Enzyme-activated irreversible inhibitors of L-ornithine:2-oxoacid aminotransferase. Demonstration of mechanistic features of the inhibition of ornithine aminotransferase by 4-aminohex-5-ynoic acid and gabaculine and correlation with in 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-1,3-cyclohexadienyl-carboxylic acid (gabaculine), which are currently considered to be enzyme-activated irreversible inhibitors of 4-aminobutyrate:2-oxoglutarate aminotransferase. The inhibitory mechanisms for the two omega-aminotransferases are identical. A close structural analog of these inhibitors, 4-aminohex-5-enoic acid, is not inhibitory for ornithine aminotransferase, whereas it effectively inhibits 4-aminobutyrate aminotransferase. The reasons for this difference are discussed. The in vitro findings are entirely transferable to the in vivo situation: 4-aminohex-5-ynoic acid and gabaculine cause a long-lasting inhibition of ornithine aminotransferase in brain and liver, and reduce significantly in vivo 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.
D000614:Aminocaproates / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000201:enzymology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D003514:Cyclohexylamines / Q000494:pharmacology; D004789:Enzyme Activation; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D009928:Organ Specificity; D009953:Ornithine-Oxo-Acid Transaminase / Q000037:antagonists & inhibitors*; D051381:Rats; D000637:Transaminases / Q000037:antagonists & inhibitors*
D000614:Aminocaproates; D003509:Cyclohexanecarboxylic Acids; D003514:Cyclohexylamines; C012987:gabaculine; D000637:Transaminases; D009953:Ornithine-Oxo-Acid Transaminase