Scientists unlock mass-produced herbal medicine with precision fermentation

Bioengineers in Japan have successfully manipulated yeast cells to produce a molecule used in herbal medicine, meaning it can be made at scale in a fermenter. The compound, artepillin C, is linked to antimicrobial, anti-inflammatory and antioxidant properties but is available from natural sources in smaller amounts of inconsistent quality. It is commercially available as a bee culture product and can be produced by some plants.

It is challenging to produce herbal medicine on an industrial scale. For example, a Japanese plant source for artepillin C, Artemisia capillaris or capillary wormwood, makes the compound in small and inconsistent amounts and a mixture with other compounds. 

“To obtain a high-yield and low-cost supply, it is desirable to produce it in bioengineered microorganisms which can be grown in fermenters,” says Tomohisa Hasunuma, a bioengineer at Kobe University, Japan, and the study’s co-author. 

The bioengineered yeast can produce ten times as much artepillin C as before. The researchers note that their achievement leads to the microbial production of other plant-derived compounds. 

Microbial production

In the study, published in ACS Synthetic Biology, the team from Kobe University details the production process it developed for artepillin C. The bioengineers used a previously identified enzyme the plant uses to manufacture a specific product. 

“The plant enzyme key to artepillin C production was only recently discovered by Yazaki Kazufumi at Kyoto University. He asked us whether we can use it to produce the compound in microorganisms due to our experience with microbial production,” explains Hasunuma. 

The team introduced the gene coding for this enzyme into Komagataella phaffii, a yeast that can produce chemical components. This yeast can be grown at higher cell densities and does not produce alcohol, which limits cell growth. 

“Another interesting aspect is that artepillin C is not excreted into the growth medium readily and tends to accumulate inside the cell,” adds Hasunuma. 

“It was, therefore, necessary to grow the yeast cells in our fermenters to high densities, which we achieved by removing some of the mutations introduced for technical reasons but that stand in the way of the organism’s dense growth.”

Artemisia capillaris, native to Japan, makes the compound in small and inconsistent amounts and a mixture with other compounds.Exploring future applications

The researchers suggest that modifying the responsible enzyme or increasing the pool of precursor chemicals may increase process efficiency. Moreover, they note that finding a way to transport artepillin C out of the cell could also improve the production. 

“If we can modify a transporter — a molecular structure that transports chemicals in and out of cells — in a way that it exports the product into the medium while keeping the precursors in the cell, we could achieve even higher yields,” Hasunuma says. 

In addition, the bioengineer suggests there is a “very real possibility” that the knowledge gained from producing artepillin C can be applied to the microbial production of other plant-derived compounds since there are “thousands of compounds” with a similar chemical structure. 

The research was conducted with researchers from Kyoto University and the RIKEN Center for Sustainable Resource Science in Japan. 

The nutrition industry continues to explore precision fermentation in various applications. For example, Gnosis by Lesaffre developed a fermented salidroside bioactive to bypass the need to harvest endangered Rhodiola species. Meanwhile, researchers in Germany designed a bioreactor system that converts hydrogen, oxygen and CO2 into yeast rich in protein and vitamin B9.