A pair of famously poisonous plants may hold the blueprint for a new generation of medicines. Researchers from Michigan State University and the Czech Academy of Sciences have identified the first steps in the biosynthesis of powerful diterpenoid alkaloids produced by larkspur and wolfsbane, two plants capable of causing paralysis and fatal neurotoxicity in extremely small doses. By reconstructing part of the plants’ chemical manufacturing system inside tobacco, the team created a biological platform capable of producing one of these complex compounds in the laboratory.
The discovery, published in Molecular Plant, could transform how scientists investigate a family of natural products associated with pain relief, antimalarial activity, anticancer research and pest control. Although these molecules have attracted scientific interest for nearly two centuries, their intricate structures and unusual chemistry have made them exceptionally difficult to synthesize. One of the best-known examples, aconitine, was isolated almost 200 years ago but remains notoriously challenging to reproduce through conventional laboratory chemistry.
Larkspur, also known as Delphinium because of its dolphin-shaped flowers, and wolfsbane, or monkshood, belong to a group of plants that manufacture diterpenoid alkaloids as chemical defenses. These specialized metabolites are built from carbon-rich diterpenoid frameworks and contain nitrogen, a feature that gives many of them powerful biological activity. The same molecular properties that make the compounds dangerous can also make them valuable starting points for drug discovery, provided researchers can understand their activity and control their production.
“Plants are the best chemists around,” said Björn Hamberger, a study author and the James K. Billman Endowed Professor in Michigan State University’s Department of Biochemistry and Molecular Biology. Over millions of years, plants have evolved enzymes capable of assembling, modifying and reshaping molecules with extraordinary precision. Scientists are increasingly studying these natural pathways not only to understand plant biology, but also to adapt them for sustainable manufacturing of medically important compounds.
The research began with an international collaboration formed after Hamberger encountered scientists from Tomáš Pluskal’s laboratory at the Czech Academy of Sciences during a conference in Barcelona. Both groups were investigating diterpenoid alkaloids, but in different plant species. The Michigan State team was focused on larkspur, while the Czech researchers were examining wolfsbane. Their shared interest allowed them to compare related biochemical systems and search for common molecular mechanisms.
To uncover the pathway, the researchers examined several species of larkspur and wolfsbane and analyzed gene activity in different plant tissues. Their goal was to identify genes that became active at the correct time and place for alkaloid production. This process resembles reconstructing an assembly line from scattered components: if a single enzyme is missing or inactive, the downstream reactions cannot proceed, and the final compound fails to appear.
The team ultimately identified a set of genes encoding six previously uncharacterized enzymes. These enzymes carry out the entry steps required to construct a diterpenoid alkaloid called atisinium. Rather than simply joining small molecules together, the enzymes guide the developing compound through a series of precise structural changes. They help the molecule fold into its complicated three-dimensional configuration and enable the incorporation of a crucial nitrogen source, an unexpected feature that was central to understanding the pathway.
To test whether the genetic blueprint worked, the scientists transferred the selected genes into tobacco plants. The tobacco acted as a living biofactory, using its own cellular machinery to produce the introduced enzymes. Once the engineered plants began making the target chemicals, researchers analyzed their molecular contents and confirmed that the six-enzyme system could successfully generate atisinium. This result provided experimental evidence linking specific genes to the earliest stages of diterpenoid alkaloid biosynthesis.
The achievement does not yet produce a finished medicine, and the compounds remain highly toxic. However, it gives researchers a new route for studying the broader alkaloid family without relying exclusively on wild plants or difficult chemical synthesis. In the future, similar pathways could be transferred into yeast, tobacco or other engineered organisms capable of producing larger and more consistent quantities. Such systems could support toxicity testing, structural modification and the search for therapeutic effects while reducing pressure on rare or slow-growing plant sources.
Garret Miller, a co-first author and former researcher in the Hamberger laboratory who is now an assistant professor of biotechnology at the University of Michigan-Flint, said that understanding how these plants create their compounds could open entirely new routes for testing. Lana Mutabdžija, a graduate student at the Czech Academy of Sciences and co-first author, added that the long-term goal is to develop new drugs inspired by natural products. By revealing how larkspur and wolfsbane build their most potent chemical defenses, the researchers have taken an important step toward turning botanical poisons into programmable sources of future therapeutics.
Subject of Research: Biosynthesis of diterpenoid alkaloids in larkspur and wolfsbane
Article Title: Characterization of the entry steps in diterpenoid alkaloid biosynthesis
Web References: https://www.sciencedirect.com/science/article/pii/S1674205226001905 ; https://doi.org/10.1016/j.molp.2026.05.022
References: Molecular Plant, DOI: 10.1016/j.molp.2026.05.022
Image Credits: Paul Henderson
Keywords: larkspur, wolfsbane, monkshood, diterpenoid alkaloids, plant biochemistry, biosynthesis, atisinium, natural products, biotechnology, drug discovery
