Computer-assisted optimization of cannabinoid biosynthesis catalysts and evaluation of their potential to produce unnatural cannabinoids
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Date
2025
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Abstract
Cannabinoids are a compound class that originally arose as secondary metabolites from the plant Cannabis sativa. Molecules such as (-)-trans-.9-tetrahydrocannabinol, cannabidiol, and cannabichromene are highly demanded on the market due to their diverse medical applications. Given the extraction process from plant, the isolation of rare cannabinoids will not be sufficient to meet global demand. Therefore, an alternative production method is required. Additionally, the interest in non-natural cannabinoids, which act on cannabis receptors, continues to rise. Ensuring the sustainable and high-titer production of these novel cannabinoid structures from the initial stages is crucial. A recent approach that has emerged is the heterologous production of cannabinoids in Saccharomyces cerevisiae. In addition to the naturally produced products from cannabinoid biosynthesis, the proteins can be used for the formation of non-natural cannabinoids through the exchange of the precursor molecules.
A bottleneck of the production of cannabinoids is the reaction from hexanoyl-CoA towards olivetolic acid (OA). This reaction results in the formation of olivetol, a byproduct that leads to the wastage of precursors including malonyl-CoA, acetyl-CoA, and glucose. Computer-based methods were applied to identify olivetolic acid cyclase (CsOAC) variants, with the result that these variants enhanced the production of OA while decreasing the production of olivetol in S. cerevisiae.
Due to the exchange of hexanoic acid, fed through the media, with other fatty acids and the use of already integrated enzymes in an S. cerevisiae strain, it is possible to easily form novel OA analogs with only minor changes in the workflow. The following step involves the prenylation of OA using NphB. It has been demonstrated that the high promiscuity of NphB enables the formation of cannabigerol acid derivatives when OA derivatives are applied as substrates. Docking results helped predict structures that are converted to CBGA derivatives.
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Cannabinoids, Saccharomyces cerevisiae, NphB, CsOAC, Protein engineering
Subjects based on RSWK
Cannabinoide, Proteindesign