Concerted Inhibition of Isocitrate Dehydrogenase by Glyoxylate Plus Oxalacetate*

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Abstract
Partially purified NADP-specific isocitrate dehydrogenase [EC 1.1.1.42] of Brevibacterium flavum was strongly inhibited by the simultaneous addition of glyoxylate and oxalacetate at low concentrations where though each of the acids singly cause only slight inhibition. Similar inhibition was observed with NADP-specific isocitrate dehydrogenases from Bacillus subtilis, Escherichia coli and pig heart. Although isocitrate dehydrogenase was also considerably inhibited by the non-enzymatic condensation product between glyoxylate and oxalacetate, the condensation reaction itself was not detected under the conditions of enzyme assay. Thus, it was concluded that the concerted inhibition did not involve intermediate formation of the condensation product. Inhibition by glyoxylate, glyoxylate plus oxalacetate, or the condensation product was competitive with respect to isocitrate while inhibition by oxalacetate was of mixed type. Further kinetic analysis indicated that glyoxylate or oxalacetate combines with enzyme which is bound with oxalacetate or glyoxylate, about 60,000 times stronger than with free enzyme. The possible role of this inhibition in the metabolic control of the TCA cycle is discussed.

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