Abstract
Spermidine, a ubiquitous polyamine, is known to be required for critical physiological functions in bacteria. Two principal pathways are known for spermidine biosynthesis, both of which involve aminopropylation of putrescine. Here, we identified a spermidine biosynthetic pathway via a previously unknown metabolite, carboxyaminopropylagmatine (CAPA), in a model cyanobacterium Synechocystis sp. PCC 6803 through an approach combining 13C and 15N tracers, metabolomics, and genetic and biochemical characterization. The CAPA pathway starts with reductive condensation of agmatine and l-aspartate-β-semialdehyde into CAPA by a previously unknown CAPA dehydrogenase, followed by decarboxylation of CAPA to form aminopropylagmatine, and ends with conversion of aminopropylagmatine to spermidine by an aminopropylagmatine ureohydrolase. Thus, the pathway does not involve putrescine and depends on l-aspartate-β-semialdehyde as the aminopropyl group donor. Genomic, biochemical, and metagenomic analyses showed that the CAPA-pathway genes are widespread in 15 different phyla of bacteria distributed in marine, freshwater, and other ecosystems.