Identification, Assay, and Functional Analysis of the Antizyme Inhibitor Family

Polyamines are small aliphatic polycations present in all living cells. Polyamines are involved in regulating fundamental cellular functions and are absolutely essential for the process of cellular proliferation. Because they fulfill essential cellular functions, their intracellular concentration is tightly regulated via a unique autoregulatory circuit that responds to the intracellular concentration of polyamines. In the heart of this circuit is a small protein called antizyme (Az), whose synthesis is stimulated by polyamines. Az inactivates Ornithine decarboxylase [(ODC), the first key enzyme in the polyamine biosynthetic pathway] and marks it for ubiquitin-independent degradation by the 26S proteasome. In addition, Az inhibits uptake of polyamines via a yet unresolved mechanism. Az itself is subjected to regulation by an ODC-related protein termed antizyme inhibitor (AzI). AzI is highly homologous to ODC, but it lacks ornithine decarboxylating activity. Since its affinity to Az is greater than the affinity Az has for ODC, it rescues ODC from degradation and enables polyamines uptake into the cell.