Antizymes

Antizymes are regulatory proteins found in many eukaryotes that control polyamine levels by inhibiting the activity of ornithine decarboxylase (ODC) and by affecting polyamine transport. They form part of a feedback system that maintains cellular polyamine homeostasis, responding to elevated polyamine concentrations by limiting further synthesis and uptake.

In mammals, antizymes are encoded by OAZ genes (for example, OAZ1, OAZ2, and OAZ3). The production of the full-length antizyme protein often relies on a programmed ribosomal frameshift, particularly for OAZ1, a mechanism stimulated by higher polyamine levels. The main mode of action is binding to ODC, which not only inhibits its catalytic activity but also targets the enzyme for degradation by the 26S proteasome in a ubiquitin-independent manner. Antizymes also downregulate polyamine transport by modulating the components of the cellular uptake system, further limiting polyamine accumulation.

Antizyme inhibitors (AZIN1 and AZIN2) are homologous proteins that resemble ODC but lack decarboxylase activity. They bind antizymes with high affinity, preventing them from inhibiting ODC and allowing continued polyamine synthesis and uptake; this creates a regulatory counterbalance within the polyamine pathway.

Biological and clinical relevance includes roles in cell growth, proliferation, and development. Dysregulation of antizymes or their inhibitors has been linked to cancer and other disorders, making the antizyme–inhibitor system a focus of research into polyamine biology and potential therapeutic targets.