Decarboxylation of α-difluoromethylornithine by ornithine decarboxylase

The mechanism of inactivation of rodent ornithine decarboxylase by α-difluoromethylornithine (DFMO) was studied using the inhibitor labelled with ¹⁴C in both the 1 and the 5 positions. [1-¹⁴C]DFMO was a substrate and was decarboxylated by the enzyme yielding ¹⁴CO₂. A radioactive metabolite derived from [5-¹⁴C]DFMO was bound to the enzyme, and the extent of binding paralleled the irreversible inactivation of ornithine decarboxylase. The partition ratio of decarboxylation to binding was approx. 3.3. These results provide support for the postulated mechanism of action of DFMO [metcalf, Bey, Danzin, Jung, Casera & Vevert (1978) J. Am. Chem. Soc. 100, 2551-2553], in which enzynmic decarboxylatio of the inhibitor leads to the generation of a conjugated imine, which then alkylates a nucleophilic residue on the enzyme.