Ancient Cannabis Enzymes Resurrected to Fuel New Medical Innovations

Researchers at Wageningen University & Research (WUR) in the Netherlands have made significant strides in understanding the evolution of cannabis and its bioactive compounds, such as tetrahydrocannabinol (THC) and cannabidiol (CBD). Their recent study uncovers how cannabis developed the ability to synthesize these cannabinoids, paving the way for potential advancements in medical applications.

The research team, led by Robin van Velzen and his colleague Cloé Villard, employed ancestral sequence reconstruction techniques to resurrect ancient enzymes responsible for cannabinoid production. This approach allowed them to explore the functional capabilities of these enzymes, which are believed to have existed millions of years ago. The findings reveal that these ancestral enzymes were not only versatile but also capable of producing multiple cannabinoids from a single precursor, in stark contrast to the highly specialized enzymes found in modern cannabis plants.

Insights into Cannabinoid Production

The study highlights that present-day cannabis varieties exhibit varying proportions of cannabinoids, largely dictated by the activity of their corresponding synthase enzymes. The researchers discovered that ancient enzymes, unlike their modern counterparts, functioned as generalists, creating THC, CBD, and cannabichromene (CBC). This flexibility makes them attractive candidates for biotechnological and pharmaceutical innovations.

Of particular interest is the cannabinoid CBC, which, despite its therapeutic potential, remains underexplored compared to THC and CBD. Modern cannabis typically contains less than 1% CBC, complicating efforts to study and produce it at scale. Van Velzen noted, “At present, there is no cannabis plant with a naturally high CBC content. Introducing this enzyme into a cannabis plant could therefore lead to innovative medicinal varieties.”

Preliminary studies indicate that CBC may possess anti-inflammatory, anticonvulsant, and antibacterial properties. However, more research is necessary to fully understand its potential benefits.

Implications for Biotechnology and Drug Development

The research team also found that the resurrected ancestral enzymes could be produced more efficiently in microorganisms, such as yeast. This discovery could facilitate the synthesis of rare cannabinoids without relying on traditional plant cultivation methods. The implications for research and drug development are substantial, potentially enabling the production of cannabinoids at a lower cost and in greater quantities.

The researchers further explored the evolutionary trajectory of cannabinoid oxidocyclases by designing hybrid enzymes through rational engineering. These hybrids displayed unique activities that were easier to produce than modern enzymes, providing valuable insights into the functional evolution of these compounds.

Overall, the study contributes significantly to the understanding of the origin, evolution, and molecular mechanisms of cannabinoid oxidocyclases. The findings were published in the Plant Biotechnology Journal and open new avenues for breeding, biotechnological applications, and medicinal research.

The work at WUR not only sheds light on the evolutionary history of cannabis but also highlights the potential for harnessing its compounds to develop innovative medical treatments, marking a crucial step forward in cannabinoid research.