Yeast accelerates discovery of medicinal compounds from plants

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Researchers at Cornell University have harnessed the power of baker’s yeast to create a cost-effective and highly efficient approach to understanding how plants synthesize medicinal compounds. A new method was used to identify the key enzymes in the kratom tree.

Aspirin, morphine, and some chemotherapy are examples of drugs derived from natural compounds produced by plants. To understand how plants produce such compounds, their transcriptomes are typically analyzed to determine which enzymes may encode enzymes that work together to facilitate production. It begins by identifying up to several hundred genes that have a Each gene must then be biochemically characterized using specific substrates and reaction conditions, a laborious and expensive task that hinders the discovery process.

A new yeast-based screening method has been published in detail in the journal Angewante Chemie It captures protein-protein interactions between plant enzymes and works with other screening methods to more precisely identify which genes are ultimately involved in how plants biosynthesize medicinal compounds.

“Traditional methods find groups of proteins that exist together in plants, but our method looks at which of those groups physically cluster and function well with each other. to complement that,” said Sijin Lee, assistant professor of chemical and biomolecular engineering. and lead author of the study. “These are the kinds of chemicals that we want to extract for pharmaceuticals.”

Once gene candidates have been predicted using plant transcriptomics, the internal genes can be inserted into baker’s yeast, the same type used for beer brewing and bread baking, to determine which yeasts produce the interacting proteins. Examine you. As a result, the number of genes that must be biochemically screened is significantly reduced.

“This method is underutilized for pathway discovery and eliminates a major bottleneck in high-throughput screening,” Li said. “It’s cheaper and safer than using chemical substrates, and it’s very efficient and accurate.”

Lee and her research group demonstrated a yeast-based method using kratom leaves. Lee said kratom is a tropical tree native to Southeast Asia that, while understudied, has received attention from her research community for its medicinal potential.

“It produces a chemical called mitragynine, which some are calling the next generation opioid because it has analgesic effects without causing dangerous respiratory depression,” Lee said, adding that the U.S. Food and Drug Administration has approved kratom’s It added that it is warning against its use because no drug containing the tree has been approved. “Producing pure mitragynine will help reduce the risks associated with using the entire kratom matrix, as it will ultimately lead to safer treatments.”

A yeast-based method identified six kratom enzymes from 20 candidates predicted by genetic screens to produce mitragynine or other target chemicals. Subsequent biochemical testing revealed that none of the 14 discarded candidates were functional enzymes, but four of the six identified by the yeast-based method were functional. Lee said the precision of this method opens the door to a more efficient discovery process and continued research on the kratom tree.

“Clinical trials require chemicals to be purified from plants or synthesized using chemical methods, which is very expensive,” Lee said. “Using the yeast method, we can more economically produce mitragynine and other chemicals that could lead to new medicines.”

reference: Wu Y, Liu C, Koganitsky A, Gong FL, Li S. Discovery of dynamic plant enzyme complexes in yeast for identification of kratom alkaloid pathway**. Angew Chem Int Ed. 2023;62(38):e202307995. Doi: 10.1002/anie.202307995

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