Converting Sugars into Cannabinoids—The State-of-the-Art of Heterologous Production in Microorganisms

The legal cannabis market worldwide is facing new challenges regarding innovation in the production of cannabinoid-based drugs. The usual cannabinoid production involves growing Cannabis sativa L. outdoor or in dedicated indoor growing facilities, followed by isolation and purification steps. This process is limited by the growth cycles of the plant, where the cannabinoid content can deeply vary from each harvest. A game change approach that does not involve growing a single plant has gained the attention of the industry: cannabinoids fermentation. From recombinant yeasts and bacteria, researchers are able to reproduce the biosynthetic pathway to generate cannabinoids, such as (-)-Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and (-)-Δ9-tetrahydrocannabivarin (Δ9-THCV). This approach avoids pesticides, and natural resources such as water, land, and energy are reduced. Compared to growing cannabis, fermentation is a much faster process, although its limitation regarding the phytochemical broad range of molecules naturally present in cannabis. So far, there is not a consolidated process for this brand-new approach, being an emerging and promising concept for countries in which cultivation of Cannabis sativa L. is illegal. This survey discusses the techniques and microorganisms already established to accomplish the task and those yet in seeing for the future, exploring upsides and limitations about metabolic pathways, toxicity, and downstream recovery of cannabinoids throughout heterologous production. Therapeutic potential applications of cannabinoids and in silico methodology toward optimization of metabolic pathways are also explored. Moreover, conceptual downstream analysis is proposed to illustrate the recovery and purification of cannabinoids through the fermentation process, and a patent landscape is presented to provide the state-of-the-art of the transfer of knowledge from the scientific sphere to the industrial application