Enzyme-activated Irreversible Inhibitors of L-Omithine:2-Oxoacid Aminotransferase DEMONSTRATION OF MECHANISTIC FEATURES OF THE INHIBITION OF ORNITHINE AMINOTRANSFERASE BY 4-AMINOHEX-5-YNOIC ACID AND GABACULINE AND CORRELATION WITH IA’ VIVO ACTIVITY*

L-Ornithine:2-oxoacid aminotransferase is a specific enzyme with respect to the amino group donor. Nevertheless it was found that this enzyme is inhibited by some 4-aminobutyrate analogs, 4-aminohex-5-ynoic acid and 5-amino-l,%cyclohexadienyl-carboxylic acid (gabaculine), which are currently considered to be enzyme-activated irreversible inhibitors of I-aminobutyrate:2-oxoglutarate aminotransferase. The inhibitory mechanisms for the two h)-aminotransferases are identical. A close structural analog of these inhibitors, 4aminohex-5-enoic acid, is not inhibitory for ornithine aminotransferase, whereas it effectively inhibits 4aminobutyrate aminotransferase. The reasons for this difference are discussed. The in vitro findings are entirely transferable to the in viva situation: 4-aminohex-5-ynoic acid and gabaculine cause a long-lasting inhibition of ornithine aminotransferase in brain and liver, and reduce significantly in uiuo ornithine degradation, whereas 4-aminohex-5-enoic acid is inactive both in vivo and in vitro toward this enzyme. The enzyme-activated irreversible inhibitors allow one for the first time to study the physiological consequences of irreversible ornithine aminotransferase inhibition.