Inhibitory Effect of 6-Azauracil on Purified Rabbit Liver 4-Aminobutyrate Aminotransferase

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Abstract
Among uracil derivatives investigated, 6-azauracil, 6-azathymine, and 5-iodouracil were found to be potent inhibitors of purified rabbit liver 4-aminobutyrate aminotransferase while 6-azauridine and 6-azauridine 5′-phosphate were not. The enzyme inhibited by 6-azauracil was reactivated by dialysis but not by addition of pyridoxal 5′-phosphate. 6-Azauracil acted as a non-competitive inhibitor with respect to β-alanine as well as 2-oxoglutaric acid, and had a K1 of approximately 0.7 mM at pH 7.3. The kinetic data suggested that 2-oxoglutaric acid acted as an inhibitor as well as an amino acceptor for the enzyme; a catalytic site was associated with an apparent K m of 0.15 mM for 2-oxoglutaric acid and a low affinity site was associated with an I 50 of approximately 5 mM for the 2-oxo acid. With inhibitory concentrations of 2-oxoglutaric acid as substrate the inhibitory effect of 6-azauracil was considerably diminished. From these findings, the inhibitory effect of 6-azauracil was revealed to be different from that of structural analogs of 4-aminobutyric acid showing that 6-azauracil is a new type of 4-aminobutyrate aminotransferase inhibitor.