Benzylisoquinoline alkaloids (BIAs) are medically useful natural products. For many BIAs, including morphine, no commercially viable syntheses exist and supply is limited to extraction from plants, particularly opium poppy. A BIA production platform that is less resource intensive and less affected by environmental and political climates is desirable.Previously, researchers engineered Saccharomyces cerevisiae and Escherichia coli to convert dopamine or norlaudanosoline to reticuline, an important branch point intermediate in BIA biosynthesis. A major challenge in heterologous BIA biosynthesis is obtaining sufficient activity in the microbial host from the numerous plant cytochrome P450s. For example, salutaridine synthase is a morphinan P450 enzyme that catalyzes C-C phenol coupling to convert reticuline to salutaridine. The human P450 CYP2D6 can perform this reaction non-regiospecifically. However, using the human enzyme in the reconstructed pathway limits flux through the morphinan branch, likely because CYP2D6 does not optimally interact with plant-derived enzymes, limiting productivity.We will present ongoing efforts to advance a microbial platform to synthesize high-value morphinan and berberine BIAs. Specifically, efforts towards (1) optimizing enzyme expression levels, (2) spatially engineering pathway enzymes, and (3) developing generalizable strategies for functional expression of plant P450s in a yeast chassis will be described.

Biosynthesis of morphinan and berberine benzylisoquinoline alkaloids in <i>Saccharomyces cerevisiae</i>

243rd National Meeting (2012)

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Biosynthesis of morphinan and berberine benzylisoquinoline alkaloids in Saccharomyces cerevisiae