Using Brewer’s Yeast to Scale the Production of Minor Cannabinoids

Researchers have found that minor cannabinoids have significant therapeutic potential, but because they occur in very small quantities in cannabis, extracting them is both difficult and expensive.

Can brewer's yeast be used as a biofactory for scaling up the production of these beneficial minor cannabinoids? 

The cultivation of cannabis in greenhouses is energy intensive and at the same time highly destructive to the environment. (1) Use of chemical fertilizers that eventually find themselves in water bodies and the use of intensive energy to keep grow lights and fans running have a huge negative impact on the environment. For example, one study showed that the cannabis industry in California accounts for about 3% of the total electricity usage in the state. (2) Such factors have prompted bioresearchers to seek alternative ways to produce phytocannabinoids.

Other than THC and CBD, cannabis sativa has over 100 other cannabinoids that are categorized as either major or minor cannabinoids. Most minor cannabinoids occur in very minute quantities in cannabis sativa. This makes it difficult and very expensive to extract them naturally.

Keasling, a pioneer of synthetic biology has done extensive work in exploiting the potential of yeast as a “green drug factory” as a cheaper and safer alternative to extracting cannabinoids.

Researchers from the University of Berkeley have bioengineered brewer's yeast to produce minor and rare phytocannabinoids that are almost impossible to extract from cannabis. (3) Extracting these minor cannabinoids from cannabis can be a costly affair and this new approach can help to bring the cost down significantly and also scale up production. This study was published in Science Daily in 2022.

Yeast is a fungus that's commonly used as a culture medium in bioresearch. Cannabinoids are not the only biomolecules that can be produced in yeast. Blood clotting factors, insulin, and growth hormone have also been produced in yeast. One of the most epic bioengineering projects has been the production of the antimalarial drug artemisinin in yeast. (4)

The Berkeley researchers inserted several cannabis sativa and yeast (Streptomyces spp) genes in a petri dish using a heterologous approach to produce phytocannabinoid precursors which are olivetolic acid and cannabigerolic acid. Olivetolic acid (OA) is synthesized by condensing hexanoic acid with three molecules of malonic acid. The OA then undergoes alkylation with geranyl pyrophosphate (GPP) to produce the precursor phytocannabinoid molecule cannabigerolic acid (CBGA).

Other specific enzymes were then added to convert CBGA into several minor cannabinoids such as cannabidivarin (CBDV) and terrahydrocannabivarin (THCV). Even though these minor cannabinoids are still under investigation, it appears that they have an effect on CB1 and CB2 receptors as well as TRPV channels and other cell signaling pathways.

According to lead scientist at UC Berkeley Jay Keasling, this is an effective way of producing high-quality but low-cost cannabinoids and it is also safe and environmentally friendly. “The cost is competitive or even better than that for plant-derived phytocannabinoids and manufacturers don't have to worry about contamination,” he said.

A related study by Schmidt and Kayser demonstrated that the production of hexanoic acid in yeast is a rate-limiting step and presents a bottleneck in scaling up the production of major cannabinoids that occur in high concentrations (such as 20% THC) in cannabis. (5) However, the researchers confirmed that yeast acts as a suitable biofactory for the production of minor and rare phytocannabinoids.

As the usefulness of minor cannabinoids in medicine and other industries continues to emerge, bioresearchers need to find better ways to exploit this new avenue of phytocannabinoid production.

References

1. Zheng, Z., Fiddes, K. & Yang, L. A narrative review on environmental impacts of cannabis cultivation. J Cannabis Res 3, 35 (2021).
2. Mills, Evan & Zeramby, Scott. (2020). Energy Use by the Indoor Cannabis Industry: Inconvenient Truths for Producers, Consumers, and Policymakers.
3. University of California – Berkeley. (2019, February 27). Yeast produce low-cost, high-quality cannabinoids. ScienceDaily. Retrieved August 13, 2022 from sciencedaily.com/releases/2019/02/190227131838.htm
4. Ro, D. K., Paradise, E. M., Ouellet, M., Fisher, K. J., Newman, K. L., Ndungu, J. M., Ho, K. A., Eachus, R. A., Ham, T. S., Kirby, J., Chang, M. C., Withers, S. T., Shiba, Y., Sarpong, R., & Keasling, J. D. (2006). Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature, 440(7086), 940–943. https://doi.org/10.1038/nature04640
5. Thomas, F., Schmidt, C. & Kayser, O. Bioengineering studies and pathway modeling of the heterologous biosynthesis of tetrahydrocannabinolic acid in yeast. Appl Microbiol Biotechnol 104, 9551–9563 (2020).