Elsevier

Biochemical Pharmacology

Volume 12, Issue 9, September 1963, Pages 989-1000
Biochemical Pharmacology

The nature of the inhibition in vitro of cerebral glutamine synthetase by the convulsant, methionine sulfoximine

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Abstract

The nature of the inhibition of glutamine synthetase of rat cerebral cortex by the convulsant agent, dl-methionine-dl-sulfoximine (MSO) has been examined. In view of the high degree of structural latency of the enzyme in brain, the inhibition of the enzyme in particulate and soluble form was studied and found to be the same. Competition between l-glutamate and MSO for the enzyme site(s) could be demonstrated as one of the mechanisms of inhibition. Preincubation of the enzyme with ATP, but not with l-glutamate, afforded some protection toward inhibition by MSO; preincubation with MSO, however, led to no enhancement of the inhibition. l-Methionine, and other compounds structurally related to l-glutamate, failed to alleviate the inhibition.

It is suggested that, as shown here in vitro, MSO acts also in vivo, by inhibiting the glutamine synthesizing system. It does so by causing depletion of ATP and, possibly, glutamate in the intracellular compartment within the boundaries of which the synthesis of glutamine occurs. It is further visualized that the differences between the effects in vitro and in vitro of methionine may be due to the necessity, fulfilled only in vitro, of replenishing discrete subcellular compartments with substrates (ATP and glutamate).

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    Supported in part by Grant H-1525 from the National Institutes of Health and by Institutional Grant 1N-24D from the United States Public Health Service to Tulane University.

    Recipient of a Tulane University Student Research Award.

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