Glutamine inhibition

Similar to what has been shown in Table 8.1 for specific growth rate, many mathematical expressions listed in Table 8.3 employ Monod-type structures for limiting phenomena, and Aiba and Shoda-type structures for inhibitory behavior. Limiting components for cell death are lactate and ammonia, that is, the presence of these byproducts increases the specific cell death rate. On the other hand, substrates, such as glucose and glutamine, inhibit cell death (Equations 48 to 52). 

W. C. Sessa, M. Hecker, J. A. Mitchell and J. R. Vane, The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor L-glutamine inhibits the generation of L-arginine by cultured endothelial cells. Proc Natl Acad Sci U S A 87, 8607-8611 (1990). 

If Pll is uridylyated, the AT-PII complex catalyzes deadenylylation. Deuridylylation of PII causes the AT-PII complex to catalyze adenylylation. The enzyme uridylyl transferase catalyzes uridylylation of PII, whereas deuridylylation is catalyzed by a different enzyme. Uridylyl transferase is allosterically regulated, with ATP and ot-ketoglutarate activating it and glutamine inhibits it. 

M.L. Paddock, S.H. Rongey, G. Feher, and M.Y. Okamura, Pathway of proton transfer in bacterial reaction centers replacement of glutamic acid 212 in the L subunit by glutamine inhibits quinone (secondary acceptor) turnover, Proc. Natl. Acad. Sci. USA 86 6602 (1989). 

Aspirin-induced mucosal damage is aggravated by bile (91 ), and taurocholic acid potentiates the faU in transmucosal electrical potential difference induced by aspirin in man (115 ). In animals, L-glutamine inhibited the back-diffusion of acid and reduced the severity of gastric lesions produced by aspirin (116). The biochemical pathology of aspirin-induced gastric damage has been reviewed (80 ). 

L-alanyl-L-2,3-epoxy-4-oxohexahydrophenylalanine [29393-20-2] C22H2gN20, inhibit glutamine metaboHsm, as does bialaphos as a source of the amino acid L-phosphinothricin [35597-44-5] 0 11 2 04 . 

Although the antibacterial and antifungal activities of bialaphos and phosphinothricin were not found to be usehil, the two agents were later used as biodegradeable, relatively nonselective, postemergent herbicides. Glutamine synthetase inhibition is toxic to plants because the enzyme is key to ammonia assimilation. There is some selectivity for individual plant species as shown by the LD for bialaphos ranging from 0.125 to 8.5 kg/ha (301—303). 

One example of a naturally occurring diazirine, duazomycin A (137 Scheme 11.20), has been reported, isolated in 1985 from a Streptomyces species during a screen for herbicidal compounds [196], It was fotind to inhibit de novo starch synthesis and it was suggested that this is due to direct inhibition of protein synthesis. Duazomycin A is structurally related to 6-diazo-5-oxo-L-norleucine (138), also reported as a natural product from Streptomyces [197], which acts as a glutamine antagonist and inhibits purine biosynthesis [198],... 

Since biosynthesis of IMP consumes glycine, glutamine, tetrahydrofolate derivatives, aspartate, and ATP, it is advantageous to regulate purine biosynthesis. The major determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, whose pool size depends on its rates of synthesis, utilization, and degradation. The rate of PRPP synthesis depends on the availabihty of ribose 5-phosphate and on the activity of PRPP synthase, an enzyme sensitive to feedback inhibition by AMP, ADP, GMP, and GDP. 

Several reactions of IMP biosynthesis require folate derivatives and glutamine. Consequently, antifolate drugs and glutamine analogs inhibit purine biosynthesis. 

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 mutation of ThrlSl, Glyl82, or Glul83 to alanine, or of Glul83 to glutamine also completely inhibited the ATP or acetylphosphate-dependent Ca transport, without effect on the phosphorylation of the enzyme by ATP in the presence of Ca or by Pi in the absence of Ca [127]. The phosphoenzyme formed from ATP retained its ADP-sensitivity at low concentration and alkaline pH, but its rate of decomposition was much slower than that of the wild-type enzyme in the presence of EGTA. These observations implicate the 181-183 region in the conformational changes related to Ca translocation. 

Novogrodosky, A., Nehring, RE., Jr and Meister, A. (1979). Inhibition of amine acid transport into lymphoid cells by the glutamine analog L-2-amino-4-oxo-5-chloropentanoate. Proc. Natl Acad. Sci. USA 76, 4932-4935. 

Willard-Mack, C. L., Koehler,R. C.,Hirata,T. etal. Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 71 589-599,1996. 

Glutamine synthetase, a brain Mn enzyme, is located mainly in astrocytes, and its synthesis may be modulated by nitric oxide (496). Inhibition of this enzyme could be relevant to aging diseases (497). There is evidence that human NT2-N neurons die via ionotropic glutamate receptor-mediated mechanisms when exposed to hypoxia in the presence of glutamate (498). 

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