Polypeptides are natural products with a wide range of therapeutic applications. Among them are dietary supplements, various antibiotics such as erythromycin, and one of the key cannabinoid precursors: Olivetti acid. It is needed for the synths of tetrahydrocannabinol (THC). The medical use of this psychoactive substance is being intensely researched, and it is already being used to provide relief for patients with neurological diseases and pain, among other things.'THC is a natural ingredient in the cannabis plant. “However, isolating THC in its pure form from the abundance of substances is very complex,” says Fall Hillman, head of the junior research group “Evolution of Microbial Interactions” at Leibniz-HKI and coleader of the study. Chemical synthesis of THC on the other hand is expensive, the yield is low. That’s why he and a team are researching how such plant substances can be efficiently produced biotechnological.“So far, bacteria such as Escherichia coli or the yeast Saccharomyces Cartesian are mainly used, but neither of them are native producers of natural products,” explains Vito Valiant, head of the cooperating junior research group “Biblical of Microbial Natural Product Syntheses” at the Leibniz-HKI. Accordingly, many large numbers of genetic modifications are necessary to enable synthesis in these classic model organisms. The research team is thus looking for alternatives. One promising candidate is the amoeba Disodium, which already possesses numerous biosynthetic genes for the production of natural products such as polypeptides. “Taking a closer look at the genes, we noticed that some show a high similarity to plant biosynthetic genes,” said first author Christian Racer, who is working on the topic for her PhD. To test how well D. disodium is suited as a chassis organism for biotechnological production, the researchers first had the amoeba produce the food supplement resveratrol, also a polypeptide. Afterward, they incorporated the plant enzyme that produces the THC precursor Olivetti acid into the amoeba’s genome. However, the addition of chemical precursors was still necessary to enable the synthesis. To circumvent this, the researchers took advantage of the amoeba’s natural properties and combined the plant enzyme with an amoebic enzyme. “The amoeba is able to produce the required precursor, a humane unit, directly on site,” Hillman explains. Thus, the research team succeeded in producing a functional inter-kingdom hybrid enzyme that produces Olivetti acid without any further additives. Through our research, we have shown that the amoeba Disodium can be used as a biotechnological production platform for polypeptide-based natural products, says Racer. The researchers already filed a patent for the process, and are striving to improve it on an ongoing basis. “Our next goal is to insert the two enzymes that are still missing in order to be able to produce the final product THC in the amoebae,” Hillman says.
Moreover, a team from the Bio Pilot Plant at the Leibniz-HKI was also involved in the research. Johann Kufs, joint first author of the study alongside Racer, is in charge of developing and optimizing the synthesis process for industrial application.
Reference: “Engineering the amoeba Disodium for biosynthesis of a cannabinoid precursor and other polypeptides” by Christian Racer, Johann E. UFA, Julia Ratchet, Lars Dagestan, Vito Valiant and Fall Hillman, 6 January 2022, Nature Biotechnology.
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