Natural microbial communities are phylogenetically and metabolically diverse. In addition to underexplored organismal groups¹, this diversity encompasses a rich discovery potential for ecologically and biotechnologically relevant enzymes and biochemical compounds^2,3. However, studying this diversity to identify genomic pathways for the synthesis of such compounds⁴and assigning them to their respective hosts remains challenging. The biosynthetic potential of microorganisms in the open ocean remains largely uncharted owing to limitations in the analysis of genome-resolved data at the global scale. Here we investigated the diversity and novelty of biosynthetic gene clusters in the ocean by integrating around 10,000 microbial genomes from cultivated and single cells with more than 25,000 newly reconstructed draft genomes from more than 1,000 seawater samples. These efforts revealed approximately 40,000 putative mostly new biosynthetic gene clusters, several of which were found in previously unsuspected phylogenetic groups. Among these groups, we identified a lineage rich in biosynthetic gene clusters (‘CandidatusEudoremicrobiaceae’) that belongs to an uncultivated bacterial phylum and includes some of the most biosynthetically diverse microorganisms in this environment. From these, we characterized the phospeptin and pythonamide pathways, revealing cases of unusual bioactive compound structure and enzymology, respectively. Together, this research demonstrates how microbiomics-driven strategies can enable the investigation of previously undescribed enzymes and natural products in underexplored microbial groups and environments.

The NMR structure of the recombinant elk prion protein (ePrP), which represents the cellular isoform (ePrP ^C ) in the healthy organism, is described here. As anticipated from the highly conserved amino acid sequence, ePrP ^C has the same global fold as other mammalian prion proteins (PrPs), with a flexibly disordered “tail” of residues 23–124 and a globular domain 125–226 with three α-helices and a short antiparallel β-sheet. However, ePrP ^C shows a striking local structure variation when compared with most other mammalian PrPs, in particular human, bovine, and mouse PrP ^C . A loop of residues 166–175, which links the β-sheet with the α2-helix and is part of a hypothetical “protein X” epitope, is outstandingly well defined, whereas this loop is disordered in the other species. Based on NMR structure determinations of two mouse PrP variants, mPrP[N174T] and mPrP[S170N,N174T], this study shows that the structured loop in ePrP ^C relates to these two local amino acid exchanges, so that mPrP[S170N,N174T] exactly mimics ePrP ^C . These results are evaluated in the context of recent reports on chronic wasting disease (CWD) in captive and free-ranging deer and elk in the U.S. and Canada, and an animal model is proposed for support of future research on CWD.