FIGURE 2: Regulation of ornithine decarboxylase activity by polyamines in yeast.

Ornithine decarboxylase (ODC) is an enzyme that catalyzes the rate-limiting commitment step in polyamine biosynthesis. It is a dimer in its active form and is inhibited by antizyme, which binds to ODC in a one-to-one complex as heterodimer. The yeast gene encoding antizyme is called OAZ1, which produces an mRNA with two ORFs. To produce the full protein, a +1 frameshift during antizyme mRNA translation is necessary at the ribosome, which is induced by the polyamines spermidine or spermine. Antizyme does not have to be present in large amounts to inhibit ODC activity, as binding of ODC by antizyme leads to presentation of the ODC degradation sequence (ODS), which induces proteasomal degradation. This step is directly promoted by polyamines. Polyamines could increase ODS presentation, enhance binding of antizyme to proteasomes, or both (dashed red arrows). Antizyme itself escapes destruction by the proteasome, thus even low levels of antizyme catalyze degradation of ODC. Antizyme stability is regulated by polyamines as well; the presence of polyamines reduces antizyme proteolysis by an ubiquitin-dependent proteasomal degradation process. The latter depends on the ubiquitin-activating enzyme (E1) Uba1, the ubiquitin–conjugating enzymes Ubc4 and Ubc5 (E2), and an unidentified ubiquitin-protein ligase (E3). Overall, polyamines influence ODC activity threefold; they enhance ODC proteolysis, increase antizyme levels by promoting its biosynthesis and inhibit its destruction, which provides a negative feedback loop for ODC regulation by polyamines.

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