synthesis in hyperammonemic rats. NMR Biomed. 6,21-26. 

Hawkins, R.A., and J.Jessy. 1991. Hyperammonemia does not impair brain function in the absence of net glutamine synthesis. Biochem. J. 277 (Pt.3) 697-703. 

Hawkins, R.A., J.Jessy, A.M.Mans, and M.R.De Joseph. 1993. Effect of reducing brain glutamine synthesis on metabolic symptoms of hepatic encephalopathy. J. Neurochem. 60(3) 1000-1006. 

Warren, K.S., and S.Schenker. 1964. Effect of an inhibitor of glutamine synthesis (methionine sulfoximine) on ammonia toxicity and metabolism. J. Lab. Clin. Med. 64(3) 442-449. 

The activity of glutamine synthetase is also controlled by reversible covalent modification —the attachment of an AMP unit by a phosphodiester bond to the hydroxyl group of a specific tyrosine residue in each subunit (Figure 24.26). This adenylylated enzyme is less active and more susceptible to cumulative feedback inhibition than is the deadenylylated form. The covalently attached AMP unit is removed from the adenylylated enzyme by phosphorolysis. The attachment of an AMP unit is the final step in an enzymatic cascade that is initiated several steps back by reactants and immediate products in glutamine synthesis. 

D.L. Purich. 1998. Advances in the enzymology of glutamine synthesis Enzymol. Relat. Areas Mol. Biol. 72 9-42. (PubMed)... 

The glutamine formed in the liver is released into the systemic circulation. Through arterial blood, the brain is also supplied with ammonium (approximately 10% of the plasma concentration). Detoxification is effected via glutamine synthesis. The glutamine formed in the brain enters the blood circulation. In the muscles, ammonium... 

The pH value in the portal vein drops in the case of increased urea synthesis. This decrease corresponds to the consumption of HC03. At the same time, intra-and extrahepatic glutamine synthesis is reduced. When the pH value falls in the blood, corresponding amounts of bicarbonate must be made available for the compensation of metabolic acidosis. This amount of HC03 is then not available for urea synthesis, which results in a curbing of the urea cycle. Additionally, the glutaminase... 

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