Regulation of Ornithine Decarboxylase

Abstract

Ornithine decarboxylase (ODC) initiates the polyamine biosynthetic pathway. The amount of ODC is altered in response to many growth factors, oncogenes, and tumor promoters and to changes in polyamine levels. Susceptibility to tumor development is increased in transgenic mice expressing high levels of ODC and is decreased in mice with reduced ODC due to loss of one ODC allele or elevated expression of antizyme, a protein that stimulates ODC degradation. This review describes key factors that contribute to the regulation of ODC levels, which can occur at the levels of transcription, translation, and protein turnover. L-Ornithine decarboxylase (ODC)2 catalyzes the first step in the polyamine biosynthetic pathway forming putrescine, which is then converted into the polyamines spermidine and spermine (1-4) (Fig. 1). In some microorganisms and in plants, putrescine can also be made from arginine via an arginine decarboxylase and subsequent conversion of the agmatine to putrescine. However, evidence for a mammalian arginine decarboxylase is controversial (5), and ODC provides the only established route for polyamine synthesis de novo. Polyamine content plays important roles in both normal and neoplastic growth and alterations of polyamine synthesis via changes in ODC content occur in response to tumor promoters and carcinogens (2, 3).ODC is very highly regulated, and ODC activity varies in response to many stimuli. These alterations in activity are brought about by changes in the amount of ODC protein, which turns over very rapidly. ODC degradation is controlled by a protein termed antizyme, which responds to polyamine concentration. ODC is also regulated at the level of transcription and the ODC gene is one of the targets of the Myc/Max transcription factor. A third level of regulation occurs in the translation of ODC mRNA. This brief review discusses these aspects of ODC and some relevant structural and comparative data focusing on relatively recent studies. Summaries of the vast literature describing earlier work on ODC, the myriad of factors altering its activity, and its value as a drug target are contained in previous reviews (2-4, 6). ODC Structure and ActivityODC is a pyridoxal phosphate (PLP)-dependent amino acid decarboxylase. Biochemical studies showed that it is a homodimer with two active sites each made up of residues from both subunits (7). Crystallographic determination of the structures of mammalian and Trypanosoma brucei ODCs (8, 9) confirmed these observations. The structure of eukaryote ODC is that of a group IV decarboxylase, structurally homologous to the bacterial and plant arginine decarboxylases, bacterial diaminopimelic acid decarboxylase, and alanine racemase but unrelated to the bacterial ODCs.Eukaryotic ODCs are, in general, highly specific for L-ornithine with a very weak activity on L-lysine and an even lower activity on L-arginine (10). However, a homolog was isolated from Paramecium bursaria chlorella virus. This protein has a key amino acid substitution (Glu for Asp) in a residue that ...

Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes

“…Therefore, the effects of treatment with 1c or 2d on polyamine biosynthesis and polyamine pools were determined in HCT116 (SI Table 1). No changes in polyamine pools were observed after 48-h exposure to 5 M of either compound and only treatment with 2d was observed to result in a modest decrease (Ϸ40%) in activity of the rate-limiting step of polyamine biosynthesis, ornithine decarboxylase (37). These results are consistent with the hypothesis that the changes in chromatin marks and gene reexpression observed are not a result of changes in polyamine pools, but are due to inhibition of LSD1.…”

Allosteric regulation of an essential trypanosome polyamine biosynthetic enzyme by a catalytically dead homolog

“…The polyamine pathway is tightly regulated in many species, including mammals, plants, and yeast, where the biosynthetic enzymes are controlled by transcriptional and translational regulation, and by several posttranslational mechanisms, including regulation of protein stability (4). AdoMetDC from the trypanosomatid parasites has evolved to be regulated by a mechanism not found in any other species.…”

“…The polyamine biosynthetic and catabolic enzymes are tightly regulated in animals, plants, and yeast (3,4,24). Unusually, in the trypanosomatid parasites, analogous regulatory mechanisms for the control of polyamine biosynthesis have not been identified.…”

“…In trypanosome parasites, the polyamine spermidine is conjugated with glutathione to form a unique cofactor termed trypanothione that functions in cellular redox reactions (7). Excess polyamines lead to cancer in mammalian cells (4), and inhibitors of polyamine biosynthesis have been widely studied for their potential as antiproliferative agents (6,8). The most successful clinical application of these inhibitors is the treatment of African sleeping sickness with the ornithine decarboxylase suicide inhibitor ␣-dif luoromethylornithine (ef lornithine) (9).…”

“…Polyamines are essential for cell growth in all organisms. They inf luence chromatin structure, modify translation initiation factor eIF5A, and regulate gene expression through a number of mechanisms (3)(4)(5)(6). In trypanosome parasites, the polyamine spermidine is conjugated with glutathione to form a unique cofactor termed trypanothione that functions in cellular redox reactions (7).…”