Nh2 H

Mg-ATP Mg-ADP

y-GCS H3C

L-BSO-W-phosphate

Enzyme inhibition FIGURE 12.6 Inhibition of g-GCS by l-BSO.

It is known that l-glutamate is phosphorylated by MgATP to form the enzyme-bound intermediate g-glutamylphosphate, which subsequently reacts with the amino group of cysteine. Similarly, l-BSO is phosphorylated on the sulfoximine nitrogen. This phosphorylated product is tightly, although not covalently, bound to the active site of the enzyme g-GCS, which remains inhibited until this product and MgADP are dissociated. The geometry of the sulfoximine group resembles the tetrahedral adduct formed in the attack of the cysteine amino group to the mixed anhydride g-glutamylphosphate and it is considered as a transition state analogue (Fig. 12.6). The l-buthionine-(S)-sulfoximine causes essentially irreversible inhibition, while the l-buthionine-(R)-sulfoximine is a reversible inhibitor that binds competitively with respect to l-glutamate.54

l-BSO has proven its efficacy as an enhancer of the antitumor activity of the alkylating agent melphalan in Phase I and II clinical trials, while other clinical trials have shown that administration of l-BSO depletes intracellular GSH levels in circulating white blood cells as much as 60-80%. However, the extent to which this depletion enhances tumor cell sensitivity without augmenting toxicity to normal cells remains to be determined.55

The second strategy that has not been still tested clinically involves the use of a hammerhead ribozyme against g-GCS mRNA (a ribozyme to cleave the g-GCS mRNA), to downregulate specifically the enzyme levels.56

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