Use of aminopropyltransferase inhibitors and of non-metabolizable analogs to study polyamine regulation and function

The polyamines spermidine and spermine are essential for the growth of mammalian cells. This review describes the properties of the two aminopropyltransferases that are responsible for their biosynthesis, the synthesis and use of specific aminopropyltransferase inhibitors, and the use of analogs of the polyamines to investigate polyamine transport and function. Highly specific and potent multisubstrate adduct inhibitors of these enzymes have been synthesized while less potent inhibitors have been obtained by the synthesis of amines that bind at the active site. Studies with these inhibitors indicate that polyamines are needed for a normal rate of growth and that, although some of the functions of polyamines may be interchangeable, other functions may have a specific requirement for spermidine or spermine. Two groups of growth-promoting polyamine analogs can be distinguished: the many that are effective in short-term experiments compared to the few that can act over a prolonged period. The more stringent structural requirements for long-term growth are probably due to a need for spermidine, or a closely related analog, as a precursor of hypusine in the protein eIF-5A. Metabolically resistant polyamine analogs can be used as model substrates for studies of the polyamine transport system, which plays a critical role in maintaining normal cellular polyamine levels. The feedback regulation by high levels of polyamines that downregulates transport is essential to prevent the accumulation of polyamines at toxic levels. Such accumulation may be associated with apoptosis and, therefore, polyamine analogs are useful tools for investigating the mechanism(s) of polyamine-mediated toxicity.