Glutamine deamination

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. 

These points have important functional implications. While neuronal glutamate may come from glucose via pyruvate, the Krebs cycle and transamination of alpha-oxoglutamate, it seems likely that most of the transmitter originates from the deamination of glutamine. After release, the high-affinity uptake sites (transporters)... 

Histamine is synthesised by decarboxylation of histidine, its amino-acid precursor, by the specific enzyme histidine decarboxylase, which like glutaminic acid decarboxylase requires pyridoxal phosphate as co-factor. Histidine is a poor substrate for the L-amino-acid decarboxylase responsible for DA and NA synthesis. The synthesis of histamine in the brain can be increased by the administration of histidine, so its decarboxylase is presumably not saturated normally, but it can be inhibited by a fluoromethylhistidine. No high-affinity neuronal uptake has been demonstrated for histamine although after initial metabolism by histamine A-methyl transferase to 3-methylhistamine, it is deaminated by intraneuronal MAOb to 3-methylimidazole acetic acid (Fig. 13.4). A Ca +-dependent KCl-induced release of histamine has been demonstrated by microdialysis in the rat hypothalamus (Russell et al. 1990) but its overflow in some areas, such as the striatum, is neither increased by KCl nor reduced by tetradotoxin and probably comes from mast cells. 

The key reaction that links primary and secondary metabolism is provided by the enzyme phenylalanine ammonia lyase (PAL) which catalyzes the deamination of l-phenylalanine to form iran.v-cinnamic acid with the release of NH3 (see Fig. 3.3). Tyrosine is similarly deaminated by tyrosine ammonia lyase (TAL) to produce 4-hydroxycinnamic acid and NH3. The released NH3 is probably fixed by the glutamine synthetase reaction. These deaminations initiate the main phenylpropanoid pathway. 

Glutamate is a commonly occurring amino acid that acts as an excitatory transmitter in CNS. The molecule may be synthesized within the nerve ending either by transamination from 2-oxoglutarate (described in Section 6.3.1.1) or by deamination of glutamine (see Section 8.2.2). However, in common with other synaptic signals, there exists an efficient uptake mechanism in the axon to recycle glutamate that has been released. 

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. 

The 2-oxoglutarate produced is recycled for transamination or may enter the TCA cycle. The ammonia liberated by oxidative deamination is used to form glutamine (from glutamate, catalysed by glutamine synthase) prior to export from the muscle cell ... 

Glutamine is exported from the muscle and extracted from blood mainly by the kidneys or the gut hepatic uptake of glutamine is relatively low in comparison. In the renal tubular cells, glutamine is deaminated in the processes of urinary acidification (see Figure 8.11) or used by the intestinal cells as a fuel. 

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. 

Some amino acids are converted to glutamate prior to deamination these are proline, arginine, histidine and glutamine (Figure 8.12). 

Figure 9.5 A summary of pathways of the three main fueb and the positions where they enter the cycle. The figure also shows the release of hydrogen atoms/electrons and their transfer into the electron transfer chain for generation of ATP and formation of water. Glutamine is converted to glutamate by deamidation and glutamate is converted to oxoglutarate by transamination or deamination. The process of glycolysis also generates ATP as shown in the Figure.

Two amino acids—asparagine and glutamine—contain acid-amide groups in the side chains, from which NH3 can be released by hydrolysis (hydrolytic deamination). In the blood, glutamine is the most important transport molecule for amino nitrogen. Hydrolytic deamination of glutamine in the liver also supplies the urea cycle with NH3. 

The involvement of isobutylhydroxylamine, (CH3)2CHCH2NH—OH (4), and of HA (NH2OH) in the biosynthesis of the antibiotics valanimycin (5) and nebularine (6), respectively, has been demonstrated in Streptomyces species (see Section n.B). In the case of nebularine, HA is released in the final step of its production by enzymatically induced deamination of adenosine, while the isobutylhydroxylamine is a precursor for the biosynthesis of valanimycin. In cyanobacterium, the presence of free and bound HA was demonstrated to be a product of enzyme-mediated glutamine oxidation ... 

Terms in bold are defined in aminotransferases 660 transaminases 660 transamination 660 pyridoxal phosphate (PLP) 660 oxidative deamination 661 l-glutamate dehydrogenase 661 glutamine synthetase 662 glutaminase 663 creatine kinase 664... 

Two of these glutamates are initially glutamines and can undergo methylation only if they are deaminated first.72 An esterase encoded by the cheB gene72 removes the methyl ester groupings as methanol. 

Figure 24-11 Integration of the urea cycle with mitochondrial metabolism. Green lines trace the flow of nitrogen into urea upon deamination of amino acids or upon removal of nitrogen from the side chain of glutamine.

These proteins contain considerable amounts of glutamine—an amino acid which is a transglutaminase 2 substrate. In the process of celiac disease development, glutamine undergoes deamination, and next the product is bound with HLA DQ8 or HLA DQ2, due to affinity 25 times higher than in the form containing glutamine... 

Arentz-Hansen, H., Komer, R., Molberg, O., Quarsten, H., Vader, W., Kooy, Y.M. 2000. The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deaminated glutamine targeted by tissue transglutaminase. J Exp Med 191 603-612. 

Know in detail how amino acids can lose their nitrogen by transamination and deamination reactions and combination of the two know in detail how nitrogen is disposed of in the organism the alanine, glutamine, and urea cycles be able to recite the names of all enzymes, cofactors, and intermediates, and be familiar with their regulatory mechanisms be able to recognize and draw structures of all intermediates involved in these reactions. 

Disposition in the Body. Readily absorbed after oral administration, but undergoes extensive first-pass metabolism by N-dealkylation and oxidative deamination to form monodesmethyl and didesmethyl metabolites, and diphenylmethoxyacetic acid which may be conjugated with glutamine or glycine bioavailability about 50%, Up to 65% of a dose is excreted in the urine in 96 hours. The major urinary metabolite appears to be diphenylmethoxyacetic acid in free or conjugated form very little is excreted as unchanged drug. 

---