Antizyme and antizyme inhibitor, a regulatory tango

Abstract

The polyamines are small basic molecules essential for cellular proliferation and viability. An autoregulatory circuit that responds to the intracellular level of polyamines regulates their production. In the center of this circuit is a family of small proteins termed antizymes. Antizymes are themselves regulated at the translational level by the level of polyamines. Antizymes bind ornithine decarboxylase (ODC) subunits and target them to ubiquitin-independent degradation by the 26S proteasome. In addition, antizymes inhibit polyamine transport across the plasma membrane via an as yet unresolved mechanism. Antizymes may also interact with and target degradation of other growth-regulating proteins. An inactive ODC-related protein termed antizyme inhibitor regulates polyamine metabolism by negating antizyme functions. The ability of antizymes to degrade ODC, inhibit polyamine uptake and consequently suppress cellular proliferation suggests that they act as tumor suppressors, while the ability of antizyme inhibitors to negate antizyme function indicates their growth-promoting and oncogenic potential.

Structural basis of antizyme-mediated regulation of polyamine homeostasis

“…which effectively restores ODC activity by competing with ODC for Az 1 binding (6,14). Together, ODC, AzIN, and the various Az isoforms form a delicate regulatory circuit to coordinate polyamine biosynthesis, in which ODC and AzIN serve as positive regulators and are considered oncogenic because they promote cell growth and transformation (15).…”

“…Regulation of polyamine homeostasis is achieved mainly by adjusting the catalytic activity and protein abundance of ornithine decarboxylase (ODC), a homodimeric and pyridoxal 5ʹ-phosphatedependent enzyme that catalyzes the committed and rate-limiting step in polyamine biosynthesis, through the actions of the regulatory proteins antizyme isoform 1 (Az 1 ) and antizyme inhibitor (AzIN) (3,6). Elevation of cellular polyamine levels induces the translation of the full-length Az 1 , an intracellular ODC inhibitory protein, by stimulating the bypassing of an in-frame stop codon on Az 1 mRNA (7,8) and by relieving the translational repression effect mediated through the N-terminal fragment of Az 1 (9).…”

“…The identification of antizyme isoform 2 (Az 2 ) and antizyme isoform 3 (Az 3 ) (12, 13), the tissue and development-specific Az isoforms, further underscores the physiological significance of keeping the cellular polyamine concentrations under tight control. Unlike Az 1 , however, Az 2 and Az 3 simply inhibit the catalytic activity of ODC without promoting its degradation, which allows a protein synthesis-independent restoration of ODC activity (6).…”

Antizyme Affects Cell Proliferation and Viability Solely through Regulating Cellular Polyamines

“…Az inhibits cell proliferation and displays antitumor activity, and therefore, it is regarded as a tumor suppressor (12)(13)(14)(15). Mammalian cells express three characterized members of the Az family of proteins (6,16). While one of them, Az3, is testis-specific and observed only in haploid germinal cells (17,18), the other two, the prototypical Az1 and Az2, are ubiquitously expressed, with Az1 being expressed at much higher levels (5,6,19).…”

Role of polyamines, their analogs and transglutaminases in biological and clinical perspectives

“…This enzyme is a rate-limiting step in polyamine biosynthesis and associates with a specific antizyme except for plants. ODC antizyme inhibitors act mainly as positive regulators of polyamine levels by binding to antizymes (Kahana 2009;Mangold 2006;López-Contreras et al 2010). There is also evidence that they may affect other important cellular proteins (Kahana 2009;Dulloo et al 2010).…”