Plant-derived chemicals (cardenolides) have long been used to treat heart disease and have shown potential as cancer therapies. But the compounds are toxic, making it difficult for doctors to prescribe a dose that works without harming the patient. Scientists have long tried to figure out how plants biosynthesize cardenolides, knowledge that could help them discover and develop safer versions of the drugs. Unfortunately, the cardenolides’ best-known plant sources—foxglove and milkweed—are not amenable to experimental techniques for identifying the genes and enzymes that are involved in producing the chemicals.

In a new study “Independent evolution of ancestral and novel defenses in a genus of toxic plants (Erysimum, Brassicaceae)” published online in eLife, a multi-institution team led by Boyce Thompson Institute (BTI) faculty member Georg Jander, PhD, and Tobias Züst, PhD, a research associate at the University of Bern’s Institute of Plant Sciences, showed that Erysimum cheiranthoides (wormseed wallflower) could be used as a model species to elucidate that information. The team has already identified 95 candidate cardenolides and has begun using the plant to investigate cardenolide biosynthesis.

“Phytochemical diversity is thought to result from coevolutionary cycles as specialization in herbivores imposes diversifying selection on plant chemical defenses. Plants in the speciose genus Erysimum (Brassicaceae) produce both ancestral glucosinolates and evolutionarily novel cardenolides as defenses,” write the investigators.

“Here we test macroevolutionary hypotheses on co-expression, co-regulation, and diversification of these potentially redundant defenses across this genus. We sequenced and assembled the genome of E. cheiranthoides and foliar transcriptomes of 47 additional Erysimum species to construct a phylogeny from 9,869 orthologous genes, revealing several geographic clades but also high levels gene discordance. Concentrations, inducibility, and diversity of the two defenses varied independently among species, with no evidence for trade-offs. Closely related, geographically co-occurring species shared similar cardenolide traits, but not glucosinolate traits, likely as a result of specific selective pressures acting on each defense. Ancestral and novel chemical defenses in Erysimum thus appear to provide complementary rather than redundant functions.”

“Twelve different plant families produce cardenolides, but nobody knows exactly how they make them,” Jander said. “I was looking for the best plant to study this pathway and settled on wormseed wallflower.” Jander is also an adjunct professor at Cornell University’s School of Integrative Plant Science.

The species is a great model for genetic studies because it has a short life cycle and is readily inbred, he said. “We need a plant that reproduces and gives us seeds quickly, which E. cheiranthoides does in about 10 weeks.”

The team’s study builds on work done in the 1990s by Alan Renwick, PhD, who is currently an Emeritus Professor at BTI.

In this study, the team assembled the complete genome of the wormseed wallflower and sequenced more than 9,000 expressed genes from E. cheiranthoides and 47 other Erysimum species. The results provide a foundation for identifying the genes that encode enzymes involved in the biosynthesis of cardenolides. For example, the team discovered potential pathways by which Erysimum species modify a basic precursor cardenolide, digitoxigenin, into eight more structurally complex molecules.

To further enable the use of E. cheiranthoides as a model, the genome was assembled with long read data and Hi-C scaffolding, a method that can provide a more contiguous genome than previous approaches, said Susan Strickler, PhD, who is the director of the BTI Computational Biology Center (BCBC) and senior research associate at BTI.

“A high quality reference genome makes it easier for us to find genes of interest and their locations, in this case genes for the biosynthesis of cardenolides,” she said.

The team is now conducting mutagenesis studies in E. cheiranthoides to allow them to find the entire cardenolide biosynthetic pathway. “Ultimately the genes underlying the biosynthetic pathways could be inserted into bacteria or yeast, which would be used to manufacture heart and cancer medicines that are safer than what are currently available,” added Jander.

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