Diversity, function, and biosynthesis of polyketides in social amoebae

Dictyostelium discoideum is a microbial eukaryote that lives as a unicellular, bacterivorous amoeba under nutrient-rich conditions. Upon food depletion, cells aggregate into a multicellular structure that develops into a fruiting body containing dormant spores. Its genome encodes numerous polyketide synthase genes that are differentially expressed during development, yet apart from two involved in stalk and spore cell differentiation, their products and functions remain largely unknown. As one of the most highly expressed polyketide synthase genes, with transcript levels peaking at the end of the multicellular cycle, pks5 was selected for detailed investigation. Gene disruption, overexpression, and comparative metabolomics led to the identification of a new compound family, the dictyodenes. These polyunsaturated fatty acids are responsible for the characteristic yellow color of fruiting bodies and act as suppressors of spore germination. Promoter reporters revealed spatially confined expression of pks5 within specialized stalk cell regions supporting the spore mass. On a global level, the role of polyketide synthases was examined by inactivating a phosphopantetheinyl transferase required for polyketide synthase enzyme function. The resulting mutant showed widespread developmental and physiological defects, including impaired macropinocytosis, chemotaxis, and sporulation. Transcriptomics provided mechanistic insight into these phenotypes, revealing dysregulation of core cellular processes and developmental markers, while untargeted metabolomics uncovered broad metabolic perturbations, including lipid metabolism signatures and putative polyketide synthase products. Together, these studies provide complementary perspectives on polyketides in Dictyostelium discoideum, from localized gene-specific functions to system-wide effects. They lay the groundwork for functional comparisons across dictyostelids, offering a broader view on polyketides in microbial eukaryotes.