An Alkaloid Biosynthetic Gene Bundle in Animals

Alkaloids include some of the most impactful molecules used in science and medicine. While plant alkaloids are well explored, much less is known about the diverse bioactive alkaloids from the animal kingdom. To solve this problem, we developed a computational method to discover genes that are bundled in chromosomal regions, enabling agnostic discovery of noncanonical biosynthetic gene clusters (BGCs) without prior knowledge of what enzymes might be involved. The method was applied to marine sponges that produce oroidin and related pyrrole-imidazole alkaloids, uncovering 36 BGCs in oroidin-producing sponges, only one of which (oro) was found in all species. Many of these clusters defy current BGC dogma, leading us to suggest the name "bundles" for this phenomenon. Five oro proteins were validated in biochemical assays. oro consists of orthologs of common, animal-specific primary metabolic genes that have been collected in one chromosomal region and repurposed for alkaloid biosynthesis. This provides a roadmap to accelerate the development of oroidins and the countless other unique natural products found in the animal kingdom.