Y-Glutamyl synthetase

The cyclic sulfoximine 93a,b, a key intermediate in the synthesis of sulfoximine 94 designed as inhibitors of Escherichia Coli y-glutamyl synthetase, was synthesized stereoselectively (96BMC(6)1437, 98BMC(6)1935). X-ray analysis (99AX(C55)1598) of 93b was performed, elucidating the configuration. 

GSH is synthesized by two enzymes, y-glutamyl cysteine is formed from cysteine and glutamate by y-glutamyl synthetase. GSH is formed from y-glutamyl cysteine and glycine by glutathione synthetase. Both enzymes are found in the brain (Figure 13.7). 

Oxidation of thiols in proteins is often involved in regulation of enzyme activity, such as glucose-6-phosphate dehydrogenase, pyruvate kinase, brain adenylate cyclase, y-glutamyl-synthetase and others (Elstner, 1990) Carbonyl compounds can be attacked by amino groups. In-... 

Phosphinic Acids for Cancer Treatments 5.1 Inhibitors of Folylpoly-y-Glutamyl Synthetase... 

Fig. 16.1 The y-glutamyl cycle and pyroglutamic aciduria. Pyroglutamic acidura occurs because of a generalized deficient activity of glutathione (y-glutamyl) synthetase (EC 6.323).

The kinetic reaction mechanism appears to be random, and for the reaction to proceed, all substrates must reside as a E-D-Ala-D-Ala-MgATP quaternary complex. Except for its activation of an a-carboxylate to form a peptide bond, the enzyme s mechanism appears to be completely analogous to that catalyzed by glutamine synthetase, which forms a y-glutamyl-phosphate intermediate. There is strong evidence for the participation... 

This enzyme [EC 6.3.2.17], which is also known as folyl-poly-y-glutamate synthetase, catalyzes the sequential ATP-dependent addition of glutamyl groups onto tetra-hydrofolyl-[Glu] to yield tetrahydrofolyl-[Glu] +i plus ADP and orthophosphate. 

Enzymes can also undergo other side reactions under conditions that divert a chemically reactive intermediate from its usual catalytic function. Again, glutamine synthetase is an excellent example (see figure above), because its side reactions include acyl-phosphate reduction by borohydride, pyroglutamate formation, and the formation of y-glutamyl hydroxamate in the presence of hydroxylamine and arsenate. 

See specific aminotransferase Glutamate as a substrate or product, GLUTAMATE DECARBOXYLASE GLUTAMATE DEHYDROGENASE GLUTAMATE SYNTHASE GLUTAMINE SYNTHETASE y-GLUTAMYL TRANSPEPTIDASE LEUCINE AMINOTRANSEERASE LYSINE 6-AMINOTRANSEERASE... 

BIFUNCTIONAL ENZYME GLUTAMINYL-tRNA SYNTHETASE AMINOACYL-tRNA SYNTHETASES y-Glutamyl carboxylase,... 

The inhibition of membrane Ca2+/Mg2+ ATPase leads to a derangement of Ca2+ levels, which will damage the mitochondria and hence also indirectly contribute to ATP depletion. Inhibition of y-glutamyl cysteine synthetase reduces the ability of the liver cell to synthesize new GSH, so reducing its ability to protect itself. Overall, some 17 enzymes have been shown to be inhibited ex vivo after treatment of animals and another 14 are known to have bound paracetamol and may or may not be inhibited. 

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. 1. The y-glutamyl cycle. I, y-Glutamylcysteine synthetase II, glutathione synthetase III, y-glutamyl transpeptidase IV, y-glutamyl cyclotransferase V. peptidase. PCA = pyrrolidone carboxylic acid AA = amino acid.

In the folate coenzymes, the pteridine ring is fully reduced to tetrahydro-folate, although the oxidized form, dihydrofolate, is an important metabolic intermediate. In the reactions of thymidylate synthetase (Section 10.3.3) and methylene tetrahydrofolate reductase (Section 10.3.2.1), the pteridine ring has a redox role in the reaction. The folate coenzymes are conjugated with up to six additional glutamate residues, finked by y-glutamyl peptide bonds. 

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