オルニチン脱炭酸酵素の調節機序研究の一軌跡

日周リズムから分解制御へ

抄録

This paper summarizes the results of my quarter-century study on the regulatory mechanism of ornithine decarboxylase (ODC), a key enzyme in polyamine synthesis. ODC turns over rapidly and is under negative feedback regulation by polyamines, which accelerate ODC degradation and induce an ODC-inhibitory protein, antizyme. Rat-liver ODC levels exhibit a circadian rhythm with the peak at night, owing to the feeding pattern. The dietary induction of hepatic ODC depends on both the quantity and quality of dietary proteins. In order to clarify the molecular mechanism of ODC regulation, rat-liver ODC was purified to homogeneity. Antizyme was also highly purified and its cDNAs were obtained. Forced expression of antizyme caused rapid ODC degradation, proving that antizyme mediates polyamine-induced destabilization of ODC. In newly established in vitro ODC degradation systems, ODC is degraded in an ATP- and antizymedependent manner by 26 S proteasome without ubiquitination. Antizyme also inactivates polyamine uptake. Nucleotide sequence analysis of antizyme mRNA revealed that programmed ribosomal frameshifting evoked by polyamines is necessary for its translation.