Polyamine Metabolism

Currently, two major pathways are distinguished along which the polyamines are metabolized: the interconversion pathway and the so-called terminal polyamine catabolism. In vertebrates, the interconversion pathway is a cyclic process which controls polyamine turnover. In conjunction with polyamine transport, it regulates intracellular polyamine homeostasis. In vertebrates, putrescine, the precursor of spermidine and spermine, is exclusively formed by decarboxylation of ornithine – as far as de novo synthesis is concerned. Spermidine and spermine synthase form spermidine from putrescine, and spermine from spermidine, by transfer of aminopropyl residues from decarboxylated S-adenosylme-thionine. In the catabolic branch of the interconversion cycle, spermine is degraded to spermidine, and spermidine to putrescine. The first step in this sequence is acetylation in the N1 position. This is followed by oxidative splitting of the acetylated polyamines, whereby the aminopropyl residues which originated from decarboxylated S-adenosylmethionine are removed. The enzyme catalyzing this step is an FAD-dependent oxidase (polyamine oxidase). Ornithine decarboxylase, S-adenosylmethionine decarboxylase, and acetyl CoA:polyamine N’-acetyltransferase are highly regulated, inducible enzymes with a high turnover rate. Depending on the physiological situation, each of these enzymes may become rate limiting.Terminal polyamine catabolism is catalyzed by Cu2+-dependent amine oxidases, of which only diamine oxidase has been well defined. By oxidative deamination of a primary amino group, each intermediate of the interconversion cycle can be transformed into an aldehyde, which is further oxidized to an amino acid or a γ-lactam. The products of the terminal catabolism as well as the acetylated polyamines are urinary excretory products. In addition to intracellularly synthesized polyamines, polyamines from various tissues and from exogenous sources (such as the gastrointestinal tract) may be utilized by those tissues which have a high demand. Polyamines play a paramount role in growth processes. In order to control growth (for example of tumors), it is necessary to block all major polyamine sources. If only one source is blocked, the remaining sources are usually capable of furnishing sufficient polyamines to support growth processes.