Glutamine synthetase inhibition/inhibitors

Cumulative Feedback Inhibition In cumulative feedback inhibition, the end products can inhibit the reaction of the target enzyme separately. Many textbooks erroneously indicate that the cumulative feedback inhibition of E. coli glutamine synthetase involves separate regulatory sites for each feedback inhibitor. See Cumulative Feedback Inhibition... 

Glufosinate (GA) is a post-emergence and nonselective herbicide [91, 92], The L-enantiomer of this herbicide, which is also called phos-phinothricin, is a natural microbial phytotoxin, produced by Strepto-myces viridochromogenes and Streptomyces hygroscopicus, and acts as an inhibitor of glutamine synthetase, while the D-enantiomer shows no activity on this enzyme. The herbicidal action involves a rapid accumulation of ammonia, a deficiency in several amino acids, an inhibition of photosynthesis and, finally, the death of the plant cell [91, 93]. 

To minimize the potential for mammalian or non pest toxicity the target should be present in plants, but not mammals. However, toxicity of xenobiotics is difficult to predict since it is often due to effects that are unrelated to inhibition of the target site. Most herbicidal inhibitors of glutamine synthetase (glufosinate) and acetyl-CoA carboxylase (diclofop and sethoxydim) have very low mammalian toxicity (2), yet both enzymes are found in animal tissues. 

Meister, A., Inhibition of Glutamine Synthetase and Y"Glutamyl-cysteine Synthetase by Methionine Sulfoximine and Related Compounds, Enzyme-Activated Irreversible Inhibitors (N. Seiler, M.J. Jung and J. Koch-Weser, eds.), Elsevier-North Holland Biomedical Press, Amsterdam pp. 187-211 (1978). 

In considering the commercially successful herbicides known to be inhibitors of amino acid biosynthesis, three aspects will be considered the kinetic description of the inhibition, the molecular interactions involved, and the relevance of the proposed target site to the observed physiological effects. Because of the extensive body of research published on the shikimate pathway and the herbicide glyphosate, this example will be taken as a paradigm of the inhibitor-enzyme relationship. The other cases considered will be the branched-chain amino acid family, histidine biosynthesis, and glutamine synthetase. 

NO negative effect of DLG on nitrate-dependent oxygen evolution was, however, observed in Anacystis cells in i ich ammonium assimilation had been inhibited by treatment with the glutamine synthetase inactivator, MSX. The results in Table 1 show that MSX-treated cells subjected to the action of DLG exhibit rates of nitrate-dependent oxygen evolution analogous to control cells (either untreated or treated with MSX) in spite of the total inhibition of the CX)2 dependent oxygen evolution caused by DLG. These observations support those of Stokes and Walker (1972) regarding the action of DLG as a pure "dark" inhibitor of OO2... 

The glutamine analogue, diazo-oxo-norleucine, and the aspartate analogue, hadacidin (iV-formyl hydroxyaminoacetic acid), inhibit guanylate synthetase and adenylosuccinate synthetase, respectively. Alanosine (2-amino-3-nitrohydroxylaminopropionic acid) is also an inhibitor of adenylate synthesis from inosinate, but its mechanism of inhibition is not yet clear (52). 

End-product inhibition of AS activity by tryptophan appears to be a rather common control mechanism among microorganisms. Nester and Jensen [71] described tryptophan inhibition of B. subtilis AS activity as the first step in sequential feedback control. Excess tryptophan would result in inhibition of the conversion of chorismate to anthrani-late. The consequent accumulation of chorismic acid would then serve as a feedback inhibitor of the DAMPS, the first enzyme in the pathway leading to chorismate synthesis. Bacillus alvei has an anthranilate synthetase which is extremely sensitive to inhibition by tryptophan [98]. In contrast to the mode of AS feedback inhibition in E. coli and S. typhimurium, the B. alvei AS is inhibited by tryptophan noncom-petitively with respect to chorismate and uncompetitively with respect to glutamine. It is the only Bacillus species, among 21 studied, which did not exhibit a sequential feedback control pattern [79]. 

Route c involves the conversion of aspartate to asparagine by glutamine-dependent asparagine synthetase (EC 6.3.5.4). The enzyme has had a checkered career and it has proved extremely difficult to prepare extracts with high activity. Joy and Ireland (1990) have described in detail suitable assay methods and discussed possible factors that may prevent the determination of maximum rates of activity. A heat-stable, dialyzable inhibitor was found in pea leaf homogenates that inhibited the lupin cotyledon enzyme (Joy et al. 1983). The presence of this inhibitor may well account for the current lack of detection of asparagine synthetase in green leaf tissue. 

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