Nematodes are very diverse (over 25,000 species) and can be either free-living, such as the model organism Caenorhabditis elegans, or parasitic, causing widespread disease in plants and animals (including humans). The focus of our research group is to identify and characterize the chemical structures of nematode hormones, pheromones, and other signaling molecules, and to investigate the biosynthesis and mechanism of action of these molecules. We employ a multidisciplinary approach, incorporating tools from biochemistry, organic chemistry, structural biology, analytical chemistry, metabolomics, and nematode genetics. Our results have provided new insights into how nematodes use small molecules to control their life cycles and will enable the development of novel strategies to target parasitic nematodes.
Development of a general framework for pheromone biosynthesis. Nematodes secrete the ascarosides as pheromones to induce development of the stress-resistant dauer larval stage, as well as to control various behaviors. The ascarosides are derivatives of the 3,6-dideoxysugar ascarylose, modified with fatty acid-derived side chains of various lengths. Peroxisomal β-oxidation cycles are required for ascaroside biosynthesis. We have shown that specific acyl-CoA oxidase enzymes, which catalyze the first step in these β-oxidation cycles, form both homo- and heterodimers and act as gatekeepers to control the mixture of pheromones that C. elegans produces. We have obtained the crystal structures of two of these acyl-CoA oxidases. Furthermore, we have shown that the acyl-CoA oxidases are regulated, surprisingly, by ATP, which binds at the dimer interface, suggesting that ascaroside biosynthesis is closely coupled to metabolic state.
Discovery of the first hybrid polyketide-nonribosomal peptide from an animal: A novel chemical signal that controls starvation survival in nematodes. Polyketides and nonribosomal peptides represent two of the most important classes of natural products used in modern medicine. Although these natural products are produced by many bacterial and fungal species, they are extremely rare in animals. Using comparative metabolomics and NMR spectroscopy, we have identified two structurally related hybrid polyketide-nonribosomal peptides from C. elegans (“the nemamides”). The nemamides are the first example of a polyketide or nonribosomal peptide biosynthesized in an assembly-line manner in a metazoan. These natural products, which are produced in two essential neurons in the worm, modulate insulin signaling and extend larval survival during starvation. Our results uncover a novel mechanism by which animals respond to nutrient fluctuations to extend their survival.
Discovery of the chemical signals that parasitic nematode species use to control their development. Our laboratory was the first to show that parasitic nematodes use ascarosides to control their development. Specifically, we have elucidated the structures of novel ascarosides that entomopathogenic nematodes use to induce development of the infective juvenile (IJ) stage, a dauer-like stage that is specialized for seeking out and infecting insect hosts. Additionally, we have shown that the plant-parasitic pinewood nematode and its vector beetle use ascarosides and other chemical signals to coordinate their development and dispersal. Our work on the chemical signals that control the development and behavior of parasitic nematodes will lead to the development of novel chemical tools to interfere with the life cycles of these nematodes.