Researchers produce a precursor to tetrahydrocannabinol (THC) in amoebae with hopes to produce high yields of pure medicinal THC using biotechnology.
A group at the Leibniz Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (Jena, Germany) are studying the production of natural products such as a THC precursor called olivetolic acid using genetically engineered amoebae. The team successfully produced a functional inter-kingdom hybrid enzyme that creates olivetolic acid, which may lead to a novel production method for medicinal THC.
THC has been FDA approved for medicinal use in several instances, such as the treatment of nausea in patients having chemotherapy or to increase appetite in patients with wasting syndrome due to AIDS. It is also being studied to treat pain caused by neurological disorders. “However, isolating THC in its pure form from the abundance of substances [in a cannabis plant] is very complex,” explained Falk Hillman, the head of the research group and senior author on the paper. While chemical synthesis is possible, it is expensive and results in a low yield of THC.
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One of the key precursors to THC is olivetolic acid, which belongs to a group of molecules called polyketides. Polyketides are natural products with various therapeutic applications such as dietary supplements and antibiotics. The team is looking at using amoebae – single-celled organisms – to produce polyketides such as olivetolic acid.
Previously, researchers have used bacteria including Escherichia coli, or the yeast Saccharomyces cerevisiae to synthesize polyketides; however, both methods require many genetic modifications to do so. The novel use of amoeba has the advantage that some already have the natural capability to produce polyketides and less genetic modification is needed to produce specific molecules such as THC.
The group decided that the most promising candidate was Dictyostelium discoideum – an amoeba that can already produce natural products such as olivetolic acid. The study started by taking a close look at the genes of the amoeba. “We noticed that some show a high similarity to plant biosynthetic genes,” explained the first author Christin Reimer. Biosynthetic genes enable the plant to make polyketides.
The group went on to test the capability of the amoeba to produce polyketides by engineering them to make another polyketide called resveratrol, which is a food supplement. Next, they managed to add the plant enzyme that produces olivetolic acid into the genome of the Dictyostelium discoideum. While this worked, external chemical precursors were needed to synthesize olivetolic acid.
Researchers then combined the plant enzyme and an amoebic enzyme in a way that meant the amoeba was able to produce the desired olivetolic acid without the addition of external chemical factors. They created a functional inter-kingdom hybrid enzyme that may lead to the biosynthesis of the active cannabinoid product THC.
The next step for the team is to develop the technology further by inserting the final two enzymes required to produce THC. These results indicate that safe production of THC with higher yields may be possible using amoebae and would be life-changing for those with diseases such as AIDS, cancer and multiple sclerosis.
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