The diamine putrescine and polyamines spermidine and spermine are ubiquitous physiological cations. They are essential for normal cell growth and differentiation. Their functions at the molecular level are not completely clarified, but are almost certainly mediated by their ability to bind various negatively charged structures and macromolecules in cells. The most important single characteristics of polyamines is likely to be their ability to bind nucleic acids and especially DNA. In addition, polyamines have important role in the regulation of some major classes of cation channels and spermidine is a precursor of an unusual amino acid hypusine needed for the synthesis of translation initiation factor 5A. Polyamine biosynthesis is regulated by two key enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase. The activities of these decarboxylases are usually low in resting cells, but increase rapidly and transiently after a wide variety of growth inducing stimuli. Polyamines themselves regulate negatively both enzymes, which emphasizes the significance of maintaining polyamine concentration between appropriate limits within cells. One central component in controlling cellular polyamine levels is antizyme protein, the synthesis of which is induced by polyamines. Antizyme has ability to inhibit ODC activity and polyamine transport to cells. ODC is targeted for proteasomal degradation by binding antizyme.
In this study we wanted to elucidate the role of ornithine decarboxylase and antizyme in the polyamine metabolism of the central nervous system. The guanosine 5’-phosphate activatable ODC was discovered and characterized from the rat brain lysates. Previously GTP-activatable ODC had been found in mammalian tissues only in some tumors. Furthermore, ODC and antizyme expression in brain was localized by in situ hybridization and immunocytochemistry. In another part of the study a transgenic mouse line expressing ODC under the control of a MMTV-LTR promotor was generated and used to study the pathological and physiological effects of deregulated ODC expression during the life of transgenic animals. In addition, the role of one of the most highly conserved regions in eukaryotic ODCs was studied using site-directed mutagenesis.