Mode of Inhibition of Ornithine Aminotransferase by L-Canaline1

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Abstract
The mechanism of inhibition of ornithine aminotransferase [EC 2.6.1.13] by L-canaline (α-amino-γ-amino-oxybutyric acid) was investigated. Spectral changes of pyridoxal 5′-phosphate in ornithine aminotransferase on addition of L-canaline showed that L-canaline formed an oxime-type compound with pyridoxal 5′-phosphate that had the same spectra as the compound formed on addition of hydroxylamine to the holoenzyme. Kinetic studies indicated that hydroxylamine was a reversible noncompetitive inhibitor, whereas L-canaline was an irreversible inhibitor of ornithine aminotransferase. Other analogs, such as δ-aminovaleric acid and α-N-acetyl-L-ornithine, also reacted with the pyridoxal 5′-phosphate of the enzyme, but these compounds were competitive inhibitors with respect to L-ornithine. L-Canaline and hydroxylamine also reacted with pyridoxal 5′-phosphate in pig heart aspartate aminotransferase [EC 2.6.1.1] to produce an oxime, but both of them were reversible and noncompetitive inhibitors of the enzyme. The K1 value of hydroxylamine for ornithine aminotransferase was 4.3×10−7M and those of L-canaline and hydroxylamine for aspartate aminotransferase were 1.7 ×10−4 M and 2.2×10−5M, respectively.