the polyketide to fatty acid transition in the evolution of animal lipid metabolism:the animal FAS-like PKSs

Animals use a distinct fatty acid synthase (FAS) most closely related to the type I polyketide synthase (PKS) enzymes. While FASs synthesize simple lipids, PKSs produce complex specialized metabolites. The evolutionary origin of the animal FAS, and its relationship to the diversity of PKSs, remain surprisingly mysterious despite the critical role of lipid synthesis in cellular metabolism. Previously, an enzyme EcPKS1 from sacoglossan molluscs was described that was closely related to animal FAS enzymes, but instead preformed PKS-like chemistry. A few other related enzymes were apparent in molluscs, mostly in the photosynthetic sacoglossans. Here, we asked whether such enzymes were limited to a small subset of species, and whether they might answer the mystery of the origin of animal lipid biosynthesis. We performed a sequence-based analysis, unexpectedly discovering a huge diversity of widespread EcPKS1-like enzymes that form a grade separating PKS from the animal FAS clade in phylogenetic analyses. PKSs and FASs are widespread among major animal phyla except for sponges and ctenophores, where they are apparently absent. Surprisingly, molluscs and arthropods contain abundant EcPKS1-like enzymes, correlated with their rich polyketide chemistry. Molluscan EcPKS1 relatives are associated with a lack of other defenses, consistent with the hypothesis that AFPKs provide a chemical defense for some lineages. By contrast, shelled molluscs (physically defended) generally contain PKSs instead. Arthropods have few or no PKSs, but their abundant EcPKS1-like enzymes contributed to their ecological and evolutionary success. For example, some of the genes found in the EcPKS1 clade were previously associated with cuticular hydrocarbon and pheromone biosynthesis. Based upon the biochemical, genetic, and phylogenetic features of these enzymes, we propose that they comprise a new family, the animal FAS-like PKSs (AFPKS). Although animal metabolism is well studied, surprising new metabolic enzyme classes such as AFPKs still await discovery and may be unrecognized drivers of hyperdiverse animal radiations including gastropods, beetles and spiders.