Glutamine methionine sulfoximine

Rowe et al. (97) found that glutamine synthetase was irreversibly inhibited by methionine sulfoximine in the presence of ATP. Also, they discovered... 

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... 

Fig. 25. EPR spectra showing the effect of Cr(III)-ATP binding on the spectrum of the glutamine synthetase-Mn(II)-methionine sulfoximine complex. Reprinted with permission of Academic Press from Villafranca et al. (114).

More recently Braganca, Faulkner, and Quastel (B15) showed that this inhibition of acetylcholine synthesis in brain slices by ammonia is consistent only in the diminution of bound acetylcholine. They further showed that the addition of inhibitors of glutamine synthesis, such as methionine sulfoxide, ethionine sulfoxide, and methionine sulfoximine (the toxic product, causing convulsions, formed in flour chemically aged with nitrogen trichloride) would partially reverse the ammonium inhibition. These observations were confirmed and extended to a wide variety of ATP-requiring reactions by Weil-Malherbe. In support of this suggestion was the observation that ammonia is taken up by the brain in hepatic coma (B8). The observations are valid and have been confirmed, but the interpretation of the data and the hypothesis are questionable. A quantitative basis for the evaluation of this mechanism can... 

RA Ronzio, A Meister (1968) Phosphorylation of Methionine Sulfoximine by Glutamine Synthetase, Proc Natl Acad Sci USA 59(1) 164-170... 

Warren, K.S., and S.Schenker. 1964. Effect of an inhibitor of glutamine synthesis (methionine sulfoximine) on ammonia toxicity and metabolism. J. Lab. Clin. Med. 64(3) 442-449. 

Alanine appears to be formed primarily by alanine dehydrogenase in A. cylindrica, C. licheniformey P. boryanumy and A. nidulanSy because the inhibition of formation of glutamate and glutamine by methionine sulfoximine is not accompanied by a comparable inhibition in the formation of alanine (Table I). Moreover, alanine formation by these species was not reduced in the presence of aminooxy acetate, an inhibitor of amino transfer reactions (I3,J4). However, in A. variabilis alanine appears to be formed by a transamination reaction, because synthesis of [ N]alanine from was strongly inhibited in the presence of... 

Two observations indicate that aspartate is formed primarily by a transamination reaction, probably from glutamate, rather than by a direct amination with NH4 in A. cylindrica. First, N-label in aspartate was reduced more than 90% by the presence of aminooxy acetate, while labeling of glutamate and glutamine was not reduced (IS). Second, [ N]aspartate was not detected when glutamate formation was inhibited either directly, by azaserine, or indirectly, when glutamine s)mthesis was inhibited by methionine sulfoximine (13). Moreover, activity of a glutamate-aspartate aminotransferase reaction has been detected in vitro in two strains of A. cylindrica (1,26). 

The sequential labeling of first citrulline and then arginine are consistent with the idea that citrulline is a substrate for the synthesis of arginine. In cyanobacteria, citrulline appears to be formed by the condensation of carbamyl phosphate with ornithine (27). The inhibition of formation of citrulline (and arginine) by methionine sulfoximine, azaserine, and aminooxy acetate could be due to the reduced formations of ornithine from glutamate and carbamyl phosphate from glutamine. In... 

Glutamine s)mthetase (GS) with Mn(II) and methionine sulfoximine (MSOX) D= 140 D estimated from the relative intensity of allowed and forbidden transitions of the central sextet (RM)... 

Glutamine synthetase Methionine sulfoximine a-Ethylmethionine sulfoximine 7-10 11... 

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... 

SELECTIVE INHIBITION OF THE SYNTHESIS OF GLUTAMINE AND GLUTATHIONE BY ANALOGS OF METHIONINE SULFOXIMINE... 

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