Regulation of polyamine biosynthesis by antizyme and some recent developments relating the induction of polyamine biosynthesis to cell growth

This review considers the role of antizyme, of amino acids and of protein synthesis in the regulation of polyamine biosynthesis. The ornithine decarboxylase of eukaryotic cells and of Escherichia coli can be non-competitively inhibited by proteins, termed antizymes, which are induced by di- and poly- amines. Some antizymes have been purified to homogeneity and have been shown to be structurally unique to the cell of origin. Yet, the E. coli antizyme and the rat liver antizyme cross react and inhibit each other's biosynthetic decarboxylases. These results indicate that aspects of the control of polyamine biosynthesis have been highly conserved throughout evolution. Evidence for the physiological role of the antizyme in mammalian cells rests upon its identification in normal uninduced cells, upon the inverse relationship that exists between antizyme and ornithine decarboxylase as well as upon the existence of the complex of ornithine decarboxylase and antizyme in vivo. Furthermore, the antizyme has been shown to be highly specific; its Keq for ornithine decarboxylase is 1.4 X 10(11) M-1. In addition, mammalian cells contain an anti-antizyme, a protein that specifically binds to the antizyme of an ornithine decarboxylase-antizyme complex and liberates free ornithine decarboxylase from the complex. In E. coli, in which polyamine biosynthesis is mediated both by ornithine decarboxylase and by arginine decarboxylase, three proteins (one acidic and two basic) have been purified, each of which inhibits both these enzymes. They do not inhibit the biodegradative ornithine and arginine decarboxylases nor lysine decarboxylase. The two basic inhibitors have been shown to correspond to the ribosomal proteins S20/L26 and L34, respectively. The relationship of the acidic antizyme to other known E. coli proteins remains to be determined. In mammalian cells, ornithine decarboxylase can be induced by a broad spectrum of compounds. These range from hormones and growth factors to natural amino acids such as asparagine and to non-metabolizable amino acid analogues such as alpha-amino-isobutyric acid. The amino acids that induce ornithine decarboxylase as well as those that promote polyamine uptake utilize the sodium dependent A and N transport systems. Consequently, they act in concert and increase intracellular polyamine levels by both mechanisms. The induction of ornithine decarboxylase by growth factors, such as NGF, EGF, and PDGF as well as by insulin requires the presence of these same amino acids and does not occur in their absence. However, the inducing amino acid need not be incorporated into protein nor covalently modified.(ABSTRACT TRUNCATED AT 400 WORDS)