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Natural Products

Learning how plants make limonoids

Chemists suggest possible biosynthetic pathway to these complex natural products

by Bethany Halford
January 30, 2023

Citrus and mahogany plants are masters of synthetic chemistry, making more than 2,800 limonoid molecules. These include azadirachtin, which is a biological insecticide, and limonin, which gives citrus fruits a bitter taste. In an effort to decipher the plants’ synthetic strategies, a team of chemists figured out several key enzymes and reactions that produce certain limonoids. The finding could provide clues to boost or dampen production of key limonoids in plants. It could also help chemists churn out these complex molecules in simpler organisms like Escherichia coli.

Researchers led by Anne Osbourn of the John Innes Centre and Elizabeth Sattely of Stanford University used genome and transcriptome mining to discover 22 enzymes that catalyze 12 reactions en route to the limonoids azadirone and kihadalactone A (Science 2023, DOI: 10.1126/science.adf1017). They then engineered the genes that make those enzymes into the plant Nicotiana benthamiana to reproduce the biosynthesis.

It’s like reverse engineering a total synthesis, Sattely says. They know the plant’s starting material, its final products, and the enzymes it can use to do chemistry. From there, they puzzle it together and rebuild the pathway. “What we describe in our paper is just a set of enzymes that can make this molecule,” she explains, but it might not be the exact biosynthetic pathway that the citrus or mahogany plants use. “We’re not doing these reactions in little test tubes,” Sattely says. Instead, all the key enzymes are in the engineered plant. “What we’ve drawn in our figure looks like maybe a potential sequence of events, but we have no control over how substrates and intermediates flow through these enzymes.”

Yi Tang, an expert in biosynthesis at the University of California, Los Angeles, says limonoid biosynthesis is one of the plant kingdom’s least understood pathways. By using a combination of transcriptomics, synthetic biology, and natural product chemistry, Osbourn and Sattely’s team “demystified what was essentially a black box prior to this work and mapped a lengthy biosynthetic sequence with newly identified enzymes,” he says in an email. “This is a milestone in biosynthesis that all future plant biosynthesis will be compared to.”


The structures in this story were updated on Jan. 31, 2023, to show stereochemistry at all bonds.



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