Markers of biosynthetic innovation in the Cyanobacteria

Cyanobacteria are a rich source of specialised metabolites of ecological, biomedical and industrial significance, yet discovery of novel compounds is constrained by rediscovery and uneven taxonomic exploration. Diversification of specialised metabolism constitutes a key evolutionary innovation associated with ecological expansion. Further, understanding how biosynthetic capacity is distributed across cyanobacterial lineages and environments is critical for guiding natural product discovery. We therefore analysed 939 cyanobacterial genomes spanning 11 orders and five habitat types to identify taxonomic and ecological hotspots of biosynthetic potential. We evaluated several indicators of biosynthetic innovation, including singleton BGCs and specialized enzymes and assessed the distribution of cyanobacterial toxin BGCs. Conserved terpene and ribosomally synthesised and post-translationally modified peptide (RiPP) clusters dominated, accounting for >50% of identified BGCs. These two classes exhibited high sequence conservation, averaging 16.41 and 28.10 similarity links per BGC, respectively. Conversely, NRPS and polyketide synthase clusters were less common (18.5% and 2.5% of total BGCs, respectively) but displayed considerable sequence diversity, with a mean of 1.9 and 0.79 links per BGC, respectively. Enzymes associated with potentially novel chemistries were rare, with halogenases and cytochrome P450s present in 4.9% and 1.27% of BGCs, respectively, whereas amidinotransferases were detected in only 0.42% of BGCs. Symbiotic, terrestrial and thermal spring cyanobacteria, particularly Nostocales, showed elevated biosynthetic potential, whereas marine Synechococcales genomes showed comparatively low biosynthetic potential. Putative toxin BGCs were enriched in freshwater Nostocales, Chroococcales and Oscillatoriales. These findings link phylogeny, ecology and genomic features to prioritise taxa, habitats and biosynthetic pathways for future natural product discovery.