ALBERT

Description: Cyanobacteria are prolific producers of natural products, including polyketides and hybrid compounds thereof. Type III polyketide synthases (PKSs) are of particular interest, due to their wide substrate specificity and simple reaction mechanism, compared to both type I and type II PKSs. Surprisingly, only two type III PKS products, hierridins and (7.7)paracyclophanes, have been isolated from cyanobacteria. Here we report the mining of 517 cyanobacterial genomes for type III PKS biosynthesis gene clusters. Approximately 17% of the genomes analysed encoded one or more type III PKSs. Together with already characterised type III PKSs, the phylogeny of this group of enzymes was investigated. Our analysis showed that type III PKSs in cyanobacteria evolved into three major lineages, including enzymes associated with (i) (7.7)paracyclophane-like biosynthesis gene clusters, (ii) hierridin-like biosynthesis gene clusters, and (iii) cytochrome b5 genes. The evolutionary history of these enzymes is complex, with some sequences partitioning primarily according to speciation and others putatively according to their reaction type. Protein modelling showed that cyanobacterial type III PKSs generally have a smaller active site cavity (mean = 109.035 Å3) compared to enzymes from other organisms. The size of the active site did not correlate well with substrate size, however, the ‘Gatekeeper’ amino acid residues within the active site were strongly correlated to enzyme phylogeny. Our study provides unprecedented insight into the distribution, diversity and molecular evolution of cyanobacterial type III PKSs, which could facilitate the discovery, characterisation and exploitation of novel enzymes, biochemical pathways, and specialised metabolites from this biosynthetically talented clade of microorganisms.