Diamine-induced inhibition of liver ornithine decarboxylase

Abstract

Repeated injections of 1,3-diaminopropane, a potent inhibitor of mammalian ornithine decarboxylase, induced protein-synthesis-dependent formation of macromolecular inhibitors or ;antienzymes' [Heller, Fong & Canellakis (1976) Proc. Natl. Acad. Sci. U.S.A.73, 1858-1862] to ornithine decarboxylase in normal rat liver. Addition of the macromolecular inhibitors, produced in response to repeated injections of diaminopropane, to active ornithine decarboxylase in vitro resulted in a profound loss of the enzyme activity, which, however, could be partly recovered after passage of the enzyme-inhibitor mixture through a Sephadex G-75 columin in the presence of 0.4m-NaCl. This treatment also resulted in the appearance of free inhibitor. In contrast with the separation of the enzyme and inhibitory activity after combination in vitro, it was not possible to re-activate, by using identical conditions of molecular sieving, any inhibited ornithine decarboxylase from cytosol fractions obtained from animals injected with diaminopropane. However, the idea that injection of various diamines, also in vivo, induces acute formation of macromolecular inhibitors, which reversibly combine with the enzyme, was supported by the finding that the ornithine decarboxylase activity remaining after diaminopropane injection appeared to be more stable to increased ionic strength than the enzyme activity obtained from somatotropin-treated rats. Incubation of the inhibitory cytosol fractions with antiserum to ornithine decarboxylase did not completely abolish the inhibitory action of either the cytosolic inhibitor or the antibody. A single injection of diaminopropane produced an extremely rapid decay of liver ornithine decarboxylase activity (half-life about 12min), which was comparable with, or swifter than, that induced by cycloheximide. However, although after cycloheximide treatment the amount of immunotitrable ornithine decarboxylase decreased only slightly more slowly than the enzyme activity, diaminopropane injection did not decrease the amount of the immunoreactive protein, but, on the contrary, invariably caused a marked increase in the apparent amount of antigen, after some lag period. The diamine-induced increase in the amount of the immunoreactive enzyme protein could be totally prevented by a simultaneous injection of cycloheximide. These results are in accord with the hypothesis that various diamines may result in rapid formation of macromolecular inhibitors to ornithine decarboxylase in vivo, which, after combination with the enzyme, abolish the catalytic activity but at the same time prevent the intracellular degradation of the enzyme protein.

Cellular control of ornithine decarboxylase activity by its antizyme

“…Several of these individual results have been confirmed and extended by other laboratories (McCann et al, 1977;Friedman et al, 1977;Jefferson and Pegg, 1977;Poso et al, 1978;Kallio et al, 1979). McCann et al, (1977) have also demonstrated the in vivo existence of the "ODC-antizyme" complex in HTC cells.…”

Induction of Cardiac l-Ornithine Decarboxylase by Nicotinamide and Its Regulation by Putrescine

“…However, the delayed appearance of the protein inhibitor of L-ornithine decarboxylase (Fig. 9), is most likely a secondary inhibitory mechanism which is out of phase with the observed induction-repression cycle, as also concluded by others [14]. It was shown that polyamines activate the enzymatic synthesis of nuclear poly(adenosine diphosphoribose) [49].…”

Control of Ornithine Decarboxylase Activity in Physarum by Polyamines

“…Evidence has been presented to suggest that the external polyamines may induce the loss of ornithine decarboxylase activity through the stimulation of the production of a protein (antizyme) which specifically binds and inactivates this enzyme [6-81. Other investigators, however, feel that the formation of this antizyme is not functional in the rapid decay in enzyme activity [9,10]. Although this sensitivity to exogenous polyamines has now been Enzyme.…”