Microbial Factories for the Production of Benzylisoquinoline Alkaloids

Both Escherichia coli and Saccharomyces cerevisiae have been engineered to convert a simple carbon source such as glucose to complex BIAs. The variety of BIA scaffolds synthesized in microbial hosts continues to increase, now encompassing benyliosquinolines, aporphines, protoberberines, protopines, benzophenanthridines, pro-morphinans, and morphinans. Key challenges for future work have been identified, including pathway bottlenecks and the generation of side-products from promiscuous enzymes. Benzylisoquinoline alkaloids (BIAs) are a family of ∼2500 alkaloids with both potential and realized pharmaceutical value, including most notably the opiates such as codeine and morphine. Only a few BIAs accumulate readily in plants, which limits the pharmaceutical potential of the family. Shifting BIA production to microbial sources could provide a scalable and flexible source of these compounds in the future. This review details the current status of microbial BIA synthesis and derivatization, including rapid developments in the past 6 months culminating in the synthesis of opioids from glucose in a microbial host. Benzylisoquinoline alkaloids (BIAs) are a family of ∼2500 alkaloids with both potential and realized pharmaceutical value, including most notably the opiates such as codeine and morphine. Only a few BIAs accumulate readily in plants, which limits the pharmaceutical potential of the family. Shifting BIA production to microbial sources could provide a scalable and flexible source of these compounds in the future. This review details the current status of microbial BIA synthesis and derivatization, including rapid developments in the past 6 months culminating in the synthesis of opioids from glucose in a microbial host.