Differential Inhibition of Glutamine and y-Glutamylcysteine Synthetases by a-Alkyl Analogs of Methionine Sulfoximine That Induce Convulsions*

The a-methyl and a-ethyl analogs of methionine sulfoximine, like methionine sulfoximine, induce convulsions in mice and inhibit glutamine synthetase irreversibly; cu-ethylmethionine sulfoximine is approximately 50% as inhibitory as methionine sulfoximine and a-methylmethionine sulfoximine. However, whereas cy-methylmethionine sulfoximine and methionine sulfoximine inhibit y-glutamylcysteine synthetase markedly, cY-ethylmethionine sulfoximine does not, nor does administration of the a-ethyl analog produce the decrease in tissue glutathione levels found after giving methionine sulfoximine or its a-methyl analog. The findings strongly indicate that methionine sulfoximine-induced convulsions are closely associated with inhibition of glutamine synthetase rather than with inhibition of y-glutamylcysteine synthetase. The cY-alkyl methionine sulfoximine analogs cannot be catabolized via the corresponding cy-keto or a-imino acids, and, like other a-substituted amino acids, are probably not metabolized to a significant extent in uiuo; this suggests that the amino acid sulfoximine molecules themselves, rather than their metabolites, are directly involved in the induction of convulsions. Possible explanations for the reported lack of correlation between the occurrence of convulsions and the levels of glutamine synthetase activity (and its substrates and product) are considered. The findings suggest that studies on the mechanism of induction of convulsions may be extended significantly and refined in biochemical terms by the use of other structurally modified convulsant molecules.