Linking Genes to Molecules in Eukaryotic Sources: An Endeavor to Expand Our Biosynthetic Repertoire

The discovery of natural products continues to interest chemists and biologists for their utility in medicine as well as facilitating our understanding of signaling, pathogenesis, and evolution. Despite an attenuation in the discovery rate of new molecules, the current genomics and transcriptomics revolution has illuminated the untapped biosynthetic potential of many diverse organisms. Today, natural product discovery can be driven by biosynthetic gene cluster (BGC) analysis, which is capable of predicting enzymes that catalyze novel reactions and organisms that synthesize new chemical structures. This approach has been particularly effective in mining bacterial and fungal genomes where it has facilitated the discovery of new molecules, increased the understanding of metabolite assembly, and in some instances uncovered enzymes with intriguing synthetic utility. While relatively less is known about the biosynthetic potential of non-fungal eukaryotes, there is compelling evidence to suggest many encode biosynthetic enzymes that produce molecules with unique bioactivities. In this review, we highlight how the advances in genomics and transcriptomics have aided natural product discovery in sources from eukaryotic lineages. We summarize work that has successfully connected genes to previously identified molecules and how advancing these techniques can lead to genetics-guided discovery of novel chemical structures and reactions distributed throughout the tree of life. Ultimately, we discuss the advantage of increasing the known biosynthetic space to ease access to complex natural and non-natural small molecules.