Genetic engineering of the biosynthesis of the anticancer monoterpenoid indole alkaloid vinblastine precursors in microorganism

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University of New Brunswick


Monoterpenoid indole alkaloids (MIAs) are among the most complex specialized metabolites with a broad range of pharmacological activities. These natural products have been used as anticancer (vinblastine and vincristine) and antiarrhythmic (ajmaline) agents since the 1970s. Despite the low yield, the plant Catharanthus roseus (Madagascar periwinkle) remains the sole commercial source for MIA vinblastine and vincristine production because of the complex structure and stereochemistry makes the total synthesis difficult and costly. The complete elucidation of the 28-genes vinblastine biosynthetic pathway in 2018 allows the assembly of this remarkable pathway in microorganisms for the industrial production of vinblastine, which also unlocks the door to producing a broad range of medicinal MIAs using the core pathway. In this thesis, the biosynthesis of early vinblastine intermediate geissoschizine from tryptamine and secologanin precursors was engineered in E. coli by inhibiting the leaky expression of genes during the biomass accumulating stage. The expression issue of the O-acetylstemmadenine oxidase in yeast was solved by replacing its signal peptide with that of the yeast carboxypeptidase Y, which allowed the biosynthesis of two late vinblastine intermediate catharanthine and tabersonine in yeast from geissoschizine intermediate. This research is the first example of microbial production of these MIAs, which lays the foundation for the complete biosynthesis of vinblastine in microbes.