Inhibition of glutamine synthetase

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. 

Our studies of the substrates [glutamate (I) and ATP] and of substrate analogs [AMP-P-(CH2)-P and methionine sulfoximine] reveal interactions between both substrate sites and both metal ion sites. Previously mentioned studies by Meister s group showed that the irreversible inhibition of glutamine synthetase in the presence of L-methionine (S)-sulfoximine and ATP was due to formation of the sulfoximine phosphate (IV). The tetrahedral geometry at the sulfur atom of the sulfoximine was suggested to be a mimic of the active structure of the adduct of y-glutamyl phosphate and ammonia (III). Data in our laboratory provide spectroscopic evidence that methionine... 

Figure 21. Inhibition of glutamine synthetase by wildfire toxin (42)...

Woolfolk, C. A. Stadtman, E. R. (1967). Regulation of glutamine synthetase III. Cumulative feedback inhibition of glutamine synthetase from Escherichia coli. Arch. Biochem. Biophys. 118,736-755. 

Cumulative Feedback Regulation. In this case, each end product causes a partial inhibition or repression when present in excess alone but all end products must be present to effect complete blockage. The most well known example is the inhibition of glutamine synthetase in E. coli by eight end products (Stadtman, 1966). 

C3b2. Inhibition of acetolactate and acetohydroxyacid synthases (B) C3b3. Inhibition of EPSP synthase (G) C3b4. Inhibition of glutamine synthetase (H)... 

In studies on the inhibition of glutamine synthetase by methionine sulfoximine it was found that this compound competes with glutamate for binding to the enzyme, and that binding of methionine sulfoximine is followed by its. phosphorylation by ATP to form methionine sulfoximine phosphate----. The phosphorylated compound binds... 

Rowe, W.B., Ronzio, R.A., and Meister, A., Inhibition of Glutamine Synthetase by Methionine Sulfoximine, Studies on Methionine Sulfoximine Phosphate, Biochemistry 2674 (1969). 

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). 

A. J. L. Cooper, Possible Treatment of End-Stage Hyperammonemic Ence-phalophaty by Inhibition of Glutamine Synthetase, Metab. Brain Dis., 2013, 28, 119. 

As the dipeptide J itself does not inhibit purified Glutamine synthetase in vitro [143], the amino acid K is considered to be the active form of J and hence, the actual toxin of wildfire disease. Since, the detailed mechanism of Glutamine synthetase inhibition by tabtoxinine-(3-lactam attracts chemical interest, a synthetic approach to the toxin K and its analogs, is of increasing importance. Spiro-(3-lactam L (Fig. 11) has been found to be an efficient precursor of toxin K. 

H S Gill, D Eisenberg (2001) The Crystal Structure of Phosphinothricin in the Active Site of Glutamine Synthetase Illuminates the Mechanism of Enzymatic Inhibition, Biochemistry 40(7) 1903-1912... 

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. 

Most of the pathways of amino acid biosynthesis are regulated by feedback inhibition, in which the committed step is allosterically inhibited by the final product. Branched pathways require extensive interaction among the branches that includes both negative and positive regulation. The regulation of glutamine synthetase from if. coli is a striking demonstration of cumulative feedback inhibition and of control by a cascade of reversible covalent modifications. 

ACTIVE FIGURE 23.4 The allosteric regulation of glutamine synthetase activity by feedback inhibition. Sign in at www.thomsonedu.com/login to explore an interactive version of this figure. 

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