No abstract

This review covers the emerging biosynthetic role of crotonyl-CoA carboxylase/reductase (CCR) homologs in extending the structural and functional diversity of polyketide natural products. CCRs catalyze the reductive carboxylation of α,β-unsaturated acyl-CoA substrates to produce a variety of substituted malonyl-CoA derivatives employed as polyketide synthase extender units. Here we discuss the history of CCRs in both primary and secondary metabolism, the mechanism by which they function, examples of new polyketide diversity from pathway specific CCRs, and the role of CCRs in facilitating the bioengineering novel polyketides.

Marine sponges are prolific sources of unique bioactive natural products. The sponge is represented by several distinct variants with largely nonoverlapping chemistry. For the Japanese chemotype Y harboring diverse complex polyketides and peptides, we previously provided genomic and functional evidence that a single symbiont, the filamentous, multicellular organism " Entotheonella factor," produces almost all of these compounds. To obtain further insights into the chemistry of "Entotheonella," we investigated another phylotype, " Entotheonella serta," present in the WA sponge chemotype, a source of theonellamide- and misakinolide-type compounds. Unexpectedly, considering the lower chemical diversity, sequencing of individual bacterial filaments revealed an even larger number of biosynthetic gene regions than for E. factor, with virtually no overlap. These included genes for misakinolide and theonellamide biosynthesis, the latter assigned by comparative genomic and metabolic analysis of a chemotype from Israel, and by biochemical studies. The data suggest that both compound families, which were among the earliest model substances to study bacterial producers in sponges, originate from the same bacterium in WA. They also add evidence that metabolic richness and variability could be a more general feature of Entotheonella symbionts.