Aspartate-Dependent Polyamine Biosynthesis in Bacteria: Chemical Synthesis of Carboxypolyamines and Mechanism-Based Design of Hydroxylamine-Containing Inhibitors of Carboxyspermidine Decarboxylase

Biogenic polyamines spermidine, spermine and some of their derivatives are small organic polycations vitally important in all domains of life. Recent studies have demonstrated that polyamine biosynthesis is subject to convergent evolution and that some bacteria employ biosynthetic pathways in which aspartate, rather than decarboxylated S -adenosylmethionine, provides the three-carbon moiety required for polyamine biosynthesis. Carboxypolyamines are among key intermediates in these metabolic pathways. At the final step of this biosynthetic route, the specific PLP-dependent carboxyspermidine decarboxylase (CASDC) converts carboxypolyamines into the corresponding polyamines. The investigation of aspartate beta-semialdehyde-dependent pathways requires commercially unavailable substrates and demand potent enzyme inhibitors. Here we report a convenient synthesis of carboxyspermidine, carboxyspermine, and carboxythermospermine allowing to study these poorly understood pathways in bacteria. The use of isosteric hydroxylamine-containing analogs of carboxypolyamines will lead to selective and effective inhibition of CASDC. The synthesis of these O -substituted hydroxylamines is also described.