Glutamine synthase, inhibitors

Both threo- (14) and eo f >"4-fluoro-DL-glutamic acid (/5) are noncompetitive inhibitors of glutamine synthase, an enzyme that catalyzes the synthesis of glutamine from L-glutamic acid and ammonia. This mhibibon may explain the... 

Molecules with structures as diverse as carbamoyl-phosphate, tryptophan, and cytidine triphosphate are feedback inhibitors of the E. coli glutamine synthase. The feedback inhibition is cumulative, with each metabolite exerting a partial inhibition on the enzyme. Why would complete inhibition of the glutamine synthase by a single metabolite be metaboli-cally unsound ... 

Acivicin is a potent inhibitor of several steps in purine nucleotide biosynthesis that utilize glutamine. The enzymes it inhibits are glutamine PRPP amidotransferase (step 1, fig. 23.10), phosphoribosyl-A-formylglycinamidine synthase (step 4, fig. 23.10), and GMP synthase (see fig. 23.11). In pyrimidine nucleotide biosynthesis the enzymes inhibited are carbamoyl synthase (step 1, fig. 23.13) and CTP synthase (see fig. 23.14). Acivicin is under trial for the treatment of some forms of cancer. 

Inhibitor studies (Leaet al., 1979) have shown that the synthesis of protein from glutamine by isolated pea cotyledons is unaffected by MSO but inhibited by azaserine, consistent with the action of glutamate synthase but not very conclusive because of the side effects of azaserine. Little if any labeling data on ammonia assimilation has so far been produced using developing seeds. 

However, models which assume that ammonia is assimilated solely via GDH cannot account in quantitative terms for the observed rates of NH/ incorporation (Rhodes et al, 1980 Fentem et ai, 1983a). Rhodes et ai, (1989) modeled the kinetics of NH4 incorporation in tobacco cell cultures and suggest that up to 30% of the ammonia assimilated may enter via the GDH reaction. However, the relative sizes of the glutamate and glutamine pools made it difficult to distinguish between the simultaneous operation of alternative pathways and Rhodes et al. were unable to verify the model when inhibitors of GS and GOGAT were used to block the glutamate synthase cycle. 

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