A safety catch for ornithine decarboxylase degradation

Feedback inhibition is a common mechanism to adjust the activity of an enzyme in accordance with the abundance of a product. The enzyme catalyzing the initial, committing step of a biosynthesis cascade is subject to negative feedback by the end-product. This kind of regulation is frequent in all cell types to regulate biosynthesis of numerous metabolites; a classical textbook example is the serine biosynthesis pathway [1]. The first irreversible reaction (A->B) is regulated by the end-product (Z) of the biosynthesis pathway (Figure 1A). In E. coli, serine inhibits 3-phosphoglycerate dehydrogenase activity by binding to a regulatory site within the enzyme. Thus, the enzyme is inactive whenever serine is in excess. Negative feedback can be implemented also in a different way: the endproduct influences abundance and activity of a proteinbased inhibitor, which regulates the enzyme catalyzing the initial step, to control the flux through the biosynthesis pathway. An example for this kind of feedback inhibition in eukaryotic cells is the regulation of polyamine-levels by feedback inhibition of ornithine decarboxylase (ODC) (Figure 1B), which is rate-limiting for the synthesis of the aliphatic polyamines putrescine, spermidine and spermine [2, 3]. These polyamines are aliphatic polycations that influence mRNA translation, ribosome biogenesis and bind and stabilize RNA as well as DNA. Thus, numerous processes are regulated by polyamines directly or indirectly. They are essential for cell proliferation, yet, their over-abundance is cytotoxic and involvement in cell death has been observed in higher eukaryotes. Therefore, polyamine uptake and biosynthesis has to be efficiently controlled to balance polyamine levels, which requires tight feedback inhibition of ODC to maintain polyamine levels in a nontoxic concentration range. During development of most human cancers a deregulation of polyamine biosynthesis takes place. Due to the importance of polyamines for cell proliferation, ODC and polyamine biosynthesis have been chosen as anticancer targets [4]. Regulation of ODC activity is based on the proteininhibitor ODC antizyme; members of this protein family have been identified in yeast, protists and mammals [5, 6]. Biosynthesis and proteolysis of antizyme is under feedback inhibition by polyamines. The inhibitor binds ODC, converts the enzymatically active dimer into an inactive heterodimer and induces degradation of ODC [4]. Feedback inhibition of polyamine biosynthesis is accomplished by increasing the abundance of the inhibitor antizyme and decreasing the abundance of ODC, the enzyme catalyzing the ratelimiting step (Figure 1B). By concept, polyamine biosynthesis levels are controlled in a simple way, but the details of how regulation is achieved are quite interesting. A conserved mechanism