Scientists Recreate Deadly Plant Compounds in the Lab, Opening Door to New Therapeutics
核心洞察
Researchers have for the first time identified and reconstructed the biosynthetic pathway for diterpenoid alkaloids (搜索) from wolfsbane and larkspur, two highly toxic plants with known medicinal properties.
An international team from Michigan State University and the Czech Academy of Sciences (搜索) transferred six key enzymes into tobacco plants, successfully producing the diterpenoid alkaloid atisinium (搜索).
The discovery provides a green, sustainable platform for producing these complex natural compounds at scale, potentially enabling new drugs for pain (搜索), malaria (搜索), and cancer (搜索).
A collaborative team of scientists from Michigan State University and the Czech Academy of Sciences (搜索) has achieved a long-elusive breakthrough: reconstructing the biochemical machinery that two of the world's most poisonous plants use to produce compounds with significant therapeutic potential. The findings, published in the journal Molecular Plant, mark the first time researchers have successfully recreated the biosynthetic pathway for diterpenoid alkaloids (搜索)—a family of chemicals that are highly toxic yet known to counter pain (搜索), malaria (搜索), cancer (搜索), and pests.
"These plants have been used in different forms of medicine throughout the world for thousands of years," said Garret Miller, co-first author of the paper and 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."
The Chemistry of Wolfsbane and Larkspur
The research focused on two plants: wolfsbane (also known as monkshood) and larkspur (also called delphinium for its dolphin-shaped flowers). Both produce diterpenoid alkaloids (搜索), molecules that sit at the intersection of the two oldest and largest classes of plant chemicals on the planet. Their structures are so complex that scientists have struggled for decades to understand exactly how plants construct them.
Aconitine (搜索), one of the most familiar compounds in this family, was isolated nearly 200 years ago. Despite this long history, researchers have still not successfully synthesized it in a laboratory.
"Plants are the best chemists around, upgrading their arsenal of natural compounds over millions of years to help them survive," said Björn Hamberger, study author and the James K. Billman Endowed Professor in MSU's Department of Biochemistry and Molecular Biology.
A Serendipitous Collaboration
The project gained momentum through an unexpected partnership. At a scientific conference in Barcelona, Hamberger met researchers from Tomáš Pluskal's laboratory at the Czech Academy of Sciences (搜索). The Pluskal Group, including co-first author Lana Mutabdžija, was independently studying the same difficult family of diterpenoid alkaloids (搜索) in wolfsbane.
"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.
Tracing the Assembly Line
The international team set out to identify the precise sequence of biochemical steps used by wolfsbane and larkspur to make diterpenoid alkaloids (搜索). The search resembled a molecular scavenger hunt: researchers examined several species of both plants and tracked thousands of genes, looking for those that became "switched on" in the right tissues at the right moment.
"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."
Because plants naturally produce specialized metabolites slowly and in tiny amounts, discovering these pathways is a vital step toward engineering plant chemistries that can tackle real-world, large-scale challenges.
Tobacco Plants as Living Biofactories
After identifying a promising collection of genes from wolfsbane and larkspur, the researchers transferred those genetic instructions into tobacco plants, which served as convenient living factories for testing. Analysis showed that the modified tobacco plants had assembled the pathway the team was seeking. Six distinct enzymes worked together to produce atisinium (搜索), a diterpenoid alkaloid.
The enzymes helped shape the molecule into its complicated final structure and enabled the addition of an essential source of nitrogen that the researchers had not expected.
Toward Sustainable Drug Production
By identifying the first biochemical steps required to make atisinium (搜索), the team has gained an important starting point for studying the broader diterpenoid alkaloid family and its potentially useful medicinal properties. Once researchers solve a pathway, they can transfer the genetic instructions for building a compound into an engineered host, such as yeast, turning it into a biological production system capable of manufacturing larger amounts of the desired chemical.
"In an ideal scenario, this could eventually help create new drugs inspired by these natural products," said Mutabdžija.
"Our vision is to provide green, sustainable tools that will allow us to harness these plants' natural power," Hamberger added.