Wolfsbane and larkspur are poisonous plants capable of causing nerve damage and paralysis at extremely low doses. Yet these same plants produce complex compounds with potential applications in pain relief, malaria treatment, cancer research, and agricultural pest control. Scientists have now recreated part of this powerful chemistry in the laboratory, opening new possibilities for sustainable drug discovery and natural-product biotechnology.
The study focused on wolfsbane and larkspur, also known as delphinium, and involved researchers from Michigan State University and the Czech Academy of Sciences. The findings were published in the journal Molecular Plant.
“These plants have been used in different forms of medicine throughout the world for thousands of years,” said Garret Miller, an MSU alumnus and co-first author of the study. Miller is now an assistant professor of biotechnology at the University of Michigan-Flint.
“We know they interact with our bodies in so many ways, and understanding how to create them can help provide totally new routes of testing.”
Why Poisonous Plants Produce Powerful Natural Compounds
Even with modern advances in chemistry and biotechnology, plants remain exceptionally capable of producing complex natural compounds.
“Plants are the best chemists around, upgrading their arsenal of natural compounds over millions of years to help them survive,” said Björn Hamberger, a study author and the James K. Billman Endowed Professor in MSU’s Department of Biochemistry and Molecular Biology.
“Humans have found countless uses for these molecules in everyday life,” added Lana Mutabdžija, a graduate student at the Czech Academy of Sciences and co-first author of the study.
“These include caffeine, capsaicin, menthol and vanillin, not to mention the fact that many of the medicines we use today either come directly from plants or are inspired by plant chemistry.”
The Hamberger Lab at MSU investigates specialized metabolites, the natural substances plants produce for survival, and studies how these compounds could be adapted for medical, agricultural, and industrial applications.
In recent years, the research team began studying larkspur, a plant named for its dolphin-shaped flowers and also known as delphinium. The scientists wanted to understand how larkspur produces diterpenoid alkaloids, a family of chemicals known for their extreme toxicity as well as their potential pharmacological value.
Solving a Decades-Long Diterpenoid Alkaloid Mystery
Understanding how plants manufacture diterpenoid alkaloids has been a significant scientific challenge.
These compounds combine structural features from two of the oldest and largest families of plant chemicals. Their highly complex molecular structures have made it difficult for researchers to determine how plants assemble them.
Aconitine, one of the best-known diterpenoid alkaloids, was isolated almost 200 years ago. Despite decades of research, scientists have not yet successfully synthesized the compound in a laboratory.
The project advanced after an unexpected international collaboration.
At a scientific conference in Barcelona, Hamberger met researchers from Tomáš Pluskal’s laboratory at the Czech Academy of Sciences. The Pluskal Group, including Mutabdžija, was investigating the same challenging class of compounds in wolfsbane, a highly poisonous relative of larkspur also called monkshood.
“When this happens, we can either go our own ways, or come together, and it’s joining up that always leads to the best science,” said Hamberger.
Mapping the Plants’ Natural Chemical Pathway
Working together, the international research team set out to identify the precise biochemical steps wolfsbane and larkspur use to produce diterpenoid alkaloids.
The investigation involved analyzing multiple species of both plants and tracking thousands of genes. The researchers searched for genes activated in the right tissues and at the right stages of plant development.
“You can imagine a biosynthetic pathway almost as an assembly line,” said Miller, who earned his Ph.D. in the Hamberger Lab. “If you have ten steps in a row needed to build a finished product, and suddenly one quits, the next steps can’t happen.”
Plants typically produce specialized metabolites slowly and in very small amounts. Identifying the genes and enzymes involved in these pathways is therefore critical for making valuable compounds in larger quantities and studying their potential uses.
Once a biosynthetic pathway has been identified, scientists can transfer the relevant genetic instructions into an engineered organism, such as yeast or another plant.
This biotechnology approach can transform the host organism into a biological production system capable of manufacturing larger amounts of a target compound for research and future development.
“In an ideal scenario, this could eventually help create new drugs inspired by these natural products,” said Mutabdžija.
Engineered Tobacco Plants Act as Living Biofactories
After identifying a promising set of genes from wolfsbane and larkspur, the researchers introduced the genetic instructions into tobacco plants. The tobacco plants served as living laboratories, allowing the team to test whether the selected genes could recreate the natural chemical pathway.
Laboratory analysis confirmed that the modified tobacco plants had assembled the pathway the researchers were investigating. Six different enzymes worked together to produce atisinium, a type of diterpenoid alkaloid.
These enzymes helped construct the compound’s complex molecular structure and enabled the addition of an essential nitrogen source, a step the researchers had not anticipated.
By identifying the initial biochemical steps required to produce atisinium, the team has established an important foundation for investigating the wider diterpenoid alkaloid family and its potential medical applications.
“Our vision is to provide green, sustainable tools that will allow us to harness these plants’ natural power,” Hamberger said.
Source: www.sciencedaily.com