Taek Soon Lee1, Darmawi Juminaga2, Sung Kuk Lee1, and Jay D. Keasling1. (1) Physical Bioscience Division, Lawrence Berkeley National Laboratory, EmeryStationEast, 5885 Hollis St., 4th Floor, Emeryville, CA 94608, (2) QB3 Institute, University of California, Berkeley, EmeryStationEast, 5885 Hollis St., 4th Floor, Emeryville, CA 94608
Alkaloids are nitrogen-containing small molecules found mostly in plants. Currently, most, if not all, alkaloids that are used as drugs are obtained by extraction from the plants that produce them, but the relatively low yield from the native plants made the drugs extremely expensive. Although enhancement of the metabolic pathways responsible for production of the drugs in the native plants has met with some success, production of the drugs in a heterologous host, particularly a microorganism, would not only allow cost-effective production of the drugs but also manipulation of the enzymes responsible for their biosynthesis to achieve more potent analogs. We studied the development of an Escherichia coli strain capable of producing benzylisoquinoline alkaloids. Specifically, we constructed a metabolic pathway to improve the production of tyrosine, the precursor to the BIAs. Using this strain, we studied to construct metabolic pathways for production of (S)-reticuline by reconstituting the genes encoding enzymes for (S)-reticuline biosynthesis. For the production of thebaine, more advanced and pharmaceutically more useful intermediate in morphine biosynthesis, we also investigated the downstream pathway from (S)-reticuline to thebaine.
