Improving the binding specificity and affinity of prenyltransferase enzymes using computational protein design********

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Cannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD) are becoming increasingly important pharmaceuticals for the treatment of a variety of human diseases such as chronic pain, epilepsy, and Parkinson's disease. Currently, these compounds are extracted from the plant Cannabis sativa, which produces hundreds of active biological compounds in addition to THC and CBD. The presence of these additional compounds makes it difficult to standardize C. sativa extracts to be used as medicine. To address this issue, Hyasynth Bio is developing an alternative production method for high purity cannabinoids that is based on yeast fermentation. This method relies on a heterologous biosynthetic pathway including non-plant prenyltransferases, which catalyze the transfer of a C5 (dimethylallyl), C10 (geranyl) or C15 (farnesyl) prenyl group derived from the corresponding isoprenyl diphosphate metabolites onto a variety of aromatic acceptors. However, these prenyltransferases display broad substrate and regio-specificity, making them able to react with many undesired aromatic yeast metabolites or prenylate desired ones at incorrect positions, which lowers the overall efficiency of the pathway. To enhance the efficiency of the fermentation process and thereby the value of these enzymes to the pharmaceutical and recreational cannabis markets, we will use computational protein design to engineer prenyltransferase variants displaying narrow specificity and enhanced binding affinity to their target substrates. These engineered prenyltransferases will directly integrate into Hyasynth Bio's metabolic engineering and fermentation process pipelines, thereby providing the company with a competitive edge in the cannabis industry and directly contributing to the development of the Canadian bio-economy.**