Discovery and biosynthesis of hybrid polyketide‐nonribosomal peptides in nematodes

Abstract

Polyketides and nonribosomal peptides are well‐known for their antibiotic, antifungal, immunosuppressant, anti‐parasitic, and anti‐cancer activities. These structurally complex natural products are biosynthesized by polyketide synthases (PKSs) and nonribosomal synthetases (NRPSs), modular megasynthases that function in either an assembly‐line or iterative manner. Although polyketides and nonribosomal peptides are produced by many species of bacteria, fungi, and plants, they are extremely rare in metazoans. The genome of the nematode Caenorhabditis elegans is predicted to encode a huge, multi‐module, hybrid PKS/NRPS (PKS‐1), as well as a multi‐module NRPS (NRPS‐1), with unknown functions. Using comparative metabolomics and NMR spectroscopy, we identified and elucidated the chemical structure of nemamide, a hybrid polyketide‐nonribosomal peptide that is biosynthesized by PKS‐1/NRPS‐1 using both iterative and assembly‐line mechanisms. In recent work, we used CRISPR‐Cas9 to make specific mutations in pks‐1 and nrps‐1 in order to investigate the roles of specific enzymatic domains in the biosynthesis of nemamide. We showed that nemamide promotes survival during starvation‐induced larval arrest and facilitates recovery from arrest in response to food. Nemamide is produced in the CAN neurons under starvation conditions and downregulates insulin/ insulin‐like growth factor‐1 (IGF‐1) signaling. Our results uncover a novel mechanism by which animals respond to nutrient fluctuations to extend survival. Homologs of PKS‐1 and NRPS‐1 are present in most nematode species, including parasitic ones, and thus, nemamide likely plays an evolutionarily conserved role across nematode species.Support or Funding InformationWe acknowledge the support of the NIH/NIGMS, NSF, and Ellison Medical Foundation.