write in Natural biotechnology, the team identifies bioactives as polyketides, structurally and functionally diverse natural products derived primarily from bacteria, fungi, and plants.
Their wide range of bioactivities have led to several applications in the food and pharmaceutical industry. Polyketides, which include polyphenols of plant origin such as resveratrol or taxifolin, are used as dietary supplements.
“A promising candidate is the amoeba Dictyostelium discoideum, which already has many biosynthetic genes for the production of natural products such as polyketides”,says first author Christin Reimer.
“As we look more closely at the genes, we have noticed that some show great similarity to plant biosynthetic genes.”
Precursor to THC
Researchers from the Leibniz Institute for Natural Products Research and Infection Biology also detail the amoeba’s ability to produce a tetrahydrocannabinol (THC) precursor, olivetolic acid.
The medical use of this psychoactive substance includes, among other things, the relief of patients suffering from neurological diseases and pain.
To test how D.discoideum was suitable as an organism for biotech production, the researchers first asked the amoeba to produce the dietary supplement resveratrol, also a polyketide.
Next, they incorporated the plant enzyme that produces the precursor tetrahydrocannabinol (THC) olivetolic acid into the amoeba’s genome.
However, the addition of chemical precursors was still necessary to allow synthesis. To avoid this, the researchers took advantage of the natural properties of the amoeba and combined the plant enzyme with an amoebic enzyme.
“The amoeba is able to produce the required precursor, a unit of hexane, directly on site”, says Falk Hillmann, Head of the Junior Research Group “Evolution of microbial interactions” at Leibniz-HKI and co-responsible for the study.
Thus, the research team succeeded in producing a functional cross-kingdom hybrid enzyme that produces olivetolic acid without any other additives.
“Through our research, we have shown that the Dictyostelium amoeba can be used as a platform for the biotechnological production of polyketide-based natural products”,adds Reimer.
“Our next goal is to insert the two enzymes that are still missing so that we can produce the final THC product in the amoebas,”said Hillmann.
E. coli and S. cerevisiae
Currently, bacteria such as Escherichia colior yeast Saccharomyces cerevisiaeare used to synthesize THC but none of them are native producers of natural products. In addition, a large number of genetic modifications are required to enable synthesis.
In a recent study, a team has reconstructed the entire cannabinoid biosynthetic pathway by S.cerevisiae,where the final cannabinoid formation was achieved by introducing the metabolic pathways to supply the precursors hexanoyl-CoA and geranyl pyrophosphate.
Source: Nat Biotechnol
Published online: doi.org/10.1038/s41587-021-01143-8
“Design of the amoeba Dictyostelium discoideum for the biosynthesis of a cannabinoid precursor and other polyketides.”
Authors: Reimer, C., Kufs, JE, Rautschek, J. et al.