UCLA

In addition to satisfying nutritional needs, humans have been consuming plants for medicinal and recreational purposes for millennia. The medicinal and recreational properties of plants are attributed to compounds that are not a product of the plant’s core metabolism, but are rather secondary metabolites, also known as natural products. Monoterpene indole alkaloids (MIAs) are an expansive class of bioactive plant natural products, many of which have been named on the World Health Organization’s List of Essential Medicines. Among MIAs’ divergent structural complexity are psychoactive MIAs such as ibogaine and mitragynine which also hold therapeutic potential. However, low production from native plant hosts necessitates a more reliable source of these compounds to meet global demands in medicine and research. The recent explosion of synthetic biology toolsets and genomics data has enabled reconstitution of plant biosynthetic pathways to build complex MIA structures in alternative hosts. In this dissertation, we report on the development of a yeast-based platform for high-titer production of the universal MIA precursor, strictosidine. Our fed-batch platform produces ∼50 mg/L strictosidine, starting from the commodity chemicals geraniol and tryptamine, and is the highest titer reported to date. Next, we describe approaches to further optimize this platform and leverage it to produce strictosidine analogs. Bioprospecting homologs of pathway genes reveal the variants from Catharanthus roseus have the highest activity in yeast. Finally, we utilized our strictosidine platform to access bioactive MIAs such as heteroyohimbine and corynantheidine-type MIAs. We also demonstrate our ability to access novel analogs of these compounds with our platform, which potentially have improved or divergent bioactivity from their native forms.