How the kava plant produces its pain-relieving and anti-anxiety molecules

Home >> News Center >> How the kava plant produces its pain-relieving and anti-anxiety molecules

How the kava plant produces its pain-relieving and anti-anxiety molecules

Kava (Piper methysticum) is a plant native to the Polynesian islands that has been used in a soothing drink of the same name in religious and cultural rituals for thousands of years. The tradition of cultivating kava and drinking it at large gatherings is a cultural cornerstone common to much of Polynesia, although specific customs - and kava strains - vary from island to island. In recent decades, kava has gained interest outside the islands for its pain-relieving and anti-anxiety properties as a potentially attractive alternative to drugs such as opioids and benzodiazepines because kavalactones, the kava's molecules of medical interest, use slightly different mechanisms to affect the central nervous system and appear non-addictive. Kava bars have appeared in the United States, kava supplements and teas are available in stores like Walmart, and athletes who need safe pain relief are praising their benefits.

This growing use suggests that there would be an important market for kavalactone based medical therapies, but there are obstacles to development: on the one hand, kava is difficult to grow, especially outside the tropics. Kava takes years to mature and, as a domesticated species that no longer produces seeds, it can only be reproduced by cutting. This can make it difficult for researchers to obtain a sufficient amount of kavalactones for investigations or clinical trials.

Now, the research by Jing-Ke Weng, a member of the Whitehead Institute and Associate Professor of Biology at MIT and Tomáš Pluskal, published online in Nature Plants on July 22, describes a way to solve this problem, as well as to create variations of kavalactone found in nature that could be more effective or safer than therapeutic products.

"We combine historical knowledge of the medicinal properties of this plant, established by centuries of traditional use, with modern research tools to potentially develop new drugs," says Pluskal.

Weng's laboratory has shown that if researchers discover the genes behind a desirable natural molecule - in this case kavalactones - they can clone these genes, insert them into species such as yeast or bacteria that grow quickly and are easier to maintain in various environments than a capricious tropical plant, and then have these microbial bio-plants mass produce the molecule. To achieve this, Weng and Pluskal first had to solve a complicated puzzle: How does kava produce kavalactones? There is no direct gene for kavalactone; complex metabolites such as kavalactones are created by a series of steps using intermediate molecules. Cells can combine these intermediates, cut out parts of them and add bits to create the final molecule, most of which are obtained using enzymes, the catalysts for the chemical reaction of the cells. Thus, in order to recreate kavalactone production, the researchers had to identify the complete plant production pathway to synthesize it, including the genes of all the enzymes involved.

Researchers were unable to use genetic sequencing or common gene editing tools to identify enzymes because the kava genome is huge; it has 130 chromosomes compared to 46 in humans. Instead, they turned to other methods, including sequencing the plant's RNA to study the expressed genes, in order to identify the biosynthetic pathway of kavalactones.

Weng and Pluskal had a good starting point: They recognized that kavalactones had the same structure as chalcones, metabolites common to all terrestrial plants. They hypothesized that one of the enzymes involved in the production of kavalactones must be linked to that involved in the production of chalcones, chalcone synthase (CHS). They searched for genes encoding similar enzymes and found two synthases that had evolved from an earlier CHS gene. These synthases, which they call PmSPS1 and PmSPS2, help to form the basic scaffolding of kavalactone molecules.

Then, after some trial and error, Pluskal discovered that genes encoding a number of adaptation enzymes that modify and add molecules to the backbone to create a variety of specific kavalactones. In order to test that it had identified the right enzymes, Pluskal cloned the relevant genes and confirmed that the enzymes they code produce the expected molecules. The team also identified key enzymes in the biosynthetic pathway of flavokavains, kava molecules that are structurally related to kavalactones and whose anti-cancer properties have been demonstrated in studies.

Once the researchers had their kavalactone genes, they inserted them into bacteria and yeasts to start producing the molecules. This proof of concept for their microbial bio-factory model demonstrated that the use of microbes could provide a more efficient and scalable production vehicle for kavalactones. The model could also allow the production of new molecules from the combination of kava genes with other genes so that microbes can produce modified kavalactones. This could allow researchers to optimize the efficacy and safety of molecules for therapeutic purposes.

"There is a very urgent need for therapies to treat mental disorders and safer options for pain relief," says Weng. "Our model eliminates several bottlenecks in the development of plant medicines by increasing access to natural medicinal molecules and allowing the creation of new molecules to nature.

Kava is only one of many plants in the world that contain unique molecules that could have great medicinal value. Weng and Pluskal hope that their model - combining the use of drug discovery from plants used in traditional medicine, genomics, synthetic biology and mass microbial production - will be used to better exploit the great diversity of plant chemistry around the world to help patients in need.