Characteristics of the Inhibition of Ornithine-δ-aminotransferase by Branched-chain Amino Acids

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Abstract
1. The inhibition of rat liver ornithine-δ-aminotransferase [EC 2.6.1.13] by branched-chain amino acids (L-valineL-isoleucineL-leucine) was highly specific among various amino acids and metabolites tested. In chemical characterization of the inhibitor structure, the carboxyl group was essential, but the α-amino group was only complementary. The inhibitory action was largely dependent on the branched structure of the hydrophobic residue. It was shown that only L-valine exists in a great enough concentration in mitochondria to inhibit the forward reaction. 2. In the overall reaction, inhibition by L-valine was absolutely competitive with respect to ornithine, noncompetitive with respect to glutamate and pyrroline-5-carboxylate, and uncompetitive with respect to 2-oxoglutarate. The kinetic results showed that L-valine interacts only with the phosphopyridoxal enzyme, resulting in inhibition of the forward reaction, but L-valine was a noncompetitive inhibitor in the reverse reaction. In the forward reaction: Km for L-ornithine, 1.0 mM; Ki for L-valine, 2.0 mM; Km for 2-oxoglutarate, 0.7 mM. In the reverse reaction; Km for L-glutamate, 25 mM; Ki for L-valine, 20 mM; Km for DL-pyrroline-5-carboxylate, 1.4 mM. The Ki value for L-valine in the forward reaction was 10 times smaller than that in the reverse reaction. Thus, the forward reaction is readily inhibited in the presence of actual intramitochondrial concentrations of L-valine. The exchange reactions (α and δ-amino exchange reacions, respectively) were also affected by L-valine, as well as the overall reaction.

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