Liver glutamine

Kuramitsu Y, Harada T, Takashima M et al. Increased expression, and phosphorylation of liver glutamine synthetase in well-differentiated hepatoeellular eareinoma tissues of patients infected with hepatitis C virus. Electrophoresis 2006 27 1651-1658. 

Homogeneous preparations of glutamine synthetase are available from many sources including Escherichia coli, Salmonella typhimurium, peas, sheep brain, and rat liver. Glutamine synthetases from bacteria have 12... 

Several hypotheses have been propounded to explain the continued formation of urea. One of the first was the suggestion that to the synthesis of urea there was a pathway alternative to the Krebs-Henseleit one (L7). Evidence for such a pathway had earlier been adduced by Bach (Bl), who concluded that, in the liver, glutamine formed from glutamic acid and ammonia could combine further with ammonia and... 

Recently it has been established that pyridazines can be formed by enzymic catalysis. For example, pyridazinones are formed from y-glutamyl hydra-zones of a-keto acids in the presence of liver glutamine transaminase, or from y-glutamyl hydrazide in the presence of L-amino acid oxidase. ... 

While ammonia, derived mainly from the a-amino nitrogen of amino acids, is highly toxic, tissues convert ammonia to the amide nitrogen of nontoxic glutamine. Subsequent deamination of glutamine in the liver releases ammonia, which is then converted to nontoxic urea. If liver function is compromised, as in cirrhosis or hepatitis, elevated blood ammonia levels generate clinical signs and symptoms. Rare metabolic disorders involve each of the five urea cycle enzymes. 

Major amino acids emanating from muscle are alanine (destined mainly for gluconeogenesis in liver and forming part of the glucose-alanine cycle) and glutamine (destined mainly for the gut and kidneys). 

Additionally, several amino acids may undergo transamination to produce glutamate which in the liver is oxidatively deaminated to form 2-oxoglutarate (2-OG, see Figure 6.6), a substrate of the TCA cycle. Alternatively, glutamate maybe converted into glutamine, an important but often overlooked fuel substrate. 

Amino groups released by deamination reactions form ammonium ion (NH " ), which must not escape into the peripheral blood. An elevated concentration of ammonium ion in the blood, hyperammonemia, has toxic effects in the brain (cerebral edema, convulsions, coma, and death). Most tissues add excess nitrogen to the blood as glutamine. Muscle sends nitrogen to the liver as alanine and smaller quantities of other amino acids, in addition to glutamine. Figure I-17-1 summarizes the flow of nitrogen from tissues to either the liver or kidney for excretion. The reactions catalyzed by four major enzymes or classes of enzymes involved in this process are summarized in Table T17-1. 

Tissue electrodes [2, 3, 4, 5, 45,57], In these biosensors, a thin layer of tissue is attached to the internal sensor. The enzymic reactions taking place in the tissue liberate products sensed by the internal sensor. In the glutamine electrode [5, 45], a thick layer (about 0.05 mm) of porcine liver is used and in the adenosine-5 -monophosphate electrode [4], a layer of rabbit muscle tissue. In both cases, the ammonia gas probe is the indicator electrode. Various types of enzyme, bacterial and tissue electrodes were compared [2]. In an adenosine electrode a mixture of cells obtained from the outer (mucosal) side of a mouse small intestine was used [3j. The stability of all these electrodes increases in the presence of sodium azide in the solution that prevents bacterial decomposition of the tissue. In an electrode specific for the antidiuretic hormone [57], toad bladder is placed over the membrane of a sodium-sensitive glass electrode. In the presence of the antidiuretic hormone, sodium ions are transported through the bladder and the sodium electrode response depends on the hormone concentration. 

Colony forming ability of the fetal liver cells was determined in the medium comprised 1.3% methylcellulose, 4.0 mM glutamine, 10 U/ml penicillin/-streptomycin, 100 U/ml GM-CSF, 100 U/ml IL-3, 50 ng/ml stem cell factor and 10 U/ml erythropoietin in IMDM. An aliquot of 10 cells was transferred to a 35 mm sterile plastic Petri dish and incubated at 37 C in a fully humidified atmosphere of 5% CO2 in air. The final colony count was performed on day 14 of culture, the colony types being defined by general morphological criteria. 

Glutamine is found in all cells in a combined form in peptides or proteins, but also in a free form. The highest free concentration of glutamine is found in muscle, where it acts as a store for use by other tissues. In fact, the total amount in all the skeletal muscle in the body is about 80 g, which is synthesised in the muscle from glucose and branched-chain amino acids (see Chapter 8). As with glycogen in the liver and triacylglycerol in adipose tissue. 

Some of the glutamine that is absorbed is metabolised in the enterocytes. It is used, along with glucose, as a fuel to generate ATP (Chapter 8). The ammonia and the alanine that are produced enter the blood for uptake by the liver. 

The ammonia produced from asparagine and glutamine is released into the hepatic portal vein, for removal by the liver and conversion to urea. The concentration of ammonia in the blood in the hepatic portal vein is about ten times higher than in the hepatic vein, indicating the quantitative importance of the liver in removing this ammonia. 

Gluconeogenesis. The gluconeogenic pathway is present in the kidney, as in the liver. Thus, amino acids (and lactate) can be converted to glucose in the kidney but a major precursor, in acidotic conditions, is glutamine. 

Figure 8.23 Formation of glutamine from glucose and branched-chain amino adds in muscle and adipose tissue and probably in the lung. Oxoacids may also be released into blood for oxidation in the liver.

Figure 8.27 Pathway of glutamine metabolism in the intestinal cells. Glutamine is metabolised to alanine to generate ATP alanine is released into the blood to be taken up by the liver.

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.

Liver a tissue that can both produce and use glutamine... 

Figure 8.30 Different roles of periportal and perivenous cells in the liver in respect of glutamine metabolism. Glutamine is converted to glucose in periportal cells via gluconeogenesis in perivenous cells, ammonia is taken up, to form glutamine, which is released into the blood. This emphasises the importance of the liver in removing ammonia from the blood, i.e. if possesses two process to ensure that all the ammonia is removed.

Glutamine is stored in muscle approximately 80 g in the total skeletal muscle in the body. This is an amount similar to that of glucose which is stored as glycogen in the liver (Chapters 2 and 6). 

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