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Plants are consummate chemists, using the sun's energy and carbon dioxide from the air, to conjure a dazzling array of complex natural products in ways that cannot be replicated synthetically in the lab.

The true potential of this superpower is only now beginning to be fully realized due to advances in genomic data gathering, AI, and biotechnology.

Researchers in the group of Professor Anne Osbourn FRS at the John Innes Centre have used these approaches in a new study that glimpses the future of rapid drug and natural product discovery.

For the article "Large-scale mining of diverse plant genomes unlocks hidden diversity of oxidosqualene cyclase function," in Nature Chemical Biology, they investigated triterpenes which have important functions in plants, defending against pests and pathogens, shaping the root microbiome, and influencing crop quality.

Triterpenes make up the largest and most structurally complex group of plant natural products and are a rich source of bioactive molecules with considerable medical and commercial interest.

Examples include the vaccine adjuvant QS-21 produced by the Chilean Soapbark Quillaja saponaria, the anti-inflammatory compound escin from horse chestnut, and bee-friendly insecticides produced by the Neem tree.

All triterpenes begin with the same chemical-starting molecule and diversify due to the actions of enzymes called oxidosqualene cyclases (OSCs) which shape and fold the original molecule in a process likened to chemical origami.

In this study, the Osbourn group set out to track these enzymes, only a small fraction of which have been studied in action. They systematically mined the genome sequences of 599 plants representing nearly 400 species—available as electronic records—for genes that encode OSCs.

From an initial 1,400 OSC gene sequences tracked down and identified, they selected 20 for functional validation.

These 20 genes were synthesized using molecular biology techniques and then transferred into a wild relative of cultivated tobacco which forms a plant-based, high-yielding transient expression system pioneered by the John Innes Centre and now carried forward commercially by partners.

Testing the products of these genes and enzymes, the team:

• Discovered completely novel chemistries which could be used as drug leads
• Reunited "orphan" triterpene structures (those that were known to exist but for which the examples of OSCs that produced them were not known) with their parent OSC.
• Found chemistries which give interesting clues towards the evolutionary journeys of OSCs.

Joint first author of the study, Dr. Michael Stephenson, a new group leader at the University of East Anglia and visiting scientist at the John Innes Centre, said, "We were surprised by how many different findings were generated from a small sample of our mined genes. Nearly every gene tested produced an interesting result, many of which opened potential avenues for further exploration.

"Most excitingly, this project has discovered novel chemistry without ever having to source and handle plant material from the species that produce it in the wild."

The study offers a clear example of using computational approaches to explore the "dark matter" of plant genomes, speeding up the gene discovery process before using molecular biology and transient expression systems to produce useful chemistry at scale for medicine and a raft of commercial applications.

Corresponding author, Professor Anne Osbourn FRS, said, "We currently have the genome sequences of around 1,800 plant species, but this is expanding exponentially. There are approximately 450,000 known plant species, all of which are likely to produce useful and interesting chemistry; this is only the tip of the iceberg of what is possible."

One of the next steps for this research is to work with industrial partners to explore the chemicals discovered for their potential as lead compounds or building blocks for drug discovery. The Osbourn group is also using this pipeline to look for further OSCs to widen the breadth of enzymes under investigation.

The work also provides practical access to highly complex structures that are impractical to produce using synthetic chemistry.

"We are exploiting the power of plants to make drugs out of sunlight and thin air," concludes Dr. Stephenson.