Abstract
The intracellular levels of polyamines, cationic molecules involved in a myriad of cellular functions ranging from cellular growth, differentiation and apoptosis, is precisely regulated by antizymes and antizyme inhibitors via the modulation of the polyamine biosynthetic and transport systems. Antizymes, which are mainly activated upon high polyamine levels, inhibit ornithine decarboxylase (ODC), the key enzyme of the polyamine biosynthetic route, and exert a negative control of polyamine intake. Antizyme inhibitors (AZINs), which are proteins highly homologous to ODC, selectively interact with antizymes, preventing their action on ODC and the polyamine transport system. In this review, we will update the recent advances on the structural, cellular and physiological functions of AZINs, with particular emphasis on the action of these proteins in the regulation of polyamine metabolism. In addition, we will describe emerging evidence that suggests that AZINs may also have polyamine-independent effects on cells. Finally, we will discuss how the dysregulation of AZIN activity has been implicated in certain human pathologies such as cancer, fibrosis or neurodegenerative diseases.
Highlights
In mammalian cells, the control of the polyamine homeostasis is critical for the maintenance of cellular functions, since these molecules participate and modulate cellular processes such as cell growth, proliferation, differentiation and apoptosis [1,2,3]
This finding was in agreement with the notion, above commented, that AZIN1 exerts a positive effect on intracellular polyamine levels by repressing the inhibitory action of antizymes on the polyamine biosynthetic and transport pathways
AZIN2 share the capacity to interact with the three AZs, and as a result both proteins are able to increase polyamine biosynthesis and uptake
Summary
The control of the polyamine homeostasis is critical for the maintenance of cellular functions, since these molecules participate and modulate cellular processes such as cell growth, proliferation, differentiation and apoptosis [1,2,3]. The post-translational control of ODC is mediated by a series of antagonistic proteins, antizymes (AZs) and antizyme inhibitors (AZINs) that down-regulate or up-regulate, respectively, the activity of ODC and the levels of polyamines [17] (Figure 1). Antizyme inhibitors (AZIN1 and AZIN2) are proteins homologous to ODC lacking enzymatic activity, that are able to interact with AZs even more efficiently than ODC, counteracting the negative effect of AZs on the biosynthesis of intracellular polyamines [17,33,34] (Figure 2). (5) Antizyme inhibitor (AZIN) binds with higher affinity to AZ decreasing the negative effect of AZ on ODC and polyamine uptake. (10) PAs stimulate the synthesis of AZs, by inducing the ribosomal frame-shifting at the stop codon of the ORF1 of AZ mRNA, allowing the translation of the ORF2.
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