Mechanism of inactivation of ornithine decarboxylase by alpha-methylornithine.

Ornithine decarboxylase from Lactobacillus 30a is gradually inactivated by treatment with alpha-methylornithine, but activity is restored by treatment of the inactivated enzyme with pyridoxal phosphate. Inactivation of the enzyme is associated with formation of pyridoxamine phosphate and 5-amino-2-pentanone, alpha-Methylornithine is decarboxylated by the enzyme about 6000 times more slowly than is ornithine under the same conditions. These observations provide an explanation for the previously observed inhibition of ornithine decarboxylase by alpha-methylornithine [M. M. Adbel-Monem, N. E. Newton, and C. E. Weeks (1974), J. Med. Chem. 17, 4447]: alpha-Methylornithine undergoes a decarboxylation-dependent transamination as a result of incorrect protonation of the quinoid intermediate which is formed by decarboxylation of the enzyme-bound pyridoxal phosphate-substrate Schiff base. This protonation produces inactive enzyme. Decarboxylation of ornithine by this enzyme produces a small amount of 4-aminobutanal, presumably also by decarboxylation-dependent transamination.