Glutamine structural analogs

The tertiary structure of glutamate racemase has already been resolved and it has also been shown that a substrate analog glutamine binds between two cysteine residues. These data enabled us to predict that the new proton-donating amino acid residue should be introduced at position 74 instead of Gly for the inversion of enantioselectivity of the decarboxylation reaction. 

Many years ago Meister s group (96-101) synthesized of a number of inhibitors or substrate analogs that would mimic the intermediates in the proposed pathway of the reactions catalyzed by glutamine synthetase. Two of these are listed below, along with the structures for substrates and two alleged intermediates. 

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... 

Several steps in the de novo purine biosynthetic pathway may be inhibited by antitumor agents. Steps requiring glutamine (2 and 5) are sensitive to azaserine, a glutamine analog. Its structure is shown in Figure 10.7. Steps requir-... 

Figure 10.7 Structure of azaserine, a glutamine analog and inhibitor of purine biosynthesis.

As shown in Fig. 12-15, the side chain of Asn 175 provides papain with a third member of a catalytic triad analogous to that of serine pro teases.Glutamine 19, together with the pephde backbone NH of Cys 25, provides an oxyanion hole. Many studies, including structure determinahons on bound aldehyde and other inhibitors, and observahon by indicate that... 

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