Genetic Engineering of Polyamine Catabolism in Transgenic Mice and Rats

The biosynthetic pathway of the polyamines is practically irreversible because it involves two decarboxylation reactions. The first evidence, however, indicating that spermidine can be converted to putrescine and spermine to spermidine emerged in the late 1960s when Siimes (1) found that radioactive spermidine and spermine yielded labeled putrescine and spermidine in rat liver in vivo. An additional 10 yr were required before the first enzyme, polyamine oxidase (PAO), of a separate polyamine backconversion pathway was purified and characterized (2). Polyamine oxidase strongly favors acetylated spermidine and spermine over the natural polyamines as its substrates (2). That the oxidation of unmodified spermidine and spermine is greatly enhanced by benzaldehyde (or other aldehydes) is in all likelihood attributable to Schiff base formation between the primary amino groups of the polyamine and the aldehydes, thus mimicking the charge distribution of acetylated polyamines (2). It soon became evident that spermidine and spermine are acetylated by a cytosolic enzyme, spermidine/spermine N 1 -acetyltransferase (SSAT), that is highly inducible and has a very short half-life (3). Recently, another oxidase involved in polyamine catabolism was found and named spermine oxidase (4,5). The latter enzyme is practically specific for spermine and does not catalyze the oxidation of spermidine or acetylated polyamines (4,5). In the SSAT/PAO-dependent backconversion pathway, SSAT clearly is the rate-controlling enzyme because PAO is a constitutively expressed enzyme occurring in great excess in comparison with inducible SSAT (6). Moreover, PAO oxidizes only acetylated polyamines.