Inhibitory effect of 6-azauracil on purified rabbit liver 4-aminobutyrate aminotransferase.
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 beta-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 Km of 0.15 mM for 2-oxoglutaric acid and a low affinity site was associated with an I50 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.
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D066298:In Vitro Techniques; D007656:Ketoglutaric Acids / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D011817:Rabbits; D000637:Transaminases / Q000037:antagonists & inhibitors*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology*
D007656:Ketoglutaric Acids; D014498:Uracil; D000637:Transaminases; D000612:4-Aminobutyrate Transaminase; C100248:azauracil