Animal biosynthesis of complex polyketides in a photosynthetic partnership

Abstract

ABSTRACTAnimals are rich sources of complex polyketides, including pharmaceuticals, cosmetics, and other products. Most polyketides are associated with microbial or plant metabolism1. For this reason, symbiotic bacteria or dietary organisms are often the true producers of compounds found in animals2,3. Although increasing evidence suggests that animals themselves make some compounds4–7, the origin of most polyketides in animals remains unknown. This problem makes it difficult to supply useful animal compounds as drugs and severely constrains our understanding of chemical diversity and the scope of biosynthesis in nature. Here, we demonstrate that animals produce microbe-like complex polyketides. We report a previously undocumented but widespread branch of fatty acid synthase- (FAS)-like proteins that have been retooled by evolution to synthesize complex products. One FAS-like protein uses only methylmalonyl-CoA as a substrate, otherwise unknown in animal lipid metabolism, and is involved in an intricate partnership between a sea slug and captured chloroplasts. The enzyme’s complex, methylated polyketide product results from a metabolic interplay between algal chloroplasts and animal host cells, and also likely facilitates the survival of both symbiotic partners, acting as a photoprotectant for plastids and an antioxidant for the slug8–12. Thus, we find that animals can unexpectedly synthesize a large and medically useful class of structurally complex polyketides previously ascribed solely to microbes, and can use them to promote symbiotic organelle maintenance. Because this represents an otherwise uncharacterized branch of polyketide and fatty acid metabolism, we anticipate a large diversity of animal polyketide products and enzymes awaiting discovery.